11-Surgical Oncology PDF

SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… rate of development of a disease. Wordy ba ssob? Haha k kaya mo ean, ean nmn...

SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… rate of development of a disease. Wordy ba ssob? Haha k kaya mo ean, ean nmn Case-control study compares a group of patients cnabi ni doc, kung may angal ka, lika sa 6th floor affected with a disease to a group of individuals kiss kta :P without the disease and looks back retrospectively to compare how frequently the exposure to a risk factor is present in each group to determine the relationship between the risk factor and the disease. ○ A relative risk 1 SURGICAL ONCOLOGY indicates an increased risk of developing the disease with exposure. Surgical oncology is very important in Surgical practice. The surgeon often is responsible for the initial diagnosis and management of solid tumors. Knowledge of cancer epidemiology, etiology, staging, and natural history is required for initial patient assessment, as well as to determine the optimal surgical therapy. Primary Surgical Therapy (Definitive) - en bloc resection of tumor with adequate margins of normal tissues and regional lymph nodes.. Adjuvant Therapy - radiation therapy, chemotherapy, immunotherapy, hormonal therapy, and biologic therapy. Ang primary goal ng surgical and radiation therapy ay local and regional control, itong si Adjuvant therapy naman systemic control by treatment of distant foci of subclinical disease para i prevent ang recurrence Modern cancer therapy is Multidisciplinary, involving the coordinated care of patients by surgeons, medical This table shows the Ten leading cancer types with the oncologists, radiation oncologists, reconstructive surgeons, estimated new cancer cases and deaths by sex in the pathologists, radiologists, and primary care physicians. United States, 2013. Cancer therapy is becoming Personalized, incorporating information about each patient’s tumor characteristics, The most common causes of cancer death in Ekalal are patient’s own genome, as well as host immune responses and cancers of the lung and bronchus, colon and rectum, and tumor microenvironment, therefore essential that surgeons prostate; in Eabab, the most common cancers are of the lung understand the principles of Molecular oncology to and bronchus, breast, and colon and rectum. These four appropriately interpret these new findings and incorporate cancers account for almost half of total cancer deaths them into practice. among men and women. Check niyo n lng table boss ya, doc mentioned this kase, don’t skip pictures sa baba ah doc emphasized kase na may iba ron na lalabas sayang nmn mga ponts ssob lodicakes BASIC PRINCIPLES OF CANCER EPIDEMIOLOGY The incidence of cancer Varies by geography. This is due in part to genetic differences and in part to differences in environmental and dietary exposures. HALLMARK OF CANCER Incidence refers to the number of new cases occurring. Incidence is usually expressed as the number of new Although there are >100 types of cancer, it has been cases per 100,000 persons per year. proposed that there are six essential alterations in cell Mortality refers to the number of deaths occurring and is physiology that dictate malignant growth: expressed as the number of deaths per 100,000 persons per year. 1. Self-sufficiency of growth signals, The two types of epidemiologic studies that are usually 2. Insensitivity to growth-inhibitory signals, conducted to investigate the etiology of cancer and the 3. Evasion of apoptosis (programmed cell death), effect of prevention modalities. These are the cohort 4. Potential for limitless replication, studies and case-control studies. 5. Angiogenesis, 6. Invasion and Metastasis. Cohort studies follow a group of people who initially do not have a disease over time and measure the KUMUNOY’S IMPROPERTY 1 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… Recently two additional hallmarks have been identified: reprogramming of energy metabolism and evading immune destruction. These hallmarks of cancer are being pursued as targets for cancer therapy. CELL PROLIFERATION AND TRANSFORMATION In Normal cells, cell growth and proliferation are under strict control. In Cancer cells, cells become unresponsive to normal growth controls, which leads to uncontrolled cell division. ○ Human cells require several genetic changes for neoplastic transformation. Abnormally proliferating, transformed cells outgrow normal cells in the culture dish (i.e., in vitro) and commonly display several abnormal characteristics. ○ These include Loss of contact inhibition (i.e., cells continue to proliferate after a confluent monolayer is formed); ○ An Altered appearance and poor adherence to other cells or to the substratum; ○ Loss of anchorage dependence for growth; ○ Immortalization; ○ Gain of tumorigenicity (i.e., the ability to give rise to tumors when injected into an appropriate host). CANCER INITIATION Tumorigenesis is proposed to have three steps: Initiation, Promotion, and Progression. Initiating events such as gain of function of genes known as Oncogenes or loss of function of genes known as Tumor-suppressor genes, which may lead a single cell to acquire a distinct growth advantage. Tumors usually arise from a single cell or clone, it is thought