Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (Head and neck cancer: ImmunoChemo and Radiotherapy with Erbitux) -- a multicente
In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before.
Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation car...Enrique Moreno Gonzalez
Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting.
Post-diagnosis hemoglobin change associates with overall survival of multiple...Enrique Moreno Gonzalez
Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Incidence of pneumonia and risk factors among patients with head and neck can...Enrique Moreno Gonzalez
This study investigated the incidence and patient- and treatment-related risk factors related to pneumonia acquired during radiotherapy (PNRT) in head and neck cancer (HNC) patients.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
The aim of this study was to evaluate the expression of the cell adhesion-related glycoproteins MUC-1, β-catenin and E-cadherin in multicentric/multifocal breast cancer in comparison to unifocal disease in order to identify potential differences in the biology of these tumor types.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation car...Enrique Moreno Gonzalez
Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting.
Post-diagnosis hemoglobin change associates with overall survival of multiple...Enrique Moreno Gonzalez
Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Incidence of pneumonia and risk factors among patients with head and neck can...Enrique Moreno Gonzalez
This study investigated the incidence and patient- and treatment-related risk factors related to pneumonia acquired during radiotherapy (PNRT) in head and neck cancer (HNC) patients.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
The aim of this study was to evaluate the expression of the cell adhesion-related glycoproteins MUC-1, β-catenin and E-cadherin in multicentric/multifocal breast cancer in comparison to unifocal disease in order to identify potential differences in the biology of these tumor types.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Purpose: An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRAS oncogene. We studied this biomarker’s correlation to anti-EGFR monoclonal antibody (mAb) therapy
response in patients with metastatic colorectal cancer.
Experimental Design: LCS6-variant and KRAS/BRAF mutational status was determined in 512 patients
with metastatic colorectal cancer treated with salvage anti-EGFR mAb therapy, and findings correlated with
outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-
variant allele to therapy exposure.
Results: In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6-
variant (TG/GG), which was found twice as frequently in the BRAF-mutated versus the wild-type (WT) group
(P = 0.03). LCS6-variant patients had significantly longer progression- free survival (PFS) with anti-EGFR
mAb monotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; P = 0.019) and in the double WT
(KRAS and BRAF) patient population (18 vs. 10.4 weeks; P = 0.039). Combination therapy (mAbs plus
chemotherapy) led to improved PFS and overall survival (OS) for nonvariant patients, and brought their
outcome to levels comparable with LCS6-variant patients receiving anti-EGFR mAb monotherapy. Combination
therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a
unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy.
Conclusions: LCS6-variant patients with metastatic colorectal cancer have an excellent response to anti-EGFR
mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm
the importance of thismutation as a biomarker of anti-EGFR mAb response in patients with metastatic colorectal cancer, and warrant further prospective confirmation.
Chemotherapy of head & neck cancer /certified fixed orthodontic courses by In...Indian dental academy
Indian Dental Academy is the Leader ina
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
Indian dental academy provides dental crown & Bridge,rotary endodontics,fixed orthodontics,
Dental implants courses.for details pls visit www.indiandentalacademy.com ,or call
0091-9248678078 continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
Interrogating differences in expression of targeted gene sets to predict brea...Enrique Moreno Gonzalez
Genomics provides opportunities to develop precise tests for diagnostics, therapy selection and monitoring. From analyses of our studies and those of published results, 32 candidate genes were identified, whose expression appears related to clinical outcome of breast cancer. Expression of these genes was validated by qPCR and correlated with clinical follow-up to identify a gene subset for development of a prognostic test.
hMSH2 Gly322Asp (rs4987188) Single nucleotide polymorphism and the risk of br...Agriculture Journal IJOEAR
Aim: Breast cancer is the most common cancer in women both in the developed and less developed world. The reported study was designed to explore associations between hMSH2 - Gly322Asp (1032G>A, rs4987188) single nucleotide polymorphism (SNP) and the risk of breast carcinoma in the Polish women.
Material and methods: Blood samples were obtained from women with breast cancer (n=225), treated at the Department of Oncological Surgery and Breast Diseases, Polish Mother’s Memorial Hospital – Research Institute between the years 2005 and 2012. A control group included 220 cancer-free women. Genomic DNA was isolated and the SNP Gly322Asp of hMSH2 was determined by High-Resolution Melter method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele.
Results: This study revealed that single nucleotide polymorphism Gly322Asp of hMSH2 is associated with both breast cancer risk and grading. Moreover, it can be linked with breast carcinoma tumor size and lymph node status. The Asp allele in patients may be a risk factor for breast carcinoma (OR 5.12; 95% CI 3.77 –6.97, p<.0001).
Conclusions: Gly322Asp single nucleotide polymorphism of hMSH2 may be a risk factor of breast cancer in the Polish women.
Usefulness of Serum Carcinoembryonic Antigen (CEA) in evaluating response to ...Enrique Moreno Gonzalez
High serum carcinoembryonic antigen (CEA) levels are an independent prognostic factor for recurrence and survival in patients with non-small cell lung cancer (NSCLC). Its role as a predictive marker of treatment response has not been widely characterized.
Abnormal expression of Pygopus 2 correlates with a malignant phenotype in hum...Enrique Moreno Gonzalez
Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported.
Impaired mitochondrial beta-oxidation in patients with chronic hepatitis C: r...Enrique Moreno Gonzalez
Hepatic steatosis is often seen in patients with chronic hepatitis C (CH-C). It is still unclear whether these patients have an impaired mitochondrial β-oxidation. In this study we assessed mitochondrial β-oxidation in CH-C patients by investigating ketogenesis during fasting.
Functional p53 is required for rapid restoration of daunorubicin-induced lesi...Enrique Moreno Gonzalez
The tumour suppressor and transcription factor p53 is a major determinant of the therapeutic response to anthracyclines. In healthy tissue, p53 is also considered pivotal for side effects of anthracycline treatment such as lesions in haematopoietic tissues like the spleen. We used a Trp53null mouse to explore the significance of p53 in anthracycline (daunorubicin) induced lesions in the spleen.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Purpose: An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRAS oncogene. We studied this biomarker’s correlation to anti-EGFR monoclonal antibody (mAb) therapy
response in patients with metastatic colorectal cancer.
Experimental Design: LCS6-variant and KRAS/BRAF mutational status was determined in 512 patients
with metastatic colorectal cancer treated with salvage anti-EGFR mAb therapy, and findings correlated with
outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-
variant allele to therapy exposure.
