1) There are multiple potential mechanisms of resistance to anti-HER2 therapies like trastuzumab, including impaired drug binding, altered downstream signaling, activation of alternate pathways, and inability to trigger immune responses.
2) While resistance continues to emerge through novel mechanisms, most affect common pathways and resistance is complex but not infinite.
3) Loss of the tumor suppressor PTEN has been associated with trastuzumab resistance in preclinical studies, but clinical data is limited and conflicting. The N9831 trial suggested PTEN loss may predict greater benefit from chemotherapy plus trastuzumab compared to chemotherapy alone.
What are the latest treatment advances for HER2-positive metastatic breast cancer? Eric Winer, MD, director of the Breast Cancer Program in the Susan F. Smith Center for Women's Cancers, discusses some of the latest research and treatment options.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held on October 17 at Dana-Farber Cancer Institute in Boston, Mass.
For more information, visit www.susanfsmith.org
Despite remarkable progress in the treatment of HER2+ breast cancer, management of this patient population continues to remain a challenge, both in the adjuvant and metastatic settings. An enhanced understanding of the treatment options available for HER2+ breast cancer patients in different settings is imperative to improving patient survival and quality of life. This activity consisting of didactic presentations and case illustrations will address treatment choices for HER2+ patients after trastuzumab progression; proposed mechanisms of resistance; combination treatment approaches; the role of anthracyclines and HER2-targeted agents in this population; and novel targeted agents under investigation, including mTOR inhibitors, antiangiogenic inhibitors, and HER2-targeted therapies.
More information:
http://imeronline.com/867dsd
Review a downloadable slide deck by Kathy D. Miller, MD, covering the most clinically relevant new data reported from Future Directions in the Treatment of Patients With HER2+ Breast Cancer: What Community Oncologists Need to Know.
Target Audience
This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of September 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
More information:
http://imeronline.com/867dsd
What are the latest treatment advances for HER2-positive metastatic breast cancer? Eric Winer, MD, director of the Breast Cancer Program in the Susan F. Smith Center for Women's Cancers, discusses some of the latest research and treatment options.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held on October 17 at Dana-Farber Cancer Institute in Boston, Mass.
For more information, visit www.susanfsmith.org
Despite remarkable progress in the treatment of HER2+ breast cancer, management of this patient population continues to remain a challenge, both in the adjuvant and metastatic settings. An enhanced understanding of the treatment options available for HER2+ breast cancer patients in different settings is imperative to improving patient survival and quality of life. This activity consisting of didactic presentations and case illustrations will address treatment choices for HER2+ patients after trastuzumab progression; proposed mechanisms of resistance; combination treatment approaches; the role of anthracyclines and HER2-targeted agents in this population; and novel targeted agents under investigation, including mTOR inhibitors, antiangiogenic inhibitors, and HER2-targeted therapies.
More information:
http://imeronline.com/867dsd
Review a downloadable slide deck by Kathy D. Miller, MD, covering the most clinically relevant new data reported from Future Directions in the Treatment of Patients With HER2+ Breast Cancer: What Community Oncologists Need to Know.
Target Audience
This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of September 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
More information:
http://imeronline.com/867dsd
CNS metastases in Her2+ mBC: does size matter?Mauricio Lema
Sponsored by Roche.
There is a debate In pretreated Her2+ mBC as to whether the indisputable benefit of T-DM1 (an antibody drug conjugate anti Her2) over lapatinib (a small anti Her2 TKI) seen in the EMILIA trial also translates to CNS disease. The subgroup analysis of the EMILIA clearly shows that patients with CNS disease do not appear to have worse outcomes when treated with the big (T-DM1) as opposed to the small (lapatinib) drug.
Her2Neu positive breast cancer is comprises of about 15-20% of all breast cancer. Among them quite a few number of patients present as de novo metastasis . In this presentation you ll find a guide how to manage it with relevant evidences. Presentation is meant for Oncology trainees.
What's the latest in breast cancer treatment and research? Erica Mayer, MD, MPH, a medical oncologist in the Susan F. Smith Center for Women's Cancers, shares the latest breast cancer news.
This presentation was originally given on Oct. 16, 2015, at the annual Young Women with Breast Cancer Forum, hosted by the Program for Young Women with Breast Cancer in the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, in Boston, Mass.