that sometimes not a single cell but rather a large number of cells in a target organ may have under- gone the initiating genetic event. Thus, many normal-appearing The normal cell cycle. it is divided into four phases. cells may have an increased malignant potential. This is During the synthetic or S phase, the cell generates a referred to as a Field effect. single copy of its genetic material,whereas in the Mutations in at least four or five genes are required for mitotic or M phase, the cellular components formation of a malignant tumor, fewer changes results to (including copies of DNA) are partitioned between a benign tumor. two daughter cells. The G1 and G2 phases represent Gene expression is a multistep process that starts from gap phases, during which the cells prepare Transcription of a gene into messenger ribonucleic acid themselves for completion of the S and M phases, (mRNA) and then Translation of this sequence into the respectively.When cells cease proliferation, they exit functional protein. the cell cycle and enter the quiescent state referred to as G0 CELL-CYCLE DYSREGULATION IN CANCER ONCOGENES The proliferative advantage of tumor cells is a result of their ONCOGENES ability to bypass a quiescent state. Oncogenes are abnormal genes that cause cancer. The Mutations or alterations in: normal counterpart of such a gene is referred to as a Proto-oncogene. 1. Expression of cell-cycle proteins, Oncogenes are usually designated by three-letter 2. Growth factors, abbreviations, such as MYC or RAS. 3. Growth factor receptors, Oncogenes are further designated by the prefix “v-” for 4. Intracellular signal transduction proteins, virus or “c-” for cell or chromosome, 5. Nuclear transcription factor Proto-oncogenes can be activated (show increased activity) or overexpressed (expressed at increased These all can lead to disturbance of the basic regulatory protein levels) by translocation (e.g., abl), promoter mechanisms that control the cell cycle, allowing unregulated insertion (e.g., c-myc), mutation (e.g., ras), or cell growth and proliferation. amplification (e.g., HER2/neu). KUMUNOY’S IMPROPERTY 2 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… CANCER INVASION Akays niyo na to mga ssob, dein na need ng ratio nito, susumbong ko kayo kay Doc Bringas at Doc Pereira!!! A feature of malignant cells in their ability to invade the surrounding normal tissue. ALTERNATION IN APOPTOSIS AND AUTOPHAGY In situ cancer → Tumors in which the malignant cells appear to lie exclusively above the basement Apoptosis is a genetically regulated program to dispose of cells. Cancer cells must avoid apoptosis for tumors to membrane. form. Invasive cancer → Tumors in which the malignant cells are Apoptotic cells are then engulfed and degraded by demonstrated to breach the basement membrane, phagocytic cells. The effectors of apoptosis are a family penetrating into surrounding stroma. of proteases called Caspases (cysteine-dependent and aspartate-directed proteases) Cell-to-cell adhesion in normal cells involves interactions Mitochondrial pathway or intrinsic pathway, death results between cell-surface proteins. Calcium adhesion from the release of cytochrome c from the mitochondria. molecules of the cadherin family (E-cadherin, P- Cytochrome c, Procaspase 9, Apoptotic Protease Activating factor (Apaf 1) → Form Apoptosome → cadherin, and N-cadherin) are thought to enhance the Activate effector Caspases. cells’ ability to bind to one another and suppress invasion. Smac/Diablo (Second mitochondria-derived activator of Migration occurs when cancer cells penetrate and attach caspase/Direct inhibitor of apoptosis-binding protein with to the basal matrix of the tissue being invaded low pI - proapoptotic protein in the mitochondria. The mitochondrial pathway can be stimulated by many This allows the cancer cell to pull itself forward within the factors, including DNA damage, reactive oxygen tissue by attachment to glycoproteins of the ECM such as species, or the withdrawal of survival factors. The fibronectin, laminin, and collagen is mediated by tumor permeability of the mitochondrial membrane determines cell integrin receptors. whether the apoptotic pathway will proceed. This neovascularization is essential for tumor growth and ○ Bcl-2 family - (Bax, BAD, and Bak) and antiapoptotic metastasis. proteins (e.g., Bcl-2 and Bcl-xL). Tumors develop an angiogenic phenotype as a result of The activity of the Bcl-2 proteins is centered on the accumulated genetic alterations and in response to local mitochondria, where they regulate membrane permeability selection pressures such as hypoxia. ○ PI3K/Akt pathway - phosphorylates and inactivates ○ Many of the common oncogenes and tumor- proapoptotic BAD. growth factor withdrawal may suppressor genes have been shown to play a role in promote apoptosis through signaling by the induction of angiogenesis. unphosphorylated BAD. In response to the angiogenic switch, pericytes retract ○ Hsp70 and Hsp27 - involved in inhibition of and the endothelium secretes several growth factors downstream apoptotic pathways by blocking such as: formation of the apoptosome complex and inhibiting release of cytochrome c from the ○ Basic fibroblash growth factor mitochondria. ○ Platelet derived growth factor (PDGF) Apoptotic pathway is the death