Results: In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6-
variant (TG/GG), which was found twice as frequently in the BRAF-mutated versus the wild-type (WT) group
(P = 0.03). LCS6-variant patients had significantly longer progression- free survival (PFS) with anti-EGFR
mAb monotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; P = 0.019) and in the double WT
(KRAS and BRAF) patient population (18 vs. 10.4 weeks; P = 0.039). Combination therapy (mAbs plus
chemotherapy) led to improved PFS and overall survival (OS) for nonvariant patients, and brought their
outcome to levels comparable with LCS6-variant patients receiving anti-EGFR mAb monotherapy. Combination
therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a
unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy.
Conclusions: LCS6-variant patients with metastatic colorectal cancer have an excellent response to anti-EGFR
mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm
the importance of thismutation as a biomarker of anti-EGFR mAb response in patients with metastatic colorectal cancer, and warrant further prospective confirmation.
Chemotherapy of head & neck cancer /certified fixed orthodontic courses by In...Indian dental academy
Indian Dental Academy is the Leader ina
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
Indian dental academy provides dental crown & Bridge,rotary endodontics,fixed orthodontics,
Dental implants courses.for details pls visit www.indiandentalacademy.com ,or call
0091-9248678078 continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
Interrogating differences in expression of targeted gene sets to predict brea...Enrique Moreno Gonzalez
Genomics provides opportunities to develop precise tests for diagnostics, therapy selection and monitoring. From analyses of our studies and those of published results, 32 candidate genes were identified, whose expression appears related to clinical outcome of breast cancer. Expression of these genes was validated by qPCR and correlated with clinical follow-up to identify a gene subset for development of a prognostic test.
hMSH2 Gly322Asp (rs4987188) Single nucleotide polymorphism and the risk of br...Agriculture Journal IJOEAR
Aim: Breast cancer is the most common cancer in women both in the developed and less developed world. The reported study was designed to explore associations between hMSH2 - Gly322Asp (1032G>A, rs4987188) single nucleotide polymorphism (SNP) and the risk of breast carcinoma in the Polish women.
Material and methods: Blood samples were obtained from women with breast cancer (n=225), treated at the Department of Oncological Surgery and Breast Diseases, Polish Mother’s Memorial Hospital – Research Institute between the years 2005 and 2012. A control group included 220 cancer-free women. Genomic DNA was isolated and the SNP Gly322Asp of hMSH2 was determined by High-Resolution Melter method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele.
Results: This study revealed that single nucleotide polymorphism Gly322Asp of hMSH2 is associated with both breast cancer risk and grading. Moreover, it can be linked with breast carcinoma tumor size and lymph node status. The Asp allele in patients may be a risk factor for breast carcinoma (OR 5.12; 95% CI 3.77 –6.97, p<.0001).
Conclusions: Gly322Asp single nucleotide polymorphism of hMSH2 may be a risk factor of breast cancer in the Polish women.
Usefulness of Serum Carcinoembryonic Antigen (CEA) in evaluating response to ...Enrique Moreno Gonzalez
High serum carcinoembryonic antigen (CEA) levels are an independent prognostic factor for recurrence and survival in patients with non-small cell lung cancer (NSCLC). Its role as a predictive marker of treatment response has not been widely characterized.
Abnormal expression of Pygopus 2 correlates with a malignant phenotype in hum...Enrique Moreno Gonzalez
Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported.
Impaired mitochondrial beta-oxidation in patients with chronic hepatitis C: r...Enrique Moreno Gonzalez
Hepatic steatosis is often seen in patients with chronic hepatitis C (CH-C). It is still unclear whether these patients have an impaired mitochondrial β-oxidation. In this study we assessed mitochondrial β-oxidation in CH-C patients by investigating ketogenesis during fasting.
Functional p53 is required for rapid restoration of daunorubicin-induced lesi...Enrique Moreno Gonzalez
The tumour suppressor and transcription factor p53 is a major determinant of the therapeutic response to anthracyclines. In healthy tissue, p53 is also considered pivotal for side effects of anthracycline treatment such as lesions in haematopoietic tissues like the spleen. We used a Trp53null mouse to explore the significance of p53 in anthracycline (daunorubicin) induced lesions in the spleen.
Cholestasis induces reversible accumulation of periplakin in mouse liverEnrique Moreno Gonzalez
Periplakin (PPL) is a rod-shaped cytolinker protein thought to connect cellular adhesion junctional complexes to cytoskeletal filaments. PPL serves as a structural component of the cornified envelope in the skin and interacts with various types of proteins in cultured cells; its level decreases dramatically during tumorigenic progression in human epithelial tissues. Despite these intriguing observations, the physiological roles of PPL, especially in noncutaneous tissues, are still largely unknown. Because we observed a marked fluctuation of PPL expression in mouse liver in association with the bile acid receptor farnesoid X receptor (FXR) and cholestasis, we sought to characterize the role of PPL in the liver and determine its contributions to the etiology and pathogenesis of cholestasis.
CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1a...Enrique Moreno Gonzalez
Glioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion.
CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1a...
Similar to Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (Head and neck cancer: ImmunoChemo and Radiotherapy with Erbitux) -- a multicente
Co-Chairs, Nasser Altorki, MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “How to Integrate Perioperative Immunotherapy Into Multimodal Treatment Plans to Improve Outcomes in Resectable NSCLC.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3xb6WS1. CME/MOC credit will be available until June 14, 2023.
Chair & Moderator, Prof. Solange Peters, MD, PhD, Mark M. Awad, MD, PhD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to Cancer Immunotherapy for this CME/MOC/CC activity titled “Parsing the Practicalities of Pathologic Response Assessment After Neoadjuvant Immunotherapy to Facilitate Progress in Early-Stage Cancers.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CC information, and to apply for credit, please visit us at https://bit.ly/3uRHyjk. CME/MOC/CC credit will be available until May 9, 2023.
Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally ad...Enrique Moreno Gonzalez
Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer.
Intensity-modulated radiotherapy with simultaneous modulated accelerated boos...Enrique Moreno Gonzalez
To present our experience of intensity-modulated radiotherapy (IMRT) with simultaneous modulated accelerated radiotherapy (SMART) boost technique in patients with nasopharyngeal carcinoma (NPC).