Learn more: http://www.susanfsmith.org
Join Dr. Erica Mayer, medical oncologist at Dana-Farber/Brigham and Women's Cancer Center, to learn about exciting metastatic breast cancer developments from the past year. Dr. Mayer presents an overview on metastatic breast cancer and the subgroups, including Hormone Receptive, HER2+, and Triple Negative, and highlights recent advances for each of these subgroups. She also discusses the importance of clinical trials and what it means to participate in a clinical trial.
For more information on the Breast Cancer Treatment Center at Dana-Farber Cancer Institute, please visit:
http://www.dana-farber.org/Adult-Care/Treatment-and-Support/Treatment-Centers-and-Clinical-Services/Breast-Cancer-Treatment-Center.aspx
Learn about the latest treatment options for advanced triple-negative breast cancer. Nancy Lin, MD, a breast oncologist in the Susan F. Smith Center for Women's Cancers at Dana-Farber, discusses new research.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held at Dana-Farber Cancer Institute in Boston, Mass. on Oct. 17, 2015.
More information is available at http://www.susanfsmith.org.
How can immunotherapy be used to treat metastatic breast cancer? Ian Krop, MD, PhD, discusses the latest research and treatment options.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held on October 17 and hosted by the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute in Boston, Mass.
For more information, visit www.susanfsmith.org
Despite remarkable progress in the treatment of breast cancer in recent years, management of estrogen receptor (ER)-positive disease remains a challenge. Through didactic and case presentations, expert faculty will address clinical debates regarding optimal treatment selection and the incorporation of new classes of targeted therapies into practice to improve outcomes and overcome resistance in the management of ER-positive breast cancer
Target Audience
This activity has been designed to meet the educational needs of medical oncologists and other healthcare providers who are involved in the care and treatment of patients with advanced estrogen receptor (ER)-positive breast cancer.
Purpose
The goal is to optimize the clinical decision-making of clinicians involved in the treatment of advanced ER-positive breast cancer by providing updates on emerging data.
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of August 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply.
More information:
http://imeronline.com/864dsd
CNS metastases in Her2+ mBC: does size matter?Mauricio Lema
Sponsored by Roche.
There is a debate In pretreated Her2+ mBC as to whether the indisputable benefit of T-DM1 (an antibody drug conjugate anti Her2) over lapatinib (a small anti Her2 TKI) seen in the EMILIA trial also translates to CNS disease. The subgroup analysis of the EMILIA clearly shows that patients with CNS disease do not appear to have worse outcomes when treated with the big (T-DM1) as opposed to the small (lapatinib) drug.
Her2Neu positive breast cancer is comprises of about 15-20% of all breast cancer. Among them quite a few number of patients present as de novo metastasis . In this presentation you ll find a guide how to manage it with relevant evidences. Presentation is meant for Oncology trainees.
What's the latest in breast cancer treatment and research? Erica Mayer, MD, MPH, a medical oncologist in the Susan F. Smith Center for Women's Cancers, shares the latest breast cancer news.
This presentation was originally given on Oct. 16, 2015, at the annual Young Women with Breast Cancer Forum, hosted by the Program for Young Women with Breast Cancer in the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, in Boston, Mass.
Learn more: http://www.susanfsmith.org
Join Dr. Erica Mayer, medical oncologist at Dana-Farber/Brigham and Women's Cancer Center, to learn about exciting metastatic breast cancer developments from the past year. Dr. Mayer presents an overview on metastatic breast cancer and the subgroups, including Hormone Receptive, HER2+, and Triple Negative, and highlights recent advances for each of these subgroups. She also discusses the importance of clinical trials and what it means to participate in a clinical trial.
For more information on the Breast Cancer Treatment Center at Dana-Farber Cancer Institute, please visit:
http://www.dana-farber.org/Adult-Care/Treatment-and-Support/Treatment-Centers-and-Clinical-Services/Breast-Cancer-Treatment-Center.aspx
Learn about the latest treatment options for advanced triple-negative breast cancer. Nancy Lin, MD, a breast oncologist in the Susan F. Smith Center for Women's Cancers at Dana-Farber, discusses new research.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held at Dana-Farber Cancer Institute in Boston, Mass. on Oct. 17, 2015.