receptor pathway, ○ Insulin-like growth factor sometimes referred to as the extrinsic pathway. The death The basement membrane and stroma around the receptor pathway may be regulated at the cell surface by the expression of “decoy” receptors for Fas (DcR3) and capillary are proteolytically degraded, a process that is TRAIL (TRID and TRUNDD). mediated in most part by uPA. Cell-surface death receptors include: The endothelium then migrates through the degraded i. Fas/APO1/CD95 (Ligand: Fas-L) matrix, initially as a solid cord and later forming lumina. ii. TNF1 (Ligand: TNF) iii. KILL-ER/DR5 (Ligand: TRAIL - TNF Apoptosis Inducing Finally, sprouting tips anastomose to form a vascular Ligand) network surrounded by a basement membrane. When receptors are bound to their ligand → form a Angiogenesis is mediated by factors produced by various death induced signaling complex (DISC) → procaspase 8 and 10 cleavage → generates active cells, including tumor cells, endothelial cells, stromal cells, initiator complexes and inflammatory cells. Autophagy (self-eating) is a major cellular pathway for Of the Angiogenic stimulators, the best studied are the protein and organelle turnover. The autophagic pathway vascular endothelial growth factors (VEGFs). is a mechanism for the delivery of cellular materials to lysosomes for degradation. Autophagy is also involved in The VEGF family consists of six growth factors and three the elimination of cancer cells by triggering a receptors nonapoptotic cell death program KUMUNOY’S IMPROPERTY 3 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… VEGF Family Growth Factors (6) Receptors (3) VEGF-A VEGFR1 or Flt-1 VEGF-B VEGFR2 or KDR/FLK-1 VEGF-C VEGFR3 or Flt-4 VEGF-D VEGF-E Placental growth factor Neuropilin 1 and 2 → may also act as receptors for VEGF Blood vessel maturation - angiopoietins ○ Angiopoietin-1 (Ang-1) ○ Angiopoietin-2 (Ang-2) Tumor angiogenesis is regulated by several factors in a coordinated fashion. In addition to upregulation of proangiogenic molecules, angiogenesis also can be encouraged by suppression of naturally occurring Schematic representation of metastatic process A. The metastatic process begins with an in situ inhibitors. cancer surrounded by an intact basement ○ Upregulation of proangiogenic molecule membrane. ○ Inhibitors (Thrombospondin 1 and Angiostatin) B. Invasion requires reversible changes in cell-cell and cell-extracellular matrix adherence, destruction of proteins in the matrix and stroma, and motility. C. Metastasizing cells can enter the circulation via the lymphatics. D. They can also directly enter the circulation. E. Intravascular survival of the tumor cells and extravasation of the circulatory system follow. F. Metastatic single cells can colonize sites and remain dormant for years as occult micrometastases G. Subsequent progression and neovascularization leads to clinically detectable metastases Overall, metastasis is an inefficient process. Although the initial steps of hematogenous metastasis (the arrest of tumor cells in the organ and extravasation) are believed to be performed efficiently Only a small subset of cancer cells is then able to initiate micrometastases, and an even smaller portion goes on to grow into macrometastases. Dormancy → Metastases can sometimes arise several years after the treatment of primary tumors ○ Example: although most breast cancer METASTASIS recurrences occur within the first 10 years Metastases arise from the spread of cancer cells from after the initial treatment and recurrences the primary site and the formation of new tumors in are rare after 20 years, breast cancer distant sites. recurrences have been reported decades The metastatic process consists of a series of steps that after the original tumor. need to be completed successfully: ○ Dormancy remains the biggest challenge in cancer biology KUMUNOY’S IMPROPERTY 4 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… ○ Persistence of solitary cancer cells in a secondary site such as the liver or bone marrow is one possible contributor to dormancy. Another explanation of dormancy is that cells remain viable in a quiescent state and then become reactivated by a physiologically perturbing event. An alternate explanation is that cells establish preangiogenic metastases in which they continue to proliferate but that the proliferative rate is balanced by the apoptotic rate. ○ Therefore, when these small metastases acquire the ability to become vascularized, substantial tumor growth can be achieved at the metastatic site, leading to clinical detection. Several types of tumors metastasize in an organ- specific pattern. ○ Mechanical - Circulatory drainage ○ “Seed and soil” theory - compatibility to the new environment Many of the oncogenes discovered to date, such as HER2 and ras, are thought to potentiate not only malignant transformation but also one or more of the steps required in the metastatic process Metastatic potential of a tumor is already predetermined by the genetic alterations that the cancer cells acquire early in tumorigenesis CANCER GENOMICS Cancer is a genetic disease that arises from an accumulation of genomic alterations. These alterations may lead to either: ○ Gain of function by oncogenes ○ Loss of function by tumor-suppressor genes. Somatic mutations → acquired gene alterations