Similar to Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (Head and neck cancer: ImmunoChemo and Radiotherapy with Erbitux) -- a multicente (20)
Gene expression analysis of a Helicobacter pyloriinfected and high-salt diet-...Enrique Moreno Gonzalez
Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model.
The life in sight application study (LISA): design of a randomized controlled...Enrique Moreno Gonzalez
It is widely recognized that spiritual care plays an important role in physical and psychosocial well-being of cancer patients, but there is little evidence based research on the effects of spiritual care. We will conduct a randomized controlled trial on spiritual care using a brief structured interview scheme supported by an e-application. The aim is to examine whether an assisted reflection on life events and ultimate life goals can improve quality of life of cancer patients.
Assessment of preoperative exercise capacity in hepatocellular carcinoma pati...Enrique Moreno Gonzalez
Cardiopulmonary exercise testing measures oxygen uptake at increasing levels of work and predicts cardiopulmonary performance under conditions of stress, such as after abdominal surgery. Dynamic assessment of preoperative exercise capacity may be a useful predictor of postoperative prognosis. This study examined the relationship between preoperative exercise capacity and event-free survival in hepatocellular carcinoma (HCC) patients with chronic liver injury who underwent hepatectomy.
Intraepithelial lymphocyte distribution differs between the bulb and the seco...Enrique Moreno Gonzalez
Evaluation of intraepithelial duodenal lymphocytosis (IDL) is important in celiac disease (CD). There is no established cut-off value for increased number of IELs in the bulb. We therefore investigated the relation between IEL counts in the bulb and duodenal specimens in non-celiac subjects.
Sticky siRNAs targeting survivin and cyclin B1 exert an antitumoral effect on...Enrique Moreno Gonzalez
Melanoma represents one of the most aggressive and therapeutically challenging malignancies as it often gives rise to metastases and develops resistance to classical chemotherapeutic agents. Although diverse therapies have been generated, no major improvement of the patient prognosis has been noticed. One promising alternative to the conventional therapeutic approaches currently available is the inactivation of proteins essential for survival and/or progression of melanomas by means of RNA interference. Survivin and cyclin B1, both involved in cell survival and proliferation and frequently deregulated in human cancers, are good candidate target genes for siRNA mediated therapeutics.
Association between variations in the fat mass and obesity-associated gene an...Enrique Moreno Gonzalez
It is clear that genetic variations in the fat mass and obesity-associated (FTO) gene affect body mass index and the risk of obesity. Given the mounting evidence showing a positive association between obesity and pancreatic cancer, this study aimed to investigate the relation between variants in the FTO gene, obesity and pancreatic cancer risk.
The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-i...Enrique Moreno Gonzalez
Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT1R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT2R) is lost. Further, our previous data indicate that patients with high CysLT1R and low CysLT2R expression have a poor prognosis. In this study, we examined whether the balance between CysLT1R and CysLT2R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA).
Clinical features and outcome of cryptogenic hepatocellular carcinoma compare...Enrique Moreno Gonzalez
Cryptogenic hepatocellular carcinoma (HCC) is thought to arise due to non-alcoholic fatty liver disease (NAFLD). This study investigated the prevalence, clinical features, and outcomes of cryptogenic HCC and compared them with those of HCC related to hepatitis B virus infection (HBV-HCC), hepatitis C virus infection (HCV-HCC), and alcohol (ALCHCC) in Korea.
Fatty liver index correlates with non-alcoholic fatty liver disease, but not ...Enrique Moreno Gonzalez
Fatty liver index (FLI) was recently established to predict non-alcoholic fatty liver disease (NAFLD) in general population, which is known to be associated with coronary artery atherosclerotic disease (CAD).
This study aims to investigate whether FLI correlates with NAFLD and with newly diagnosed CAD in a special Chinese population who underwent coronary angiography.
Antibiotic exposure and the development of coeliac disease: a nationwide case...Enrique Moreno Gonzalez
The intestinal microbiota has been proposed to play a pathogenic role in coeliac disease (CD). Although antibiotics are common environmental factors with a profound impact on intestinal microbiota, data on antibiotic use as a risk factor for subsequent CD development are scarce.
Implication from thyroid function decreasing during chemotherapy in breast ca...Enrique Moreno Gonzalez
Thyroid hormones have been shown to regulate breast cancer cells growth, the absence or reduction of thyroid hormones in cells could provoke a proliferation arrest in G0-G1 or weak mitochondrial activity, which makes cells insensitive to therapies for cancers through transforming into low metabolism status. This biological phenomenon may help explain why treatment efficacy and prognosis vary among breast cancer patients having hypothyroid, hyperthyroid and normal function. Nevertheless, the abnormal thyroid function in breast cancer patients has been considered being mainly caused by thyroid diseases, few studied influence of chemotherapy on thyroid function and whether its alteration during chemotherapy can influence the respose to chemotherapy is still unclear. So, we aimed to find the alterations of thyroid function and non-thyroidal illness syndrome (NTIS) prevalence druing chemotherapy in breast cancer patients, and investigate the influence of thyroid hormones on chemotherapeutic efficacy.
Optimal schedule of Bacillus Calmette-Guerin for non-muscle-invasive bladder ...Enrique Moreno Gonzalez
To explore the necessity of maintenance, efficacy of low-dose and superiority of various combination therapies of Bacillus Calmette-Guérin (BCG) in treatment of superficial bladder cancer (BCa).
Environment inside even a small tumor is characterized by total (anoxia) or partial oxygen deprivation, hypoxia. It has been shown that radiotherapy and some conventional chemotherapies may be less effective in hypoxia, and therefore it is important to investigate how different drugs act in different microenvironments. In this study we perform a large screening of the effects of 19 clinically used or experimental chemotherapeutic drugs on four different cell lines in conditions of normoxia, hypoxia and anoxia.
The dyslipidemia-associated SNP on the APOA1/C3/A5 gene cluster predicts post...Enrique Moreno Gonzalez
Post-surgery therapies are given to early-stage breast cancer patients due to the possibility of residual micrometastasis, and optimized by clincopathological parameters such as tumor stage, and hormone receptor/lymph node status. However, current efficacy of post-surgery therapies is unsatisfactory, and may be varied according to unidentified patient genetic factors. Increases of breast cancer occurrence and recurrence have been associated with dyslipidemia, which can attribute to other known risk factors of breast cancer including obesity, diabetes and metabolic syndrome. Thus we reasoned that dyslipidemia-associated nucleotide polymorphisms (SNPs) on the APOA1/C3/A5 gene cluster may predict breast cancer risk and tumor progression.
