- Non-alcoholic fatty liver disease (NAFLD) has been renamed to metabolic dysfunction associated steatotic liver disease (MASLD) to better reflect its pathogenesis.
- MASLD includes hepatic steatosis in the presence of cardiometabolic risk factors like obesity, diabetes, and dyslipidemia.
- Risk factors, pathogenesis, clinical features, diagnosis, and management of MASLD were discussed with emphasis on lifestyle modifications, weight loss, treatment of cardiometabolic conditions, and potential pharmacotherapy.
Oesophageal and gastric varices classificationsDrJawad Butt
The Sarin classification identifies two types of gastroesophageal varices: varices found where esophageal varices are present, and two types of isolated gastric varices found without esophageal varices present. The classification system grades esophageal varices based on their size as small, medium, or large. The AASLD recommends simplifying this to a two-grade system of small or large varices based on a 5 mm cutoff. The North Italian Endoscopic Club classification scores varices based on size, severity of red wale marks, and Child-Pugh class to define a risk of bleeding.
- Non-alcoholic fatty liver disease (NAFLD) has been renamed to metabolic dysfunction associated steatotic liver disease (MASLD) to better reflect its pathogenesis.
- MASLD includes hepatic steatosis in the presence of cardiometabolic risk factors like obesity, diabetes, and dyslipidemia.
- Risk factors, pathogenesis, clinical features, diagnosis, and management of MASLD were discussed with emphasis on lifestyle modifications, weight loss, treatment of cardiometabolic conditions, and potential pharmacotherapy.
Oesophageal and gastric varices classificationsDrJawad Butt
The Sarin classification identifies two types of gastroesophageal varices: varices found where esophageal varices are present, and two types of isolated gastric varices found without esophageal varices present. The classification system grades esophageal varices based on their size as small, medium, or large. The AASLD recommends simplifying this to a two-grade system of small or large varices based on a 5 mm cutoff. The North Italian Endoscopic Club classification scores varices based on size, severity of red wale marks, and Child-Pugh class to define a risk of bleeding.
This document discusses cirrhosis and its complications over two parts. Part I covers what cirrhosis is, its etiologies, clinical presentations, physical exam findings, laboratory tests, liver biopsy, and prognosis for different etiologies. Part II covers complications of cirrhosis including portal hypertension, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatopulmonary syndrome, and hepatocellular carcinoma screening and treatment. Liver transplantation is also discussed as a treatment option.
Wilson's disease is an inherited disorder that causes copper to accumulate in the liver and other organs. This document discusses the pathophysiology, clinical manifestations, diagnosis, and treatment of Wilson's disease. It provides guidelines from the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. Key points include that Wilson's disease should be considered for any unexplained liver or neurological conditions, a low ceruloplasmin level supports the diagnosis, treatment is lifelong chelation therapy or zinc, and liver transplantation may be needed for decompensated cirrhosis.
This document discusses jaundice and approaches to evaluating its underlying causes. It defines jaundice as yellowish discoloration from bilirubin deposition. Liver enzymes, imaging like ultrasound and CT, and procedures like ERCP can help differentiate causes like viral hepatitis, alcoholic liver disease, autoimmune conditions, and obstructive jaundice. A careful history, exam, and pattern of lab and imaging abnormalities can often reveal the etiology of jaundice. A liver biopsy may be needed in some unclear cases to establish a diagnosis.
This document presents a case report of a 54-year-old diabetic male who presented with bilateral emphysematous pyelonephritis (EPN), a rare and life-threatening infection involving gas in the renal parenchyma. Despite initial treatment with antibiotics, the patient deteriorated and developed multiple organ dysfunction. Imaging revealed extensive EPN. Due to the patient's critical condition, nephrectomy was not pursued. He was managed medically with prolonged antibiotics and supportive care. After 4 weeks, follow up imaging showed no significant changes but the patient remained dependent on hemodialysis. The document then reviews EPN including causes, presentation, diagnosis, staging, and management approaches.