More information is available at http://www.susanfsmith.org.
How can immunotherapy be used to treat metastatic breast cancer? Ian Krop, MD, PhD, discusses the latest research and treatment options.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held on October 17 and hosted by the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute in Boston, Mass.
For more information, visit www.susanfsmith.org
Despite remarkable progress in the treatment of breast cancer in recent years, management of estrogen receptor (ER)-positive disease remains a challenge. Through didactic and case presentations, expert faculty will address clinical debates regarding optimal treatment selection and the incorporation of new classes of targeted therapies into practice to improve outcomes and overcome resistance in the management of ER-positive breast cancer
Target Audience
This activity has been designed to meet the educational needs of medical oncologists and other healthcare providers who are involved in the care and treatment of patients with advanced estrogen receptor (ER)-positive breast cancer.
Purpose
The goal is to optimize the clinical decision-making of clinicians involved in the treatment of advanced ER-positive breast cancer by providing updates on emerging data.
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of August 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply.
More information:
http://imeronline.com/864dsd
Breast Cancer - Molecular Basis of HER2+ DiseaseFaryn
This presentation was part of a graduate level advanced molecular cell biology course. It reviews Breast Cancer epidemiology, signs 7 symptoms, diagnosis, genetic testing, hormonal testing and treatment options (briefly), then discusses the specifics of HER2+ cases at the cellular level. It shows how Herceptin and Tykerb work in the cell to block signal cascades, etc.
It is a PPT presentation talks about the magnitude of benefit from Adding Trastuzumab to Adjuvant Chemotherapy in Breast Cancer. It will discuss briefly the most important clinical evidence in this setting. The aim of such work is to know how worthy is to give your patient Trastuzumab with her adjuvant chemotherapy in your clinical practice as a medical oncologist.
Best of ASCO Metastatic Non-Small Cell Lung CancerH. Jack West
Dr. Jack West's presentation on highlights in advanced non-small cell lung cancer from ASCO 2014, focusing on new agents ramucirumab and necitumumab for broad NSCLC populations, crizotinib and ceritinib for ALK-positive NSCLC, EGFR inhibitor-options of afatinib and bevacizumab added to erlotinib for first line treatment of EGFR mutation-positive NSCLC, and AZD9291 or CO1686 for EGFR mutation-positive patients with acquired resistance.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
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.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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.
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.
CDSCO and Phamacovigilance {Regulatory body in India}NEHA GUPTA
The Central Drugs Standard Control Organization (CDSCO) is India's national regulatory body for pharmaceuticals and medical devices. Operating under the Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, the CDSCO is responsible for approving new drugs, conducting clinical trials, setting standards for drugs, controlling the quality of imported drugs, and coordinating the activities of State Drug Control Organizations by providing expert advice.
Pharmacovigilance, on the other hand, is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. The primary aim of pharmacovigilance is to ensure the safety and efficacy of medicines, thereby protecting public health.
In India, pharmacovigilance activities are monitored by the Pharmacovigilance Programme of India (PvPI), which works closely with CDSCO to collect, analyze, and act upon data regarding adverse drug reactions (ADRs). Together, they play a critical role in ensuring that the benefits of drugs outweigh their risks, maintaining high standards of patient safety, and promoting the rational use of medicines.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
Best Ayurvedic medicine for Gas and IndigestionSwastikAyurveda
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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
ABC1 - G.W. Sledge - Resistance to anti-HER2 therapies
1. Resistance to Anti-HER2 Therapy
George W. Sledge, Jr. MD
Indiana University
Simon Cancer Center
2. What Do We Mean by “Resistance”?
• ChemoRx resistance Throw away the drug
• Targeted therapy resistance:
– Is resistance absolute?
– Should we maintain selective pressure?