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
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Evaluation of antidepressant activity of clitoris ternatea in animals
Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (Head and neck cancer: ImmunoChemo and Radiotherapy with Erbitux) -- a multicente
2. Differentiation of irradiation and cetuximab induced
skin reactions in patients with locally advanced head
and neck cancer undergoing radioimmunotherapy:
the HICARE protocol (Head and neck cancer:
ImmunoChemo and Radiotherapy with Erbitux) – a
multicenter phase IV trial
G Habl1*,†
*
Corresponding author
Email: gregor.habl@med.uni-heidelberg.de
K Potthoff1,†
Email: karin.potthoff@med.uni-heidelberg.de
MF Haefner1
Email: Matthias.haefner@med.uni-heidelberg.de
A Abdollahi2
Email: a.amir@dkfz-heidelberg.de
JC Hassel3
Email: jessica.hassel@med.uni-heidelberg.de
E Boller4
Email: emil.boller@iomedico.com
M Indorf4
Email: martin.indorf@iomedico.com
J Debus1
Email: juergen.debus@med.uni-heidelberg.de
1
Department of Radiation Oncology, University of Heidelberg Medical Center,
Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
2
Molecular and Translational Radiation Oncology, Heidelberg Ion Therapy
Center (HIT), University of Heidelberg Medical School and National Center for
Tumor Diseases, German Cancer Research Center, Heidelberg, Germany
3
Department of Dermatology, University of Heidelberg Medical Center, National
Center for Tumor Diseases, Heidelberg, Germany
4
iOMEDICO AG, Freiburg, Germany
†
Equal contributors.
3. Abstract
Background
In order to improve the clinical outcome of patients with locally advanced squamous cell
carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based
chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal
antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy
with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most
frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of
treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often
overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical
and molecular differentiation between radiogenic skin reactions and skin reactions caused by
cetuximab which may correlate with outcome, have never been described before.
Methods/design
The HICARE study is a national, multicenter, prospective phase IV study exploring the
different types of skin reactions that occur in patients with LASCCHN undergoing
radioimmun(chemo)therapy with the EGFR inhibitor cetuximab. 500 patients with
LASCCHN will be enrolled in 40 participating sites in Germany. Primary endpoint is the rate
of radiation dermatitis NCI CTCAE grade 3 and 4 (v. 4.02). Radioimmunotherapy will be
applied according to SmPC, i.e. cetuximab will be administered as loading dose and then
weekly during the radiotherapy. Irradiation will be applied as intensity-modulated radiation
therapy (IMRT) or 3D-dimensional radiation therapy.
Discussion
The HICARE trial is expected to be one of the largest trials ever conducted in head and neck
cancer patients. The goal of the HICARE trial is to differentiate skin reactions caused by
radiation from those caused by the monoclonal antibody cetuximab, to evaluate the incidence
and severity of these skin reactions and to correlate them with outcome parameters. Besides,
the translational research program will help to identify and confirm novel peripheral blood
based molecular predictors and surrogates for treatment response and resistance.
Trial registration
Clinical Trial Identifier: NCT01553032 (clinicaltrials.gov)
EudraCT number: 2010-019748-38
Background
Squamous cell carcinomas of the oropharynx, hypopharynx and larynx are the sixth leading
cancer by incidence worldwide with more than 500000 new cases a year. At the time of
diagnosis most patients display signs and symptoms of locally advanced disease and have
lymph node metastases [1]. SCCHN is mostly caused by tobacco and alcohol consumption
and/or infection with high-risk types of human papillomavirus (HPV) [2]. SCCHN often
4. show an overexpression of epidermal growth factor receptors (EGFR) which is described to
be associated with a poor prognosis [3-6]. Standard treatment for resectable tumors is surgery
including reconstruction plus post-operative radiotherapy and, for those patients found at
surgery to have high risk features (extracapsular extension and/or R1 resection), post-
operative chemoradiation with single agent platinum [7,8]. At present, for non-resectable
patients who can tolerate it, combined concomitant chemoradiation with platinum is the
standard treatment [9,10]. Organ-preservation protocols with combined chemoradiation
therapy and surgery for salvage are increasingly being performed. These protocols are
particularly effective for young patients with a good performance status presenting with
moderately-advanced laryngeal or pharyngeal SCC. For patients who are not capable to
receive standard platinum-based chemoradiation due to age, generally reduced condition
and/or comorbidities, e.g. heart and renal disease or cirrhosis of the liver, the treatment of
choice is radioimmunotherapy with cetuximab [7,8,11,12]. Whereas results of a standard
chemoradiation are based on thousands of patients, results of the combined
radioimmunotherapy are only based on about 200 patients in the experimental arm of the
pivotal trial [11,12]. A study comparing the standard platinum-based chemoradiation with the
novel radioimmunotherapy protocol with the anti-EGFR antibody cetuximab, however, is still
missing. Hence, guidelines still recommend standard radiochemotherapy with cisplatin for
patients able to receive chemotherapy [9,10].
Cetuximab is a chimeric monoclonal IgG1 antibody specifically targeting the epidermal
growth factor receptor (EGFR). EGFR signal cascades are involved in cell proliferation, in
cell cycle regulation, in angiogenesis, cell migration and invasion and in metastases.
Cetuximab binds to the EGFR in a 5 to 10 times higher affinity than endogen ligands leading
to a downregulation of EGFR molecules on the cell surface. Intracellular phosphorylation of
the EGFR is inhibited and consequently the down stream signalling is deficient resulting in
cell cycle arrest, increased expression of pro-apoptotic enzymes and decrease in the
production of matrix metalloproteinases. Effects of EGFR inhibition that have been described
are a reduction of cell proliferation, an inhibition of cell division processes and tumor growth
and an increase of apoptosis [13,14]. Furthermore, cetuximab treatment leads to a decrease in
the production of vascular endothelial growth factor (VEGF) blocking angiogenic processes
in the tumor. Cetuximab has been found to potentiate the effects of radiotherapy in
experimental systems [13-15].