This document provides an overview of the history and current practices of prostate biopsy. It discusses the evolution from open transperineal biopsy to current standard of care transrectal ultrasound (TRUS)-guided biopsy. Recent studies have shown multiparametric MRI can improve detection of clinically significant cancer and potentially reduce unnecessary biopsies. The document reviews patient preparation, biopsy techniques including systematic and targeted biopsy approaches, complications, and post-biopsy management. It provides guidance on appropriate patient selection and when to consider additional investigation or repeat biopsy.
This document summarizes research on the AR-V7 splice variant of the androgen receptor in prostate cancer. It finds that AR-V7 expression is associated with resistance to enzalutamide and abiraterone, two new therapies for castrate-resistant prostate cancer. A study evaluated AR-V7 mRNA in circulating tumor cells from patients on these drugs and found that AR-V7 detection was associated with shorter progression-free and overall survival. The presence of AR-V7 may help predict which patients will not respond to these therapies and require alternative treatment approaches.
Diagnosis of Inflammatory bowel disease have challenges including differentiating from Irritable bowel disease using noninvasive biomarkers. Fecal calprotectin is a novel fecal marker which meets the diagnostic & monitoring requirements for IBD.
This document discusses the treatment of non-muscle invasive bladder cancer. It begins by outlining risk stratification into low, intermediate, and high risk groups based on tumor grade and stage. For high risk disease, the primary treatment is intravesical BCG immunotherapy, with intravesical chemotherapy as an alternative. Maintenance BCG therapy provides the best chance of preventing recurrence and progression. Side effects are discussed and managed based on their severity. Second line options in the event of BCG failure include a second course of BCG, combination BCG+interferon therapy, or radical cystectomy for high risk cancers.
Olga staging system for diagnosis of gastritisSamir Haffar
This document summarizes the OLGA staging system for classifying and assessing the risk of gastric cancer from gastritis. The OLGA system stages gastritis from Stage 0 to Stage IV based on the degree and location of gastric atrophy identified on biopsy. Stages 0-II are considered low risk for gastric cancer while Stages III-IV are high risk. The staging is done by combining an antrum atrophy score and corpus atrophy score assessed from biopsies of the gastric antrum and corpus according to a standardized sampling protocol.
Vesicoureteric reflux , a common condition in children which could be misdiagnosed . Early diagnosis can help prevent renal scarring and other complications
This document discusses the Barcelona Clinic Liver Cancer (BCLC) staging system for hepatocellular carcinoma. The BCLC staging system stratifies patients into 5 stages (0, A, B, C, D) based on tumor characteristics, liver function, physical status, and performance status. The stages determine first-line treatment options including surgical resection, liver transplantation, local ablation, transarterial chemoembolization, sorafenib, or palliative care. The BCLC staging system aims to predict outcomes and guide treatment selection. It is recommended by major liver organizations and has been validated in multiple studies.
The 2012 Annual Business Meeting of the National Defender Investigator Association will be held on April 19th at 5:00 pm at the Grand Hyatt Atlanta Hotel in the Grand Ballroom. The meeting will take place during the 2012 NDIA National Conference and is open to all members in good standing who may vote and discuss agenda items.
Este documento describe los pasos para instalar localmente Xampp y Wordpress en sistemas Linux, Windows y portátil. La instalación de Xampp solo requiere descargar el archivo correspondiente al sistema operativo y ejecutarlo. Para Wordpress se debe crear una base de datos, descargar e instalar los archivos en un directorio de Xampp y completar la configuración.