3. Trastuzumab treatment beyond progression sensitises
tumour cells to chemotherapy
Initial treatment Treatment beyond progression
Control
Tumour volume (mm3) Tumour volume (mm3) lgG 30
mg/kg
1000 1000
Trastuzumab
Control lgG
30 mg/kg 30 mg/kg
Paclitaxe
l 60
* Herceptin mg/kg
300 30 mg/kg 300
*
Trastuzumab +
100 100
paclitaxel
1 8 15 22 22 29 36 43 50 57
Days after treatment start Days after treatment start
MDA-MB-361 tumour xenograft; *p<0.05 by U-test
IgG, immunoglobulin; paclitaxelqw iv; Trastuzumab or IgGqwip Shirane et al 2005
4. Trastuzumab Benefits Beyond Progression
GBG 26/BIG 3-05
(Closed Early With Poor Accrual)
Capecitabine
Progression on
taxane + trastuzumab
Capecitabine + trastuzumab
von Minckwitz G, et al. J Clin Oncol. 2009:27:1999-2006.
5. Trastuzumab Remains Effective
After Progression
100
90 2-sided P
OR: P = .011 CB: 75.3%
80 CB: P = .0068 (95% CI: 64.2-84.4)
70
60 CB: 54.1%
% of pts
(95% CI: 42.1-65.7)
50
40 NC
>24wks
30
20 27.0% 48.1%
OR CR: 2.7% CR: 7.7%
(95% CI: 17.3-38.6) (95% CI: 36.5-59.7)
10 PR: 24.3% PR: 40.3%
0
X XH
OR = overall response = CR+PR
von Minckwitz G, et al. J Clin Oncol. 2009:27:1999-2006.
CB = clinical benefit = CR+PR+NC>24wks
6. Lapatinib + Trastuzumab Upon
Progression on Trastuzumab:
EGF104900
Lapatinib 1500 mg PO QD
(n = 148)
Primary endpoint:
Heavily pretreated patients PFS
Optional crossover to
with HER2-positive metastatic trastuzumabarm
breast cancer and if PD after 4 wks (n = 77) Secondary endpoints:
progression on trastuzumab OS
Lapatinib 1000 mg PO QD + ORR
(N = 296) Trastuzumab 4 mg/kg loading CBR
dose, then 2 mg/kg IV wkly
(n = 148)
Stratified by visceral disease
and hormone receptor status
PO, orally; QD, once daily.
Blackwell K, et al. SABCS 2009. Abstract 61.
7. Lapatinib + trastuzumab improves OS compared to
lapatinib in patients progressing on or after trastuzumab
Blackwell KL, et al. J ClinOncol2010; 28;1124–1130
8. Conclusion #1:
Trastuzumab resistance is incomplete,
and both switching chemotherapy and
combined HER2 inhibition benefit
patients progressing on trastuzumab.
Resistance is
Futile!
Locutis of Borg
9. But Is Resistance Futile?
No: Tumors
Trastuzumab keep finding
novel
resistance
HER2+ Cancer
mechanisms
10. What are the mechanisms of
resistance?
• Impaired trastuzumab binding
• Altered downstream signaling
• Signaling through an alternate receptor
• Failure to trigger an immune response
• Pharmacokinetic failures
11. Mechanisms of resistance (1)
Impaired trastuzumab binding to HER2:
• A constitutively active truncated form of HER2 receptor that
lacks binding site of trastuzumab (p95 HER2).
• Epitope masking by mucin 4 or CD44/polymeric hyaluronan
complex.
• Loss of HER2 complex Pohlmann PR, et al. Clin Cancer Res 20
12. Mechanisms of resistance (2)
• Altered HER2
downstream
signaling.
Increased ligand
production (ADAM17)
• Signaling through an
alternate receptor
pathway
Pohlmann PR, et al. Clin Cancer Res 2009
13. Mechanisms of resistance (3)
• Failure to trigger immune-mediated mechanisms to destroy tumor cells
FcγRIII F158 polymorphism interfere with antibody-dependent cellular
cytotoxicityfunction
Pohlmann PR, et al. Clin Cancer Res 2009
14. Trastuzumab Resistance:
The List Grows
• HER2 protein expression
• Sprouty 2 expression (via PTEN & ERK)
• Cyclin E amplification/overexpression; loss of
p27Kip1 (downstream HER2 effectors)
• Calpain inactivation (via pHER2 cleavage)
• miR21 upregulation (via PTEN)
• Loss of HER2 amplification (post-adjuvant Trast)
• Notch-1 overexpression
15. Pharmacokinetic Resistance: Inability to Penetrate the CNS
Lapatinibas 1st-Line Treatment in HER-2+ Advanced Breast
Cancer
Gomez HL et al, ASCO 2005, abstract #3046
Patient D: Brain Lesion Baseline and 12 Weeks
16. Lapatinib/RTK Resistance
• Many trastuzumab resistance mechanism do
not apply: (IGF-1, p95, PTEN, HER3, PI3K/AKT)
• Increased pSRC kinase (via PTEN/PI3K/AKT)
• Altered antiapoptotic proteins (MCL-1 and
survivin)
• Activated FOXO3a and increased expression of
estrogen receptor
• Quasi-resistance: lack of immune reponse
17. Conclusion #2:
There are many mechanisms of
resistance; most affect common
pathways.