present within the tumor; to distinguish them from germline mutations ○ DNA sequence changes (substitution, insertions, deletions, rearrangements, copy number losses and gains) ○ Somatic mutations in cancer cell genome have accumulated over the lifetime of the patient Germline mutations → inherited from parents and transmitted to offspring. KUMUNOY’S IMPROPERTY 5 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… DNA in normal cells is continuously damaged by internal and external mutagens. Most of this damage is repaired; however, a small fraction may remain as fixed mutations. Mutation rates increase in the presence of substantial exogenous mutagenic exposures, such as tobacco carcinogens or various forms of radiation, including ultraviolet light Somatic mutations are also increased in several rare inherited diseases such as: ○ Fanconi anemia, ○ Ataxia telangiectasia ○ Xeroderma pigmentosum To date about 300 genes that have been reported to be mutated and implicated in cancer development GENES ASSOCIATED WITH HEREDITARY CANCER RISK Human cancer genes have been gained from hereditary cancers. Hereditary cancers → the individual carries a particular germline mutation in every cell. To date, over 70 genes have been associated with hereditary cancers A few of these hereditary cancer genes are oncogenes, but most are tumor-suppressor genes Factors that may suggest presence of hereditary cancer 1. Tumor development at a much younger age than usual BRCA1, BRCA 2 AND HEREDITARY BREAST-OVARIAN 2. Presence of bilateral disease 3. Presence of multiple primary malignancies CANCER SYNDROME 4. Presentation of a cancer in the less affected sex It is estimated that 5% to 10% of breast cancers are (e.g., male breast cancer) hereditary. 5. Clustering of the same cancer type in relatives Of women with early-onset breast cancer (age 40 years 6. Occurrence of cancer in association with other or younger), nearly 10% have a germline mutation in one conditions such as mental retardation or pathognomonic skin lesions of the breast cancer genes BRCA1 or BRCA2. The cumulative risks of breast cancer and ovarian It is crucial that all surgeons caring for cancer patients cancer by age 70 in families with BRCA2 mutation have be aware of hereditary cancer syndromes, because been estimated to be 84% and 27%, respectively. a patient’s genetic background has significant implications for patient and family counseling, APC GENE AND FAMILIAL ADENOMATOUS POLYPOSIS planning of surgical therapy, and cancer screening Patients affected with familial adenomatous polyposis (FAP) characteristically develop hundreds to thousands and prevention of polyps in the colon and rectum. The polyps usually appear in adolescence and, if left GENES ASSOCIATED WITH HEREDITARY CANCER RISK untreated, progress to colorectal cancer. The product of the adenomatous polyposis coli tumor- suppressor gene (APC) plays an important role in: ○ Cell-cell interactions ○ Cell adhesion ○ Regulation of β-catenin ○ Maintenance of cytoskeletal microtubules KUMUNOY’S IMPROPERTY 6 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… Alterations in APC lead to dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, including: ○ Cell-cycle progression ○ Migration ○ Differentiation ○ Apoptosis MISMATCH REPAIR GENES AND HEREDITARY NONPOLYPOSIS COLORECTAL CANCER Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch Syndrome ○ Lynch Syndrome → autosomal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis Lynch Syndrome 1 Lynch Syndrome 2 Early age of onset at Similar colonic phenotype 44 years old accompanied by: High risk for carcinoma of the endometrium Transitional cell carcinoma of the ureter and renal pelvis Carcinomas of the stomach, small bowel, ovary, and pancreas Diagnostic Criteria for HNPCC → referred to as the Amsterdam criteria, or the 3-2- 1-0 rule. RB1 GENE ○ The classic Amsterdam criteria were revised The retinoblastoma gene rb1 was the first tumor to include other HNPCC-related cancers. suppressor to be cloned. These criteria are met when: The rb1 gene product, the Rb protein, is a regulator of ○ Three or more family members have transcription that controls the following in normal histologically verified, HNPCC-associated development: cancers (one of whom is a first-degree ○ Cell cycle relative of the other two) ○ Differentiation ○ Two or more generations are involved, at ○ Apoptosis least one individual was diagnosed before age 50 years, Most children with an affected parent develop ○ No individuals have FAP bilateral retinoblastoma, some develop unilateral retinoblastoma. RET PROTO-ONCOGENE AND MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 The RET (rearranged during transfection) gene → encodes for a transmembrane receptor tyrosine kinase that plays a role in proliferation, migration, and differentiation of cells derived from the neural crest. RET gene are associated with: KUMUNOY’S IMPROPERTY 7 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… arrest or apoptosis. A majority of p53 mutations are Medullary thyroid carcinoma in found within a central DNA recognition motif and disrupt isolation or DNA binding by p53. Multiple endocrine neoplasia type 2 (MEN2) syndromes. Criteria for classic LFS in an individual (the proband) MEN2A associated with: Medullary thyroid carcinoma and A. a bone or