Combined radioimmunotherapy with cetuximab is a well accepted treatment option in
patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) if
they are not able to receive surgery or combined radiochemotherapy due to stage, reduced
general condition and/or comorbidities. In the pivotal, international, randomized Phase III
trial of 424 patients with locally or regionally advanced squamous cell carcinoma of the
oropharynx, hypopharynx or larynx with no prior therapy, the addition of cetuximab to
radiation when compared to radiation alone resulted in a higher response rate, a 9.5- month
improvement in median duration of locoregional control [24.4 months versus 14.9 months], a
longer disease-free survival and a 9% increase of the 5 year overall survival (OS). [11]. In
retrospective comparison with chemoradiation trials, immunoradiation with cetuximab
showed similar control rates in terms of overall survival (OS) and local control rate (LCR)
[16]. Since the radioimmunotherapy with cetuximab is a feasible treatment option that overall
shows a low incidence of systemic side effects and a favourable toxicity profile, it is
especially indicated for older patients and patients with comorbidities. Recently updated
EHNS-ESTRO-ESMO guidelines recommend radioimmunotherapy with cetuximab with a
level of evidence of II and a recommendation grade B [8].
5. Skin reactions are known to be the most frequent side effect of EGFR inhibitor therapy.
About 90% of patients treated with cetuximab develop an acneiform rash, but only 15% of
patients develop a grade 3 or 4 skin rash [17-20]. Besides, patients on cetuximab treatment
might develop other skin reactions like a xerosis cutis followed by a severe pruritus, hair and
nail alterations, a stomatitis and eye abnormalities. All of those skin reactions can result in
non-compliance as well as in an interruption or even discontinuation of an effective antitumor
treatment approach. Besides, patients often feel anxious related to the cosmetic appearance of
the rash and have the feeling to be stigmatized which can lead to psychosocial side effects
and can negatively affect patient quality of life [21].
The most frequently seen side effect of radiotherapy in patients with head and neck cancer is
radiation dermatitis that occurs in approximately 90% of patients. If cetuximab is
administered simultaneously, an overlap of radiation and cetuximab induced skin reactions is
seen in the radiation field which may lead to very severe skin toxicity [22,23]. An
retrospective evaluation of acute toxicity of skin and mucosa in patients with head and neck
cancer receiving radiotherapy (RT) alone or in combination with radiotherapy plus
chemotherapy (RCT) or with cetuximab (RIT) published by Garcia-Huttenlocher et al.
showed grade 3 overall skin toxicity in 27.6% of the RIT patients compared to 0% in patients
only receiving RT and compared to 7% in patients receiving RCT [22]. Cetuximab associated
acneiform rash grade 3 was observed in 7% of the RIT patients. In this publication cetuximab
did not lead to a higher rate of RT interruptions compared to RT and RCT. Eight weeks after
RT all patients had recovered from these dermatological side effects [22]. Bonner et al.
reported on 21% of patients with grade 3/4 radiation dermatitis in the RT group. In the
radioimmunotherapy group, however, a significant increase to 35% of grade 3/4 radiation
dermatitis was observed. Since there is a discussion about a possible correlation between the
intensity of acneiform rash and the efficacy of therapy [11], Bonner et al. conducted a
subgroup analysis showing an overall survival benefit in patients developing an acneiform
rash grade 2–4 compared to patients with acneiform rash grade 0–1. Such patients survived
for a median of 69 months, whereas patients who had no reaction or only a mild rash had a
median survival of 26 months [11]. Thus, it might be possible that the acneiform rash is a
predictive biomarker for immunological response and, furthermore, that it is conductive for
optimal outcome. A similar pattern has already been shown for other types of cancer [24-26].
Vermorken and colleagues,,
however, conducted a thorough analysis of cetuximab-induced
skin reactions and acne-like rash with clinical markers of activity. Although development of
skin reactions and acne-like rash appeared to trend toward improved response and disease
control, early development of these toxicities was not associated with improved response or
overall survival [27].
Budach et al. reported on two patients who had severe radiation dermatitis while receiving
radioimmunotherapy with cetuximab [23]. Severe radiation dermatitis may occur after
irradiation alone, but grade 4 lesions are rarely observed. Coexisting conditions like
previously received chemotherapy or radiotherapy or even intensive sun exposure in the past
may predispose for aggravation of radiation and cetuximab induced skin reaktions. Liver or
renal dysfunction with possible alterations of pharmacodynamics of cetuximab may also
predispose patients to develop more severe radiation dermatitis [28]. In a retrospective survey
in EORTC institutes, the members observed that in 49% of patients treated with cetuximab
and concurrent radiotherapy developed grade 3 or 4 radiation dermatitis [29]. Hence, the
incidence of these severe skin reactions was twice as high compared to that reported by
Bonner et al. [11,12]. The real percentages of grade 3 and 4 radiation dermatitis during
combined radioimmunotherapy with cetuximab, however, have never been evaluated.
6. Furthermore, the differentiation between radiation dermatitis and cetuximab induced
acneiform rash seems to be important for therapeutic and prognostic reasons but has never
been explored in detail so far. Thus, a prospective, multicenter large-scaled study is
warranted to distinguish radiation dermatitis from cetuximab induced skin reactions, to
determine the real incidence of the different types of skin reactions in a large cohort of
patients, and, besides, to identify and evaluate biomarkers and surrogates correlating with
clinical efficacy and outcome.
The HICARE trial is a prospective, open phase IV trial exploring the prominent side effects
of skin toxicities of combined radioimmun(chemo)therapy with the EGFR inhibitor
cetuximab (Erbitux®) in patients with LASCCHN in great detail. The HICARE study is a
national multicenter trial in Germany, 40 centers will participate.
Methods/design
Study design
The HICARE study is designed as an open-label, prospective, multicenter, one-armed phase
IV study according to the German drug law evaluating the incidence and severity of radiation
dermatitis and acneiform rash in patients with locally advanced head and neck cancer treated
with combined radioimmuno(chemo)therapy with cetuximab.