Resistance mechanisms are complex
but not infinite.
19. PTEN Impact on Sensitivity or
Resistance to Trastuzumab
• Preclinical data suggest PTEN loss associated with
trastuzumab resistance
– O’Brien NA, 2010; Stemke-Hale K, 2008; Saal LH, 2005; Nagata Y,
2004
• Clinical data available to date: limited and conflicting
– PTEN loss associated with trastuzumab resistance
• Dave, 2011; Esteva, 2010,
Faratian, 2009 N = 122
– PTEN loss NOT associated with
trastuzumab resistance
• Fabi, 2010; Gori, 2009;
Yonemori, 2009
Faratian et al Cancer Res 69(16):6713–20
20. DFS by Treatment Arm for Pts with
PTEN Negative Tumors: N9831
100
90 AC →T+H → H
AC → T → H
80
Arm N Events HR 95% CI p 5yr
Event free (%)
70 DFS AC → T
A 176 53 72.3
B 146 38 0.85 0.55-1.30 0.44 77.8
60
A 176 53 72.3
C 138 19 0.47 0.28-0.79 0.005 86.7
50 B 146 38 77.8
C 138 19 0.56 0.32-0.97 0.04 86.7
40
0 1 2 3 4 5
Years from randomization
Perez EA, et al. ASCO 2011; Abst 79057
21. Multifactorial Resistance: Clinical Data
Mechanism/Reference Outcome (all significant p values)
• p95HER2/CCR 16:4226, 2010 • PFS HR = 1.9, OS HR = 2.2
• PTEN/Cancer Res 69:6713,2009 • OS HR = 3.0
• HER2 prot exp/Ann Oncol 22: • TTP HR = 3.7, OS HR = 2.0
2014,2011
• Sprouty 2/PLOS One 6: • OS HR = 2.28
e23772, 2011
• Cyclin E/PNAS 108: 3761, 2011 • Lower RR and PFS
• FcR Polymorphisms/JCO 26: • PFS HR = 5.3
1789, 2008
24. Conclusion #3:
Laboratory mechanisms of resistance have
not been confirmed in any meaningful
sense in the clinic:
1. We lack large data sets
2. Most studies are small, lack
confirmatory studies, level 4 evidence
3. Adjuvant studies can reject
metastatic hypotheses
4. Assays not validated and variable
5. Multifactorial resistance mechanisms
not examined
25. What are the Therapeutic Implications
of Resistance Mechanisms?
• Since different resistance mechanisms
affect different drugs, combined HER2
pathway blockade should be superior.
• Multifactorial nature of resistance
suggests that no single therapeutic
approach will overcome resistance.
26. What are the Therapeutic Implications
of Resistance Mechanisms?
• Since many resistance mechanisms have
common downstream effectors (e.g.,
mTOR), downstream inhibition may
prove useful.
• Improved measurement of resistance
mechanisms might improve targeting.
30. Figure 1 Proposed mechanisms of trastuzumab resistance
Nahta R et al. (2006) Mechanisms of Disease: understanding resistance to HER2-targeted therapy in human breast cancer
Nat Clin Pract Oncol 3: 269–280 doi:10.1038/ncponc0509
31. Figure 1 Molecular targets and therapeutic approaches in trastuzumab and lapatinib
resistance
Esteva, F. J.et al.(2009)Molecular predictors of response to trastuzumab and lapatinib in breast cancer
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2009.216
37. Trastuzumab-DM1 (T-DM1), is
designed to combine the anti-
tumor activity of trastuzumab
with a means of delivering highly
potent chemotherapy directly
into HER2-expressing cells.