La Web 2.0 se refiere a un cambio en la concepción de Internet, permitiendo una mayor interacción entre usuarios y el desarrollo de redes sociales donde puedan expresarse y compartir contenidos. Las características clave incluyen páginas dinámicas con recursos multimedia compartibles y interfaces fáciles de usar que permiten la participación activa de los usuarios. Algunas herramientas populares son blogs, wikis, redes sociales y plataformas de compartir recursos. La Web 2.0 puede beneficiar la educación al permitir la
This document discusses cirrhosis and its complications over two parts. Part I covers what cirrhosis is, its etiologies, clinical presentations, physical exam findings, laboratory tests, liver biopsy, and prognosis for different etiologies. Part II covers complications of cirrhosis including portal hypertension, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatopulmonary syndrome, and hepatocellular carcinoma screening and treatment. Liver transplantation is also discussed as a treatment option.
Wilson's disease is an inherited disorder that causes copper to accumulate in the liver and other organs. This document discusses the pathophysiology, clinical manifestations, diagnosis, and treatment of Wilson's disease. It provides guidelines from the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. Key points include that Wilson's disease should be considered for any unexplained liver or neurological conditions, a low ceruloplasmin level supports the diagnosis, treatment is lifelong chelation therapy or zinc, and liver transplantation may be needed for decompensated cirrhosis.
This document discusses jaundice and approaches to evaluating its underlying causes. It defines jaundice as yellowish discoloration from bilirubin deposition. Liver enzymes, imaging like ultrasound and CT, and procedures like ERCP can help differentiate causes like viral hepatitis, alcoholic liver disease, autoimmune conditions, and obstructive jaundice. A careful history, exam, and pattern of lab and imaging abnormalities can often reveal the etiology of jaundice. A liver biopsy may be needed in some unclear cases to establish a diagnosis.
This document presents a case report of a 54-year-old diabetic male who presented with bilateral emphysematous pyelonephritis (EPN), a rare and life-threatening infection involving gas in the renal parenchyma. Despite initial treatment with antibiotics, the patient deteriorated and developed multiple organ dysfunction. Imaging revealed extensive EPN. Due to the patient's critical condition, nephrectomy was not pursued. He was managed medically with prolonged antibiotics and supportive care. After 4 weeks, follow up imaging showed no significant changes but the patient remained dependent on hemodialysis. The document then reviews EPN including causes, presentation, diagnosis, staging, and management approaches.
This document provides an overview of the history and current practices of prostate biopsy. It discusses the evolution from open transperineal biopsy to current standard of care transrectal ultrasound (TRUS)-guided biopsy. Recent studies have shown multiparametric MRI can improve detection of clinically significant cancer and potentially reduce unnecessary biopsies. The document reviews patient preparation, biopsy techniques including systematic and targeted biopsy approaches, complications, and post-biopsy management. It provides guidance on appropriate patient selection and when to consider additional investigation or repeat biopsy.
This document summarizes research on the AR-V7 splice variant of the androgen receptor in prostate cancer. It finds that AR-V7 expression is associated with resistance to enzalutamide and abiraterone, two new therapies for castrate-resistant prostate cancer. A study evaluated AR-V7 mRNA in circulating tumor cells from patients on these drugs and found that AR-V7 detection was associated with shorter progression-free and overall survival. The presence of AR-V7 may help predict which patients will not respond to these therapies and require alternative treatment approaches.
Diagnosis of Inflammatory bowel disease have challenges including differentiating from Irritable bowel disease using noninvasive biomarkers. Fecal calprotectin is a novel fecal marker which meets the diagnostic & monitoring requirements for IBD.
This document discusses the treatment of non-muscle invasive bladder cancer. It begins by outlining risk stratification into low, intermediate, and high risk groups based on tumor grade and stage. For high risk disease, the primary treatment is intravesical BCG immunotherapy, with intravesical chemotherapy as an alternative. Maintenance BCG therapy provides the best chance of preventing recurrence and progression. Side effects are discussed and managed based on their severity. Second line options in the event of BCG failure include a second course of BCG, combination BCG+interferon therapy, or radical cystectomy for high risk cancers.