Study objectives
Primary endpoint of the study is the rate of radiation dermatitis grade 3 and 4 according to the
National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI CTCAE),
version 4.02. Secondary endpoints are skin related parameters like the rate of radiation
dermatitis grade 1 and 2, the rate of cetuximab-induced acneiform rash grade 1–4, the rate of
cetuximab-induced rhagades (all grades), the rate of cetuximab-mediated nail changes (all
grades). Furthermore secondary endpoints include parameters of efficacy, i.e. objective
response rate (ORR), locoregional control rate (LCR), progression free survival (PFS),
overall survival (OS), safety parameters, i.e. the median dose density of radiation and the
safety profile of the applied radiation protocol as well as quality of life (QoL). In addition,
feasibility aspects of the treatment schedule in common routine practice and applied to
patients presenting an increased comorbidity rate compared to the study population studied in
the pivotal phase III trial will be evaluated. For translational research genomic analyses of
peripheral blood samples are carried out at several time points during the trial. The results of
the translational research will be correlated with safety parameters, clinical outcome and
quality of life.
Trial organization
The HICARE study was designed by the study initiators at the Department of Radiation
Oncology of the University of Heidelberg. It is an investigator initiated trial (IIT). The trial is
conducted as multicenter trial and 40 centers all over Germany will participate. The trial
medication cetuximab is commercially available and it will be administrated in combination
with radiotherapy as recommended by the SmPC [30}.
7. Coordination
The overall coordination is performed by the Department of Radiation Oncology of the
University of Heidelberg. The Department of Radiation Oncology of the University of
Heidelberg is responsible for overall trial management, trial registration, database
management, quality assurance and reporting. Biometrical data analyses are conducted by the
CRO iOMEDICO.
Investigators
The investigators are experienced oncologists, i.e. radiooncologists and medical oncologists,
specialized in treating patients with locally advanced head and neck cancer. Patients will be
recruited and treated by the investigators of the 40 participating sites in Germany (see
acknowledgement).
Quality assurance
According to the guidelines of Good Clinical Practice (GCP) and other applicable guidelines
and regulations the site monitoring will be performed by an independent monitor.
Ethics, informed consent and safety
The final protocol was approved by the leading ethics committee of the Medical Faculty of
the University of Heidelberg (AFmu-387/2010), the local ethics committee of every
participating center and the Paul-Ehrlich-Institute. The HICARE trial is registered at the
European Clinical Trials Database (EudraCT-No. 2010-019748-38) and at
www.clinicaltrials.gov, number NCT01553032. The HICARE study complies with the
Declaration of Helsinki in its recent German version, the Medical Association’s professional
code of conduct, the principles of Good Clinical Practice (GCP) guidelines and the Federal
Data Protection Act. The trial will also be carried out adhering to local legal and regulatory
requirements.
For each patient recruited into the study, written informed consent is essential prior to
inclusion into the study after extensive information about the intent of the study, the study
regimen, potential associated risks and side effects as well as potential alternative therapies.
The investigator will not undertake any diagnostic measures specifically required for the
clinical trial until valid consent has been obtained.
Patient selection
A total of 500 patients with locally advanced (UICC stage III, IVA or IVB), non-metastatic,
squamous cell carcinoma located in the oral cavity, oropharynx, hypopharynx, or larynx with
measurable disease will be included. For participation in the trial lymph node involvement is
allowed, but a spread of the tumor to other parts of the body is an exclusion criterion. Each
patient will receive the combined radioimmunotherapy as described above, i.e. radiation
therapy (IMRT or 3D-radiation) and cetuximab.
Inclusion criteria include:
8. • Signed written informed consent
• Age ≥ 18 years of age
• Eastern Cooperative Oncology Group performance status (ECOG) of 0 to 2
• Life expectancy > 6 months
• Histologically confirmed locally advanced (stage III or IVA, IVB), non-metastatic
squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx and larynx (T2-
4, Nx, M0).
• Adequate bone marrow, liver and renal function according to SmPC of cetuximab
based on laboratory assessments raised within 7 days prior to start of study treatment.
• Women of childbearing potential must have had a negative serum or urine beta-HCG
pregnancy test within 7 days prior to the first administration of study treatment or
must have a documented condition that prohibits pregnancy (e.g. post-menopausal;
hysterectomy).
• Commitment to use of adequate contraception: patients enrolled in this trial must be
willing to use effective birth control measures during the course of the trial and the
subsequent 2 months
Exclusion criteria include:
• Previous radiotherapy for carcinoma of the head and neck
• Nasopharyngeal carcinoma
• Distant metastases
• Prior exposure to EGFR pathway targeting therapy
• Surgery within the last 30 days
• Known allergic/hypersensitivity reaction to any drug scheduled for the study
treatment
• Previous or concurrent cancer within 5 years prior to study entry that is distinct in
primary site or histology except adequately treated basal cell carcinoma or
preinvasive cervical carcinoma.
• Substance abuse, medical, psychological or social conditions that may interfere with
the patient’s participation in the study or evaluation of the study results as judged by
the investigator
• Any condition that is unstable or could jeopardise the safety of the patient and their
compliance in the study as judged by the investigator
• Legal incapacity or limited legal capacity
• Pregnant or breast-feeding women
Work-up
Routine staging includes physical examination, chest X-ray, head and neck panendoscopy
under anaesthesia, and head and neck computed tomography (CT) scan or magnetic
resonance imaging (MRI) and abdominal ultrasound. All patients will be evaluated for head
and neck surgery. In case resection is either surgically or medically impossible or the patient
refuses to undergo the procedure, standard chemoradiation with carboplatin and 5-FU
(without cetuximab) will be chosen according to current guidelines. In case that primary
chemoradiation is medically impossible due to comorbidities, reduced general condition, in-
and exclusion criteria for radioimmunotherapy will be evaluated and patients will be checked
for eligibility for the HICARE trial. It is to note that a combination of the applied
radioimmunotherapy with a chemotherapy in terms of a combined
radioimmunochemotherapy (e.g. with cisplatin or carboplatin/5-FU) is not an exclusion
9. criteria and, if applied, will be evaluated separately. Patients previously treated with
induction chemotherapy are allowed to participate in this trial. Should a patient be eligible,
information about participation in the study including potential risks and benefits is given to
the patient. As soon as written consent is obtained, patients can be included into the trial and
the required documentation will be provided by the study center (Clinical Trial Center,
Department of Radiooncology, University of Heidelberg Medical Center).
After inclusion, for planning of the radiotherapy each patient receives a CT-scan in an
individually adjusted precision immobilization device.
If a patient refuses treatment within the HICARE trial, the same standard combined
radioimmunotherapy will be offered if chemoradiation is not applicable.