DM-1 (also known as
maytansine) is an inhibitor of
tubulin polymerization, binding
tubulin competitively with vinca
alkaloids.
39. Analysis 1
DFS by Treatment Arm for Pts with
PTEN Positive Tumors
100
90 AC →T+H → H
80
AC → T → H
Arm N Events HR 95% CI p 5yr
Event free (%)
70 DFS AC → T
A 425 120 73.9
B 504 106 0.70 0.54-0.92 0.009 81.0
60
A 425 120 73.9
C 413 77 0.65 0.48-0.86 0.003 85.1
50 B 504 106 81.0
C 413 77 0.90 0.67-1.21 0.49 85.1
40
0 1 2 3 4 5
Years from randomization
Perez EA, et al. ASCO 2011; Abst 79057
40. Analysis 1
Impact of PTEN on DFS Based for Different Treatment
Arm Comparisons: N9831 Adjuvant
• Arm C vs Arm A
– PTEN+ HR: 0.65 (p=0.003)
Interaction p=0.16
– PTEN- HR: 0.47 (p=0.005)
• Arm B vs Arm A
– PTEN+ HR: 0.70 (p=0.009)
– PTEN- HR: 0.85 (p=0.44) Interaction p=0.47
• Arm C vs Arm B
– PTEN+ HR: 0.90 (p=0.49)
– PTEN- HR: 0.56 (p=0.04) Interaction p=0.08
Perez EA, et al. ASCO 2011; Abst 79057
42. Table 1 Characteristics and mechanisms of action of trastuzumab and lapatinib
Esteva, F. J.et al.(2009)Molecular predictors of response to trastuzumab and lapatinib in breast cancer
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2009.216
43. Table 3 Efficacy of HER2-directed therapy in trastuzumab-resistant metastatic breast
cancer
Esteva, F. J.et al.(2009)Molecular predictors of response to trastuzumab and lapatinib in breast cancer
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2009.216
44. Table 2 Treatment of HER2 breast cancer: trastuzumab-based combinations beyond
trastuzumab progression
Di Cosimo, S. & Baselga, J.(2010)Management of breast cancer with targeted agents: importance of heterogenicity
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2009.234
45. Figure 1 Overall response rates in HER2-positive and hormone
receptor-positive metastatic breast cancer
Cortés, J. et al.(2010)HER2 and hormone receptor-positive breast cancer—blocking the right target
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2010.185
46. Figure 2 Receptor cross-talk and response to therapy
Cortés, J. et al.(2010)HER2 and hormone receptor-positive breast cancer—blocking the right target
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2010.185
General mechanisms ofresistance to trastuzumab: obstacles fortrastuzumab binding to HER2. A, aconstitutively active truncated form ofHER2 receptor that has kinase activitybut lacks the extracellular domain andthe binding site of trastuzumab isoriginated from metalloproteasedependentcleavage of the full-lengthHER2 receptor (p185; refs. 45, 130).Trastuzumab does not bind to p95HER2and therefore has no effect against it.The remaining intracellular domain ofp95HER2 has operational kinasedomains and can be targeted by the TKinhibitor lapatinib (63)
B, epitopemasking by MUC4 or CD44/polymerichyaluronan complex. MUC4 is a largemembrane-associated mucin producedby epithelia as part of the epithelialprotective mechanisms. MUC4 hasmultiple repeat regions containingserine and threonine. Glycosylation ofthese repeats forces them into a highlyextended, rigid conformation andmakes them hydrophilic (69). MUC4 isnormally present on the apical surfacesof epithelial cells, but overexpressed inseveral carcinomas. MUC4 has closeassociation with HER2 and may masktrastuzumab cognate epitope,interfering with antibody binding andactivity. CD44/hyaluronan polymercomplex activates RAS and PI3Kpathways, but it is not clear if theseeffects depend on HER2. Inhibition ofhyaluronan synthesis in vitro reduceshyaluronan polymer binding to CD44,and increases trastuzumab binding toHER2.