Olga staging system for diagnosis of gastritisSamir Haffar
This document summarizes the OLGA staging system for classifying and assessing the risk of gastric cancer from gastritis. The OLGA system stages gastritis from Stage 0 to Stage IV based on the degree and location of gastric atrophy identified on biopsy. Stages 0-II are considered low risk for gastric cancer while Stages III-IV are high risk. The staging is done by combining an antrum atrophy score and corpus atrophy score assessed from biopsies of the gastric antrum and corpus according to a standardized sampling protocol.
Vesicoureteric reflux , a common condition in children which could be misdiagnosed . Early diagnosis can help prevent renal scarring and other complications
This document discusses the Barcelona Clinic Liver Cancer (BCLC) staging system for hepatocellular carcinoma. The BCLC staging system stratifies patients into 5 stages (0, A, B, C, D) based on tumor characteristics, liver function, physical status, and performance status. The stages determine first-line treatment options including surgical resection, liver transplantation, local ablation, transarterial chemoembolization, sorafenib, or palliative care. The BCLC staging system aims to predict outcomes and guide treatment selection. It is recommended by major liver organizations and has been validated in multiple studies.
The 2012 Annual Business Meeting of the National Defender Investigator Association will be held on April 19th at 5:00 pm at the Grand Hyatt Atlanta Hotel in the Grand Ballroom. The meeting will take place during the 2012 NDIA National Conference and is open to all members in good standing who may vote and discuss agenda items.
Este documento describe los pasos para instalar localmente Xampp y Wordpress en sistemas Linux, Windows y portátil. La instalación de Xampp solo requiere descargar el archivo correspondiente al sistema operativo y ejecutarlo. Para Wordpress se debe crear una base de datos, descargar e instalar los archivos en un directorio de Xampp y completar la configuración.
La Web 2.0 se refiere a un cambio en la concepción de Internet, permitiendo una mayor interacción entre usuarios y el desarrollo de redes sociales donde puedan expresarse y compartir contenidos. Las características clave incluyen páginas dinámicas con recursos multimedia compartibles y interfaces fáciles de usar que permiten la participación activa de los usuarios. Algunas herramientas populares son blogs, wikis, redes sociales y plataformas de compartir recursos. La Web 2.0 puede beneficiar la educación al permitir la
The three sentence summary is:
Indian markets closed higher led by gains in IT, banks and other sectors following better results from Infosys and recovery in European markets. Market breadth was strong with advances outnumbering declines. Asian markets rose following gains on Wall Street and optimism about solutions to Europe's debt crisis, and the Indian markets were expected to open positively taking cues from Asia.
Este documento describe la experiencia de Inés Durana Samper en establecer un programa de cuidado de enfermería en el hogar llamado "Cuidado en Casa Ltda" en Colombia en la década de 1960. El resumen describe la formación académica avanzada de Samper y cómo su programa buscó profesionalizar la práctica de enfermería al brindar atención independiente en el hogar. El programa tuvo éxito al atender a 30 pacientes por día con 120 profesionales y asistentes, aunque enfrentó desafíos