soft tissue sarcoma when younger pheochromocytoma (in 50%) or than 45 years parathyroid adenoma (in 20%) B. a first-degree relative with cancer before age 45 MEN2B associated with: years Medullary thyroid carcinoma Maranoid habitus C. another first- or second-degree relative with Mucosal neuromas, and either a sarcoma diagnosed at any age or any cancer diagnosed before age 45 years Ganglioneuromatosis of the gastrointestinal tract CARCINOGENS The first report indicating that cancer could be caused by environmental factors was by John Hill, in 1761 he noted the association between nasal cancer and excessive use of tobacco snuff Currently, approximately 60% to 90% of cancers are thought to be due to environmental factors. Any agent that can contribute to tumor formation is referred to as a carcinogen and can be a: ○ Chemical ○ Physical ○ Viral agent CHEMICAL CARCINOGENS Classified into three groups based on how they contribute to tumor formation: First Group Genotoxins → can initiate carcinogenesis by causing a mutation Second Group Cocarcinogens → by themselves cannot cause cancer but potentiate carcinogenesis by enhancing the P53 AND LI-FRAUMENI SYNDROME potency of genotoxins. Li-Fraumeni syndrome (LFS) was first defined on the basis of observed clustering of malignancies, including: Third Group Tumor promoters → enhances tumor ○ Early-onset breast cancer formation when given after exposure to ○ Soft tissue sarcomas genotoxins. ○ Brain tumors ○ Adrenocortical tumors ○ Leukemia PHYSICAL CARCINOGENS Can occur through induction of inflammation and cell Approximately 70% of LFS families have been shown to proliferation over a period of time or through exposure to have germline mutations in the tumor-suppressor gene physical agents that induce DNA damage p53. Chronic irritation and inflammation that been P53 is the most commonly mutated within cancer cells. associated with an increased risk of cancer: When cells are exposed to stressors, p53 acts as a ○ Chronic nonhealing wounds transcription factor for genes that induce cell-cycle KUMUNOY’S IMPROPERTY 8 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… ○ Burns ○ Inflammatory bowel syndrome H pylori infection is associated with gastritis and gastric cancer Lung and mesothelial cancers by asbestos fibers and silica are other examples of foreign body-induced physical carcinogenesis Radiation is the best-known agent of physical carcinogens and is classified as ionizing radiation: ○ X-rays ○ Gamma rays ○ Alpha and beta particles or nonionizing radiation (UV) Radiation can induce a spectrum of DNA lesions that includes damage to the nucleotide bases and cross- linking, and DNA single- and double-strand breaks (DSBs) which causes chromosomal abnormalities and gene mutation. VIRAL CARCINOGENS At present, several human viruses are known to have oncogenic properties, and several have been causally linked to human cancers Viruses may cause or increase the risk of malignancy through several mechanisms including: ○ Direct transformation ○ Expression of oncogenes that interfere with cell-cycle check- points or DNA repair ○ Expression of cytokines or other growth factors ○ Alteration of the immune system Oncogenic viruses may be RNA or DNA viruses. Important part of the initial evaluation of any patient. A patient’s cancer risk not only is an important determinant of cancer screening recommendations but also may alter how aggressively an indeterminant finding will be pursued for diagnosis KUMUNOY’S IMPROPERTY 9 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… specimens, and has cost implications for the Cancer risk assessment starts with taking a complete health care system. history that includes history of environmental exposures to Screening guidelines potential carcinogens and a detailed family history. ○ updated periodically to incorporate Risk assessment for breast cancer, for example, emerging technologies and new data on includes obtaining a family history to determine the efficacy of screening measures. whether another member of the family is known to carry a breast cancer susceptibility gene TUMOR MARKERS Tumor markers are substances that can be detected There are several models that can estimate risk in higher than normal amounts in the serum, urine, or based on complex family histories and assist tissues of patients with certain types of cancer. clinicians in estimating breast cancer risk or the Tumor markers are produced either by the cancer likelihood that a BRCA mutation is present including: cells themselves or by the body in a response to the ○ Claus model cancer. ○ Tyrer-Cuzick model Prognostic marker and predictive marker are ○ BRCAPRO model sometimes used interchangeably ○ Breast and Ovarian Analysis of Dis- ease Prognostic Marker → generally is used to describe Incidence and Carrier Estimation Algorithm molecular markers that predict disease-free survival, (BOADICEA) disease-specific survival, and overall survival Gail Model → One of the most commonly used Predictive Tissue Markers → used in the context of models for risk assessment in breast cancer predicting response to certain therapies; can prospectively ○ uses risk factors such as: identify patients who will benefit from a certain therapy an individual’s age, age at menarche, Predictive Markers (Examples; Breast Cancer) age at first