Investigational drug according to German drug law
Cetuximab (Erbitux®)
The commercial available monoclonal antibody cetuximab will be applied according to the
German SmPC [30]. Cetuximab is given with a loading dose of 400 mg/m2
of body surface as
an intravenous infusion on day 1. Subsequently, the regular weekly dose during the
radiotherapy is 250 mg/m2
of body surface on days 8, 15, 22, 29, 36 and 43. A prophylactic
premedication with corticosteroids and antihistamines is required to reduce the incidence of
infusion-related reactions such as allergic or hypersensitivity reactions.
Radiation therapy
Irradiation is applied as modern standard radiotherapy for LASCCHN, i.e. intensity
modulated radiation therapy (IMRT) or 3D-conformalradiotherapy. Within the HICARE trial,
the standard radiotherapy scheme of the institution can be applied. A summary of radiation
protocols routinely used for this indication is given in Table 1. Radiation therapy can be
carried out on an outpatient basis unless the patient’s condition requires hospital admission.
Table 1 Possible radiotherapy protocols for treatment of patients with LASCCHN
according to Bonner et al. (12), plus modification for IMRT
Regime Total dose Single dose (once a day) Single dose (twice a day)
Once a day 70 Gy in 35
fractions
2 Gy/fraction;
5fractions/weekduration: 7
weeks
--
Twice a day 72-76,8 Gy in 60–
64 fractions
-- 1,2 Gy/fraction; 10 fractions/week
Duration: 6–6,5 weeks
Concomitant
boost
72 Gy in 42
fractions
32,4 Gy; 1,8 Gy/fraction; 5
fractions/week duration: 3,6
weeks
a.m.: 21,6 Gy; 1,8 Gy/fraction; 5
fractions/week Duration: 2,4 weeks p.m.:
18 Gy; 1,5 Gy/fraction; 5 fractions/week
Duration: 2,4 weeks
(helical)
IMRT
66 Gy in 30
fractions
Intergrated Boost 5 fractions
/week duration: 6 weeks
--
10. Supportive therapy
Antihistamines such as clemastine or dimentinden and steroids are administered
intravenously prior to the application of cetuximab according to the SMPC [30]. Skin
reactions, especially acneiform rash and xerosis cutis, are treated according to current
treatment recommendations. Whenever it is necessary, metoclopramide or 5-HT3-antagonists
are used for antiemetic treatment.
Radiation induced skin reactions are treated with mild moisturizing lotion according to in-
house protocols.
Translational research
HPV
Patients will not be selected by human papillomavirus (HPV) status, but since HPV is
increasingly being found in head and neck cancers and since there is a prognostic importance
of the HPV status [2,31-33], tumor samples will be tested for HPV status. It remains to be
seen if the particular subgroup of patients with HPV-positive tumors is the one in the
HICARE trial that may benefit more from the addition of cetuximab and may have better
outcomes than those with HPV-negative tumors.
Blood samples
For the translational research program, genomic DNA and Total-RNA (including micro
RNAs) of peripheral blood samples will be collected from each subject prior to the first
administration of cetuximab (day 1), additionally during the treatment on day 8 (prior to the
second administration of cetuximab) and on day 22 (prior to the fourth administration of
cetuximab). The goal of these studies is to identify molecular predictors of normal tissue and
tumor response to combined radioimmunotherapy using transcriptomics, microRNA or
epigenomic approaches.
Assessment of skin reactions
Skin-related toxicities like cetuximab-induced acneiform skin rash and radiation dermatitis
will be graduated by a physician in every participating center. Each week just before the
cetuximab application a photo series will be taken to get an objective measure for grading
skin toxicities. Photos will be taken with the same type of camera. These photos will be
blinded and separately reevaluated by experienced physicians authorized by the sponsor, i.e.
a radiooncologist, a medical oncologist and a dermatologist. Based on the photo
documentation it will be possible to define the correct graduation of the acute skin toxicities
and, besides, to compare them with historical data from the Bonner trial [11,12] if using NCI
CTCAE v. 4.2 and the former version 3.0 to receive this comparability with the pivotal trial
[34,35].
Quality of life assessment
Assessment of quality of life is one of the secondary objectives of the trial. The following
questionnaires will be used: EORTC QLQ-C30, the head and neck cancer-specific module
11. EORTC QLQ H&C as well as the Dermatology Life Quality Index (DLQI). The EORTC
QLQ30 is a general measure of quality of life in cancer patients, whereas the DLQI is a
specific measures 10-question validated questionnaire which is frequently been used in
dermatology. These assessments will be performed at the baseline visit, on day 22 during the
course of the treatment, within the last week of radiotherapy and at the first follow-up visit.
Safety and discontinuation of treatment
Radiotherapy-related toxicities will be assessed using the NCI Common Toxicity Criteria
(CTCAE v.4.2) and the outdated version 3.0 in order to achieve a comparison to former
studies, furthermore by duration, onset, and relationship to study treatment [34,35]. Toxicity
will be evaluated at baseline, weekly during radiation therapy (blood count, electrolytes,
chemistry, clinical examination, patient visits) and at follow-up visits. Unacceptable toxicity
is defined as unpredictable or irreversible grade 4 toxicity. Expectable possible acute
radiation-induced toxicities (up to 3 months after irradiation) comprise skin toxicity
(desquamation, epitheliolysis, edema, bleeding, necrosis, erythema, hyperpigmentation, rash,
pruritus), nausea, vomiting, fatigue, weight loss, loss of appetite, pneumonitis,
haematological toxicity including leukopenia, thrombocytopenia or anaemia. Adequately
treated these symptoms could be resolved within two to three weeks. However, transient
parenteral nutrition therapy and hydration might be necessary in some patients. All acute
radiation-induced toxicities should completely resolve within a few weeks post radiation
therapy.
Cetuximab-induced adverse events are treated according to SmPC and according to current
treatment recommendations [21]. Importantly, according to SmPC cetuximab should be
delayed for up to two subsequent infusions in patients facing a grade 3 acneiform rash.
Cetuximab can be restarted after resolution of the rash to grade 2 or less. Cetuximab needs to
be delayed on a second or third occurrence of a grade 3 skin reaction for up to two
consecutive cycles and dose reduction to 200 mg/m2
or 150 mg/m2
, respectively, will be
needed. Any further occurrence of grade 3 acneiform rash will lead to discontinuation of
cetuximab treatment according to the recommendations of the SmPC.