metastatik hastalıkta hormonal tedavi - Berna Öksüzoğlu
1. Metastatik Meme Kanserinde Hormonal Tedavi Dr. Berna Öksüzoğlu Ankara Onkoloji Eğitim ve Araştırma Hastanesi 2. Medikal Onkoloji Kliniği
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5. Zamanla MMK Daha Uzun Mu Yaşıyor Nedeni yeni ilaçlar; AI, taksan, trastuzumab Giordano SE, Buzdar AU Cancer 2004; 100: 44 Chia SK, Cancer 2007; 110: 973 Yıllar Ortanca Sağkalım 1991-1992 438 gün 1994-1995 450 gün 1997-1998 564 gün 1999-2001 667 gün
6. 1999-2009 arası randomize 1. basamak KT çalışmaları, PFS ve OS kaydı 36 çalışma (13.083 kadın) Ortanca PFS ve OS; 7.6 ve 21.7 ay ER(+) tm ve her2(+)herceptin kullanan çalışmalarda OS daha iyi
7. ESMO Kılavuzu Klinik Öneriler MMK risk değerlendirme ve tedavi kararını etkileyen faktörler
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12. Ö stro j en Yanıtlı Genlerin Transkripsiyonunda Östrojen Etkileri trans krips i y on trans k rip s i yo n co-act HSP kaybı f os f or i la sy on, dimeri z a sy on k onforma sy onal değişiklik ER + E H S P co-act E AF1 E AF1 AF2 E AF1 E AF1 AF2
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14. Meme Kanserinde Östrojen Bağımlı Büyümenin Antagonize Edilmesi Estro j en Ov erler Extragonadal Perifer a l yağ , cilt , kas , kemik , CNS, meme ve perit ü moral fibroblast, metasta zlar AI Tamoxifen , Fulvestran X Postmeno pozal OFS GnRH analogları veya o of erektomi Premenop ozal K an s er hücresi ER ER
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16. Antiöstrojenlerin Kimyasal Yapıları OH (CH 2 ) 9 SO(CH 2 ) 3 CF 2 CF 3 OH Fulvestrant ( steroidal ) HO 7 Ralo ks ifen HO S OH O O N Ös tr o diol HO Tamo ks ifen O NMe 2
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19. Ö stro j en Yanıtlı Genlerin Transkripsiyonunda Tamoksifen Etkileri trans k rip siy on t rans k rip s i y on yok co-act HSP kaybı f os f or i la sy on, dimeri z a sy on k onforma sy onal değişiklik ANTAGONI Z M A AGONI Z M A ER + T H S P T AF1 T AF1 AF2 T AF1 T AF1 AF2 co-act
23. Over Ablasyon Yöntemleri Radyoterapi , Kemoterapi , LHRH analogları ( Goserelin Leuprolide) Cerrahi kastrasyon (o oferektomi)
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25. GnRH Analoglarının Etki Mekanizması LHRH ( hipotalamus) Pitüiter bez Ö stro j en ler Progesteron Ov er LHRH re s ept ö r downregülasyonu Gonadotropin ler (FSH + LH)
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27. Goseralin Etki Mekanizması Şekil A ( tumor flare ) Goseralin akut uygulama sonrası LH hip erse kresyonu ve androjen artışı Şekil B Goseralin kronik uygulama sonrası LH hipo se kresyonu goserelin goserelin goserelin goserelin goserelin goserelin goserelin goserelin goserelin Pit üi t e r Hücre LH Pit ü it e r Hücre LH goserelin goserelin goserelin goserelin goserelin goserelin goserelin goserelin goserelin
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29. Östrojen Biyosentezi Aromata z İ nhibit örleri Etki Mekanizması 20,22-L i ya z 11 -H i dro ksi la z 18-H i dro ksi la z 17,20 Lyase Farmakolojik Hedef Ko lesterol Pregnenolone Progesteron 11-Deoxycorticosterone K orti k osteron 17 -H i dro ksi la z 21 -H i dro ksi la z 11-Deo ksik orti z ol Testosteron Deh i droepiandrosteron Androstenedion Ko rti z ol Aldosteron aromata z Ö stron Ö stradiol 17 - Hydro ksi pregnenolon 17 - Hydro ksi progesteron