live birth, number of first-degree relatives with breast cancer, Estrogen Assessment can identify patients who number of previous breast biopsy receptor (ER) can benefit from anti- estrogen therapies specimens, and (e.g., tamoxifen) whether the biopsy specimen results HER2 Anti-HER2 targeted therapies (e.g., revealed atypical ductal trastuzumab) hyperplasia Oncotype DX Can be used to predict recurrence in CANCER SCREENING assay women with node-negative, ER-positive Early detection is the key to success in cancer breast cancer who are treated with therapy tamoxifen ○ Screening for common cancers using relatively noninvasive tests is expected to MammaPrint (Gene expression profiling platform lead to early diagnosis, allow more assessing a 70-gene transcriptional conservative surgical therapies with signature) decreased morbidity, and potentially The usefulness of this assay in making improve surgical cure rates and overall therapy-related decisions was tested survival rates prospectively in a large-scale study, the How prevalent the cancer is in the population Microarray in Node-Negative Disease ○ Key factors that influence screening May Avoid Chemotherapy (MIND- ACT) guidelines are how prevalent the cancer is trial. in the population, what risk is associated with the screening measure, and whether early diagnosis actually affects outcome. Serum markers → are under active investigation False-positive screening because they may allow early diagnosis of a new ○ likely to induce significant emotional distress cancer or may be used to follow cancer response to in patients, leads to unnecessary biopsy therapy or monitor for recurrence KUMUNOY’S IMPROPERTY 10 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… Serum Markers ASPIRATION information on tissue architecture BIOPSY (FNAB) Can make the diagnosis of malignancy BUT cannot differentiate PSA (Prostate Levels may be elevated in the blood invasive and non-invasive tumors. specific antigen) of men with benign prostate conditions such as: Easy and relatively safe like FNAB Prostatitis and BPH (benign Performed either by direct palpation prostatic hyperplasia,) (e.g., a breast mass or a soft tissue mass) or can be guided by an Men with prostate cancer. CORE NEEDLE imaging study. BIOPSY (CNB) Disadvantage of sampling error CEA Elevated CEA levels have been Ensure that histologic findings are (carcinoembryo detected in patients with: consistent with clinical scenario and nic antigen) Primary colorectal cancer know appropriate interpretation of Breast, lung, ovarian, prostate, each histologic finding. liver, and pancreatic cancer. Advantage of providing MORE AFP (Alpha- a glycoprotein normally produced by TISSUE FOR HISTOLOGIC EVALUATION Fetoprotein) INCISIONAL Disadvantage of being an a developing fetus. elevated level of BIOPSY OPERATIVE PROCEDURE AFP suggests the presence of either: Reserved for very large lesions in primary liver cancer or a which a definitive diagnosis cannot germ cell tumor of the ovary be made by CNB. or testicle. Should be performed with curative CA 19-9 can be measured at the start of EXCISION BIOPSY intent - obtaining adequate tissue around the lesion to ensure therapy and every 1 to 3 months while NEGATIVE SURGICAL MARGINS therapy is given; elevations in serial CA 19-9 levels may indicate progressive Biopsy findings determine the TUMOR HISTOLOGY and disease and should be confirmed by GRADE - Assist in therapeutic planning. additional studies CANCER STAGING CANCER DIAGNOSIS Cancer staging is a system used to describe the anatomic Definitive diagnosis of solid tumors - obtained by extent of a malignant process in an individual patient performing a biopsy specimen of the lesion. Staging systems may incorporate relevant clinical PROCEDURE DEFINITION PROGNOSTIC FACTORS such as: ○ Tumor size Colonoscope, Gastroscope, ○ Location ENDOSCOPIC Bronchoscope, Cystoscope ○ Extent BIOPSY Biopsy specimen of mucosal lesions ○ Grade are usually obtained endoscopically ○ Dissemination to regional lymph nodes or distant sites (Distant metastasis) Lesions that are easily palpable, PUNCH BIOPSY such as those of the skin, can either Neoplasia I and II baka naman mga teh??? Diba ang cancer be excised or sampled by punch staging is defined in terms of three anatomic diseases? Oh biopsy. ano nga ulit yon??? Diba T-Size of the primary tumor, N- Presence (or absence) and extent of nodal metastases, then M-Presence (or absence) and extent of distant metastases, CT SCAN OR Deep seated lesions can be SO ANO??? TNM STAGING YAN JUSKO. Yun lang din sinasabi ULTRASOUND localized with CT scan or ultrasound GUIDED guidance for acquisition of biopsy ng mga bullet points diyan. specimens. Accurate staging is essential in designing an appropriate treatment regimen for the patient ○ E.g., Patient with Breast CA - Staging workup would Easy and relatively safe include a radiograph, bone scan, and liver FINE NEEDLE Disadvantage of not giving KUMUNOY’S IMPROPERTY 11 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… ultrasound or CT scans to evaluate for lung, bone, and It is generally accepted that a formal lymphadenectomy liver metastases respectively. is likely to minimize the risk of regional recurrence of most In recent years - Increased usage of molecular imaging cancers. such as PET scan, or PET/CT which uses ○ E.g., the introduction of mesorectal excision of rectal flurorodeoxyglucose (FDG) cancer has been associated with decline in local- ○ FDG PET assesses the rate of glycolysis regional recurrence, and this procedure has TNM staging applies only to tumors that have been become the new standard of operative microscopically confirmed to be malignant. management. Lymphatic mapping ○ Performed in clinically negative LN by using ISOSULFAN BLUE DYE, TECHNETIUM-LABELED SULFUR COLLOID or albumin, or a combination of both techniques to detect sentinel nodes. ○ Sentinel nodes - the first node to receive drainage from the tumor site, and MOST LIKELY CONTAIN MULTIDISCIPLINARY APPROACH METASTASES. ○ To improve patient survival rates, a multimodality approach, including systemic therapy and radiation therapy, is key for most tumors. Alternatives and reconstructive options ○ Surgeons should not only know the technique for performing a cancer operations but also know the alternatives to surgery ○ Surgeons should also be well versed in reconstructive options Complications of pre-op or post-op Chemo and Radiation Therapy (RT) ○ Surgeons should be familiar with the indications for and complications of preoperative and False negative biopsy specimen results may be due to postoperative chemotherapy and RT. identifying the wrong node or to missing sentinel node (i.e. surgical error). SURGICAL MANAGEMENT OF THE PRIMARY TUMOR (T) ○ May also be due to the cancer cells’ establishing metastases not in the first node encountered but in Goal of surgical therapy: ONCOLOGIC CURE second-echelon node (i.e. biologic variation Negative surgical margin (microscopically) Oh eh ano naman yung second-echelon? Well, echoserang ○ Px in which the primary tumor is not resectable with lymph node lang yan. Char. Basically, ang second-echelon negative surgical margins are considered to have nodes are non-sentinel nodes (duhh kaya nga second) na INOPERABLE DISEASES. nagre-receive directly ng lymphatic drainage from the Operability sentinel nodes… ayun.. GMG mo na lang di rin aq sure ○ Best determined before surgery with appropriate HAHA :P imaging studies that can define the extent of local- regional diseases. SURGICAL MANAGEMENT OF DISTANT METASTASES (M) Although RT and Systemic therapy can decrease local recurrence rates in the setting of positive margins, Treatment of a patient with distant metastases depends adjuvant therapy cannot substitute for adequate on: therapy. ○ Number and sites of metastases ○ Cancer type SURGICAL MANAGEMENT OF THE REGIONAL LYMPH ○ Rate of tumor growth NODE BASIN (N) ○ Previous treatment delivered ○ Responses to previous treatments Most neoplasms metastasize via the lymphatics. ○ Patient’s age ○ Most oncologic operations have been designed to ○ Physical condition remove the primary tumor and draining lymphatics ○ Desires LUHH pano yung desires? HAHA en bloc. CURATIVE SURGERY for distant metastases Pag sinabing en bloc, as one or as a unit. So if makita niyo na ○ GOAL: Resect the metastases with negative margins. “en bloc tumor resection” ganyan, it means it involves the ○ E.g., In patients with hepatic metastases that are removal of the entire tumor without opening the capsule. unresectable because their location near Diba sa mga tumor or neoplasms may capsule sila (i.e. Lipoma), recall kayo Patho ba naman yan emz. So tatanggalin yung buong yon, hence, en bloc. KUMUNOY’S IMPROPERTY 12 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… intrahepatic blood vessels precludes a margin-negative or fixed number of cells. Ang tawag dito is “log-kill hypothesis”. resection, or because they are multifocal, or hepatic function So, sa example diba, yung certain Chemo drug dose mo raw, is inadequate. Tumor ablation with cryotherapy or it will reduce the cancer cell population from 10^12 to 10^9. radiofrequency is an alternative. If naman, ang starting population mo ng cancer cells is let’s say 10^6 (hypothetically), you will need the same dose of that chemo drug to reduce the population to 10^3. In both cases, yung same dose ng chemo drug mo reduced the population by 3 orders of magnitude (same percentage, from 10^12 to CHEMOTHERAPY 10^9 then yung isa from 10^6 to 10^3) or what we call “3- Patients with documented distant metastases → logs”. Kaya nga ayan oh, nakalagay 3-log cell kill. AYun sana Chemotherapy is the primary modality of therapy nagets niyo pls nag-effort ako HUHU The goal of therapy is to DECREASE THE TUMOR BURDEN, Chemotherapeutic agents can be classified according prolonging survival to the phase of the cell cycle during which they are Rare to achieve cure with Chemotherapy for metastatic effective. disease for most solid tumors Cell cycle phase-nonspecific agents (e.g. Alkylating Neoadjuvant Chemotherapy agents) have a LINEAR-DOSE RESPONSE, such that the ○ Administered either post-op or pre-op fraction of cells killed increases with the dose of the drug. ○ GOAL: Eradication of micrometastatic disease, with AYAN NA NGA SINASABI KO SA FIRST ORDER KINETICS the intent of decreasing relapse rates and improving DIBA??? Sa pharma, ang 1st order kinetics is rate of survival rates elimination of the drug is proportional to its plasma ADVANTAGES OF PRE-OP CHEMOTHERAPY (CTX) concentration (HIGHER PLASMA CONCENTRATION = HIGHER ELIMINATION)!!! Sa Surgery naman, rate of