Adverse events
Patients’ toxicities are to be classified and documented according to the NCI Common
Toxicity Criteria v. 4.2. Toxicity is documented weekly during RIT and prior to each
application of cetuximab as well as at the follow-up visit. The investigators will report all
Serious adverse events (SAE) immediately to the sponsor or his legal representative. Serious
adverse events (SAE) are any untoward medical condition that occur and result in death, are
life-threatening, require hospitalization or prolongation of existing inpatient’s hospitalization,
result in persisting or significant disability or incapability, or are a congenital abnormality of
birth defect. For all SAE, the documents and patient data must be verified by the responsible
study personnel.
Statistical considerations
The primary objective is the rate of radiation dermatitis CTC AE grade 3 and 4 and will be
calculated based on the individual events as reported by the investigators. Bonner et al. [12]
reported an incidence of radiation dermatitis of 18% for patients treated with radiotherapy
alone compared to 23% for patients treated with radiotherapy and cetuximab. Based on data
12. of this pivotal trial, 500 patients (with a drop-out rate of 5%) will be needed to show the 95%
confidence interval to stay within the limits of 4% uncertainty (binomial test). The sample
size is also sufficient to analyse the secondary objectives. The statistical analysis will be
carried out using the updated versions of Statistica (StatSoft Europe GmbH) and R (www.r-
project.org). Descriptive analyses will be done of all documented data. To compare the study
population of the HICARE trial with the data of the pivotal trial by Bonner et al. [11,12],
descriptive statistical methods without formal testing will be used. The analysis of the
primary objective and further safety parameters will be done with all patients who received at
least 1 dose of study medication cetuximab and at least 1 fraction of RT. Analyses of efficacy
parameters will be done by the intention to treat population. Details on the evaluation can be
found in the statistical analysis plan prepared for the study and which will be finalized and
authorized by the study biostatistician and the principal investigator prior to performing any
analysis.
Objective response evaluation
Objective response will be evaluated according to RECIST criteria v.1.01 [36].
Discussion
For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall
survival at 5 years compared with radiotherapy alone, confirming cetuximab plus
radiotherapy as an important treatment option in this group of patients [11,12]. However,
there are no data available about a formal comparison between the combination of
radiotherapy with cisplatin or cetuximab. The current guidelines still recommend using
standard radiochemotherapy in patients with LASCCHN fit enough to undergo chemotherapy
because there is no randomized, prospective trial comparing radiochemotherapy versus
immunoradiotherapy in this patient group [8,37]. Chemoradiation is known to be associated
with significant toxicities and, furthermore, its efficacy is questioned in the elderly
population. The magnitude in effect of the radioimmunotherapy with cetuximab, however, is
similar or even better than that achieved by chemoradiation and it proved to be less toxic
[8,11]. The control rates were the same in retrospective comparison with radiochemotherapy
trials [16].
For better patient selection, i.e. for definition of a patient cohort that benefits more from the
less intense and less toxic radioimmunotherapy regimen and a patient cohort that benefits
more from the more intense chemoradiation-based approach, patient characteristics including
clinical and molecular prognostic markers and predictive surrogates have to be defined.
Several clinical characteristics of patients with HNSCC have been linked to favourable
prognosis, including non-smoker, minimum exposure to alcohol, good performance status,
and absence of co-morbid disorders [38]. Several studies have shown a correlation between
genetic aberrations, i.e. a p53 mutation, and lower response rates to chemotherapy and shorter
overall survival times [39-42]. The HPV-status is associated with outcome, too [2]. To date in
LASCCHN specific genetic alterations, however, are not known [43]. Testing for genetic and
proteomic alterations in a large patient cohort may define prognostic and predictive
biomarkers that help to identify patients who are at great risk for progression or treatment
resistance and patients who might benefit most from radioimmunotherapy.
13. Skin reactions, the most common side effect of radiotherapy and also of anti-EGFR-treatment
strategies like cetuximab, have not been evaluated and characterized in detail. Interestingly,
almost all studies addressing EGFR-inhibitor-induced skin rash done in patients with
metastatic colorectal cancer suggest that its severity is a suitable surrogate marker for
efficacy of anti-EGFR therapy [44-47]. In patients with LASCCHN, the pivotal trial by
Bonner et al. also showed that cetuximab-treated patients with prominent cetuximab-induced
acneiform rash grade 2 or above had a better overall survival than patients with no or grade 1
rash [11]. A retrospective exploration of several trials done with panitumumab, another anti-
EGFR monoclonal antibody, confirmed an association between clinically graded skin toxicity
and patient-reported outcome, quality of life, longer progression-free survival and overall
survival [26]. Other trials in patients with metastatic colorectal cancer and other solid tumors
did not show any correlation between skin rash and efficacy of anti-EGFR therapy [48].
Thus, a clinical trial is warranted in patients with LASCCHN to evaluate the efficacy and
toxicity of the radioimmunotherapy with cetuximab in a large patient cohort and to focus on
biomarker research to better select patients who might benefit better from this treatment
approach than others. .
The HICARE study will be one of the largest clinical trials ever being performed in patients
with LASCCHN. It will help to better understand the different clinical characteristics of skin
reactions induced by radiotherapy and by cetuximab treatment, to identify molecular
predictors and surrogates for treatment response and resistance and to better define a patient
population where a less toxic regimen like the radioimmunotherapy with cetuximab would
constitute the primary treatment option and other patient populations where a more intense
chemoradiation-based approach is needed.
Abbreviations
CRO, Clinical research organization; EGFR, Epidermal growth factor receptor; GCP, Good
clinical practice; Gy, Gray; RECIST, Response evaluation criteria in solid tumours; RIT,
Radioimmunotherapy; SmPC, Summary of product characteristics
Competing interest
The other authors declare that they have no competing interests.
Authors’ contributions
GH, KP and JD planned and coordinate the study. GH, KP, MH, JH, and JD are conducting
the study. Medical care is covered by GH, KP and MH. GH, KP and JD are responsible for
the patient recruitment. EB performed the statistical calculations and will be responsible for
the final statistical analysis. MI represents iOMEDICO AG, the CRO responsible for
document development, eCRF programming and general study logistics. All authors read and
approved the final manuscript.
14. Acknowledgements
This trial is funded in part by research grants from Merck KGaA, Darmstadt, Germany.
Merck Serono has reviewed the publication; the views and opinions described in the
publication do not reflect those of Merck Serono.
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