38. Pre-/perimenop oz al MMK F a z III Çalışmalar Goseralin vs Ooferektomi Goseralin vs Goseralin + tmx Obje k ti f yanıt oranı (%) Ortanca sağkalım Taylor CW, et al ‘Zoladex’ 3.6mg Cerrahi o fe re k tom i ‘Zoladex’ 3.6mg Cerrahi J Clin Oncol o ferek tom i 1998; 16: 994 – 9. ( n =29*) ( n =30*) ( n =69) ( n =67) 31 27 37 months 33 months Boccardo F, et al ‘Zoladex’ 3.6mg Cerrahi oferektomi ‘Zoladex’ 3.6mg Cerrahi Ann Oncol veya over radyoterapi o ferektomi 1994; 5: 337 – 42. veya ov e r rad yoterapi ( n =22*) ( n =15*) ( n =24) ( n =18) 27 ( + 19) 47 ( + 25) 36 months 38 months Jonat W, et al ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg + + tamo ks ifen (40mg) tamo ks ifen (40mg) Eur J Cancer Part A ( n =159) ( n =159) ( n =159) ( n =159) 1995; 31A: 137 – 42. 31 38 29 months 32 months Kombine (goser+tamoks) kolda ortanca TTP farkı ( 5.3 vs 6.5 ay) Sadece kemik met olanlarda objektif yanıt, TTP ve OS farkı * Değerlendirilebilen hastalar
1973-82 arası 1581 hasta antrasiklinli tedavi almış (en fazla 2 yıl)- %16.6 (263 hasta) tam yanıt, %3.1 (49 hasta)>5 yıl tam yanıt devam, premenap, genç ortanca yaş, iyi PS. İlk 3 yıl hızla çoğu progrese sonra progresyon riski sabitleniyor 1988-93 arası 315 hastadan 40 hasta tam yanıt ve DFS> 5yıl – krc. met yok, iyi PS, düşük met bölge sayısı 40. Breast Cancer: Stage IV Stage IV, or metastatic, breast cancer is a lethal disease. The most common sites of metastases are soft tissue (skin or draining lymph nodes), bone, and viscera (eg, liver, lung).
LHRH = Luteinising Hormone Releasing Hormone EBCTCG = Early Breast Cancer Trialists’ Collaborative Group
ER proteini sadece çekirdekte değil plazma mebranında da bulunur. Bu ER.ü nongenomik fonksiyonlara sahiptir ve nukleustaki gen ekspresyoundaki transkripsiyonel aktiviteden farklıdır. Bu non-genomik aktiviteler bazı büyüme faktörlerinin (EGFR, her2-neu ve IGF gibi) aktivasyonunu içerir. Östrojenle bu reseptörlerin aktivasyonu tm büyümesini arttırabilir (aynı büyüme faktörü ligandı gibi). Sonra büyüme faktör yolağındaki aktive kinazlar ER ve koaktivatör proteinleri fosforilleyip daha da aktive edebilir ve nükleustaki transkripsiyonel etki güçlenir (cross-talk) Prolif ve sağkalım için kısır döngü oluşur
AI, aromatase inhibitor; CNS, central nervous system; ER, estrogen receptor; GnRH, gonadotropin-releasing hormone; OFS, ovarian function suppression; OVX, ovariectomized. In premenopausal women, estrogen primarily comes from the ovaries with a smaller contribution from extragonadal aromatization, predominantly emanating from fat, skin, and muscle, but also from other areas such as bone and the central nervous system. Interestingly, breast and peritumoral fibroblasts also contribute to estrogen synthesis both at the site of primary breast tumors and at the site of metastases. Suppressing ovarian function minimizes the contribution of the primary source of estrogen in premenopausal women, but adding tamoxifen or an aromatase inhibitor would be required to completely block the entry of estrogen into breast cancer cells. In patients in whom ovarian function ceases (because of menopause or cancer therapy), peripheral aromatization requires suppression or estrogen antagonism. This can be accomplished with monotherapy using aromatase inhibitors or with tamoxifen. Importantly, aromatase inhibitors cannot be given as monotherapy to premenopausal women but must be administered in conjunction with ovarian function suppression. This is because as single agents, aromatase inhibitors are unable to fully suppress ovarian estrogen synthesis and cause a reflex rise and increased risk of fertility and unwanted pregnancy.