elimination of cancer cells is proportional to the dose of I Preoperative regression of tumors can drug (HIGHER DOSE = HIGHER CHANCES OF facilitate resection of tumors that were KILLING/ELIMINATING HAHA). initially inoperable. In contrast, the cell cycle phase-specific agents have a Allow more conservative surgery for patients plateau with respect to cell killing ability, and cell kill will not increase with further increase in drug dose. II Treatment of micrometastases without the delay of postoperative surgery III Ability to assess a cancer’s response to treatment clinically DISADVANTAGE ○ Introduce special challenges to tumor localization, margin analysis, lymphatic mapping and pathologic staging PRINCIPLES OF CHEMOTHERAPY FIRST ORDER KINETICS ○ Chemotherapy destroys cells via first-order kinetics. ○ With the administration of a drug at a constant percent, age of cells is killed, not a constant number of cells. ○ If a patient with 10¹² tumor cells is treated with a dose that results in a 99.9% cell kill (3-log cell kill), the tumor burden will be reduced from 10¹² to 10⁹ cells (or 1kg to 1 g). Kanina may Patho tapos ngayon may Pharma naman? Alam niyo at this point iniisip ko na kung gusto ko pa rin ba maging Surgeon HAHAHA niweis, ganito, remember 1st order kinetics sa Pharma? Where the rate of elimination is proportional Some tumors, most notably breast and prostate CA, (yung fixed fraction or percentage) to plasma originate from tissues whose growth is under hormonal concentration? Medj ganon rin yung idea here, ang sinasabi control lang is sa Chemotherapy, if you administer a certain dose of drug/unit time, it will kill/eliminate a constant or fixed percentage of the cancer cell population, and not an exact KUMUNOY’S IMPROPERTY 13 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… The first attempts at hormonal therapy were through surgical ablation of the organ producing the hormones involved, such as Oophorectomy for breast CA CURRENT HORMONAL ANTI-CANCER AGENTS ○ Androgens ○ Anti-androgens ○ Anti-estrogens ○ Estrogen ○ Glucocorticoids ○ Gonadotropin inhibitors ○ Progestins ○ Aromatase inhibitors ○ Somatostatin analogues Homones or hormone-like agents can be administered to inhibit tumor growth by blocking or antagonizing the naturally occurring substance. Other substances that block the synthesis of of the natural hormone: ○ Aromatase inhibitors - blocks the peripheral conversion of endogenous androgens to estrogen in postmenopausal women. Basic principle of molecular therapeutics: exploit the molecular differences between normal cells and cancer cells to develop targeted therapies Major groups of targeted therapy agents: ○ Inhibitors of Growth Factor receptors ○ Inhibitors of Intracellular signal transduction ○ Cell cycle inhibitors ○ Apoptosis based therapies ○ Anti-angiogenic compounds Protein Kinase is an attractive therapeutic targets with the success of ○ IMATINIB mesylate (Gleevec) in treating CML and GI stromal tumors, GOAL: To induce or potentiate inherent antitumor ○ Trastuzumab (Herceptin) - Treatment for breast CA immunity that can destroy cancer cells ○ Vemurafanib - Treatment for Melanoma ○ The ability of the immune system to recognize tumor- associated antigens present on human cancers and to direct cytotoxic responses through humoral or T- cell mediated immunity. NON-SPECIFIC IMMUNOTHERAPY ○ Stimulates the immune system as a whole through administration of bacterial agents or their products such as Bacille-Calmette-Guerin (BCG). ○ This approach is thought to activate the effectors of antitumor response such as NK Cells and Macrophages, as well as polyclonal lymphocytes Gene therapy - possible approach in modifying the genetic program of cancer cells as well as treating metabolic diseases. ○ Uses a variety of strategies, ranging from the replacement of mutated or deleted tumor suppressor gene enhancement of immune responses to cancer cells. ○ Main difficulty: getting technology from the laboratory to the clinic - lack of a perfect delivery system. KUMUNOY’S IMPROPERTY 14 1  SUBJECT: bH4$1c SuRg ghAAAARrr LECTURER: Doc Rayner Baloloy, totoy tumalon ka, dumapa kung kailangan… Ionizing radiation is energy strong enough to remove an orbital electron from an atom. ○ This radiation can be electromagnetic, like a high- energy photon, or particulate, such as an electron, proton, neutron, or alpha particle X-rays traverse the tissue, depositing the maximum dose beneath the surface, and thus spare the skin. Electrons are used to treat superficial skin lesions, superficial tumors, or surgical beds to a depth of 5 cm. Gamma rays typically are produced by radioactive sources used in brachytherapy The basic unit is the amount of energy absorbed per unit of mass (joules per kilogram) and is known as a gray (Gy). One gray is equivalent to 100 rads, the unit of radiation measurement used in the past. Radiation deposition results in DNA damage manifested by single- and double-strand breaks in the sugar phosphate back- bone of the DNA molecule Radiation damage is manifested primarily by the loss of cellular reproductive integrity DNA damage from indirectly ionizing radiation is dependent on the phase of the cell cycle. The most radiation-sensitive phases are G2 and M, whereas G1 and late S phases are less sensitive. KUMUNOY’S IMPROPERTY 15 1