Fig. 4. General mechanisms of resistance to trastuzumab: presence of upregulation of HER2 downstream signaling pathways. PTEN is a tumor suppressor.Trastuzumab binding stabilizes and activates PTEN and consequently down-regulates the PI3K/Akt signaling pathway (39). When PTEN function is lost,PI3K remains constitutively active regardless of binding of trastuzumab to HER2. PTEN loss correlates with clinical unresponsiveness to trastuzumabtreatment. Genomic aberrations in the PI3K pathway are a common event in a variety of cancer types (127). Multiple components of this pathway are affectedby germline or somatic mutation, amplification, rearrangement, methylation, overexpression, and aberrant splicing, but only in a few instances PIK3CAand PTEN mutations are seen simultaneously (86). Genomic aberrations in the PI3K pathway produce constitutive activation of the pathway, which will signaldownstream to the nucleus regardless of trastuzumab binding to HER2. This is the case with activating mutations of PIK3R1 and PIK3CA, encoding genesfor PI3K p85α and p110α, respectively. Increased Akt kinase activity and PDPK1 overexpression have also been implicated with trastuzumab resistance.
Fig. 5. General mechanisms of resistance to trastuzumab: presence of signaling through an alternate receptor and/or pathway. Signaling may continueregardless of trastuzumab binding to HER2 when other receptors remain active on the tumor cell. The activity of certain receptors may also increase as aresult of trastuzumab blockage of HER2, as a cell survival mechanism (see text for details). Trastuzumab-induced growth inhibition in HER2-overexpressingcells can be compensated for by increased IGF-IR signaling, resulting in resistance to trastuzumab. In preclinical models in which HER2-overexpressingtumor cells are cultured in the presence of ligand, resembling what is likely to happen in vivo, trastuzumab does not interfere with HER2/HER3heterodimerization and therefore does not block signaling from these heterodimers (42). c-Met is frequently co-expressed with HER2 in cell lines andcontributes to trastuzumab resistance through sustained Akt activation.
Fig. 6. General mechanisms of resistance to trastuzumab: failure to trigger immune-mediated mechanisms to destroy tumor cells. ADCC is a process inwhich the Fab region of an antibody binds to its cognate antigen present on a target cell (for instance cancer cell), whereas its Fc region engages with the Fcreceptor present on an effector cell from immune system. This process triggers degranulation of cytotoxic granules from effector cell toward the target celland culminates with target cell apoptosis (131). In humans, the Fc receptor family comprises FcγRI (CD64); FcγRII (CD32), with three isoforms FcγRIIa, FcγRIIb(inhibitory), and FcγRIIc; and FcγRIII (CD16), including two isoforms FcγRIIIa and FcγRIIIb (132). There is a correlation between the clinical efficacy oftherapeutic antibodies in humans and their allotype of high-affinity (V158) or low-affinity (F158) polymorphic forms of FcγRIIIa. Epitope masking previouslydiscussed in the obstacles for trastuzumab binding to HER2 section would also play a role by preventing antibody-based cell destruction
The investigational agent, trastuzumab-DM1 (T-DM1), is designed to combine the anti-tumor activity of trastuzumab with a means of delivering highly potent chemotherapy directly into HER2-expressing cells. DM-1 (also known as maytansine) is an inhibitor of tubulin polymerization, binding tubulin competitively with vinca alkaloids. Compared with drugs like vincristine, however, it is 20 to 100 times more potent, said principal investigator Murali Beeram, MD, of the Institute for Drug Development, San Antonio. "DM-1 was developed in 1975 but was found to be too toxic for standard chemotherapy," Dr. Beeram said. "We tagged it in a very small amount to the trastuzumab molecule with a linker. The linker provides a stable bond between the two agents that is designed to prolong exposure and reduce the toxicity of T-DM1. We are, in essence, sending a chemotherapy payload into the cell via the antibody. We get a twofold effect—an increase in the efficacy of trastuzumab and direct delivery of the cytotoxic agent, which reduces treatment toxicity." The compound was well tolerated. The only grade 3-4 toxicity was a rapidly reversible grade 4 thrombocytopenia at the highest dose in one patientA phase II trial of the immunoconjugate is being initiated in HER2-positive metastatic breast cancer patients. Genentech, which is developing the new agent, has enlisted ImmunoGen, Inc. to develop a commercial-scale process for making T-DM1, using ImmunoGen's tumor-activated prodrug (TAP) technology.