Toremifen vs Tamoksifen meta-analizi; 5 çalışma: fark yok, RR %24 vs TTP 25.3 ve 4.9 vs 5.3 ay Pyrhonen S, Breast Cancer Res Treat 1999; 56: 133-43
Fulvestrant (‘Faslodex’) has a steroidal structure similar to that of the naturally occurring hormone estradiol, differing by the addition of a long side-chain at the 7- position, which is responsible for its antagonistic properties. This steroidal structure of fulvestrant is markedly different from that of two typical SERMs ( S elective E strogen R eceptor M odulators), tamoxifen and raloxifene.
İlk 3 ay sıcak basması sonra plato Keikleri koruma premenapozlarda belirgin değil Flush için venlafaxine, gabapentin, düşük doz megesterol (paroksetin kullanmamalı-CYP2D6yı inhibe eder ve tamoks metabolize olamaz Tamoksifen ER.ye bağlandığında hücre siklusu G1de arrest olur, prolif durur. Bir miktar apoptozis olur.. IGF-I konsantrasyonunda azalma diğer bir mekanizma ancak esas mekanizma ER aracılıklı olan. A beneficial effect of tamoxifen citrate (Nolvadex ® ) is seen in pre- and postmenopausal patients, in ER-positive and ER-negative cases, as well as node-negative and node-positive cases, although the greatest benefit is seen in postmenopausal, ER-positive patients † Tamoxifen is the only endocrine therapy indicated in the treatment of early disease In addition to the survival benefits associated with adjuvant therapy, tamoxifen also reduces the incidence of contralateral tumours compared with controls (no treatment/placebo) Tamoxifen is well tolerated and has proven efficacy benefits; however, it is associated with a small increased risk of endometrial cancer ER = oestrogen receptor Nolvadex ® is a trade mark, the property of Zeneca Limited † In the US, Nolvadex ® is not indicated for premenopausal node-positive patients
Daha nadir direnç mekanizmaları; ER mutasyonu, ER fosforilasyonu %7-10 CYP2D6yı kötü metabolize edenler ve tamok yararı az
ICI 182,780 (‘Faslodex’) has a steroidal structure similar to that of the naturally occurring hormone, oestradiol, differing by the addition of a long side-chain at the 7- position, which is responsible for its antagonistic properties This steroidal structure of ICI 182,780 is markedly different from those of two typical SERMs ( S elective E strogen R eceptor M odulators), tamoxifen and raloxifene
Surgical oophorectomy , results in immediate and permanent reduction in ovarian steroid production. The current laparoscopic surgical techniques are associated with less operative morbidity and are the usual means of removing the ovaries in the standard surgical situation. However, women who have a genetic predisposition to ovarian cancer—for example, women who carry mutations in the BRCA1 or BRCA2 genes—require open surgery with removal of the uterus. Node sampling and peritoneal washing are often recommended at the time of surgery for these women. Women who choose to have their uterus removed at the time of surgery would also have an open procedure. The removal of the ovaries permanently prevents the production of ovarian steroids such as estrogen and alleviates the burden of continued, expensive monthly injections (ie, with GnRH agonists). One of the difficult aspects of treatment in women who have received chemotherapy is the need for continued injections throughout the duration of their hormone therapy in order to reduce and prevent the production of estrogen by the ovaries. The use of a surgical oophorectomy can prevent the need for continued intervention. However, surgery induces early menopause and renders the recovery of ovarian estrogen production impossible. Therefore, this procedure is a difficult decision for most young women facing a diagnosis of breast cancer and the implications of early menopause.
The normal stimulus for the release of gonadotrophins, follicle stimulating hormone (FSH) and luteinising hormone (LH), from the pituitary gland is pulsatile secretion of LHRH by the hypothalamus In the premenopausal female, LH induces the secretion of oestrogens from the ovary, the most important of which is oestradiol ‘ Zoladex’ acts on the hypothalamic-pituitary axis by a process known as ‘receptor downregulation’
A third, popular way to cause ovarian suppression in premenopausal women with early‑stage breast cancer is through the use of GnRH analogues, or GnRH agonists. These agents suppress ovarian function through agonist properties. High doses of GnRH agonists flood the body with hormone-releasing agent and prompt suppression of ovarian function. These agents are given as monthly or every-3-month injections and were first used in the treatment of metastatic prostate cancer. Available GnRH agonists include goserelin, leuprolide, and triptorelin. Monthly injection is the most appropriate administration schedule because data indicate it is more effective than injection every 3 months. When GnRH agonists are discontinued, particularly in young women, the effects are generally reversible, and menses may restart. This reversibility is likely to be age related: Suppression of menses is less likely to be reversible in women older than 40 years of age compared with women younger than 40 years of age. The duration of GnRH agonist therapy and its relationship to recoverability of ovarian function in not fully understood. Most studies have investigated 2 years of therapy and recovery. Whether 5 years of therapy affects the recoverability of ovarian function or not is unknown. The extent to which fertility is preserved in women receiving long-term ovarian suppression with GnRH agonists is also unknown. Isolated reports of breakthrough ovarian function in women who have substantial residual ovarian function (eg, in women younger than 35 years of age) have been reported. Breakthrough ovarian function in these women is managed through the regular monitoring of estradiol levels, which can help ensure continued ovarian suppression, as opposed to assuming that an amenorrhea state is equivalent to full ovarian suppression. Gonadotropin‑releasing hormone agonists possess fairly modest side effects that are similar to the effects of menopause. All individual side effects from GnRH agonists are associated with suppression of ovarian function. This can benefit patients by allowing them to experience the effects of menopause while still retaining a chance that ovarian function will return once treatment is stopped, in contrast to the immediate and final ovarian suppression with surgery. Although patients treated with GnRH agonists will not require surgery, it is necessary that they return to clinic monthly for injections during a long treatment course.
Following initial administration of ‘Zoladex’ 3.6mg depot, all the LHRH receptors on the surface of the pituitary cell become occupied by goserelin (Figure A) This results in a transient increase in serum LH, but the occupied LHRH receptors form clusters and gradually disappear into the cell, leading to a profound suppression of LH and, subsequently, of oestradiol New receptors are constantly resynthesised but, once again, they become occupied by the goserelin, which is continually released from the ‘Zoladex’ 3.6mg depot Hence, on chronic administration of ‘Zoladex’ 3.6mg, the continuous presence of goserelin prevents a sufficiently large amount of LHRH receptors from being stimulated by the pituitary gland to produce a normal amount of LH and, therefore, the production of oestrogens is suppressed to postmenopausal levels, essentially producing a ‘medical castration’ (Figure B) Reference Furr BJA. Hormone Res 1989; 32 (Suppl1): 86–92.
Oestrogens are the end-products of a complex sequence of steroid intermediates, involving the key cytochrome P-450 enzyme, aromatase The aromatase enzyme converts the androgens, androstenedione and testosterone, into the oestrogens, oestrone and oestradiol, respectively Non-selective aromatase inhibitors, such as aminoglutethimide, have actions on other cytochrome P-450 enzymes, such as 20,22-lyase, 17 -hydroxylase, 21 -hydroxylase, 11 -hydroxylase, 18-hydroxylase and 17,20-lyase. These result in unwanted side effects Selective aromatase inhibitors, such as formestane and anastrozole, inhibit only the aromatase enzyme
DeVita 2008
CR = Complete response PR = Partial response
The results of the studies by Taylor et al and Boccardo et al show that ‘Zoladex’ 3.6mg is an effective alternative to oophorectomy for the treatment of advanced breast cancer in premenopausal women with ER+/unknown tumours
Avrupa ve amerika çalışması
(AI hafif daha iyi)
third-generation aromatase inhibitors and inactivators (vorozole, letrozole, examestane, and anastrazole