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Introduction to cell Biology Oncology Lecture 1 1- Cell reproduction: Cells must reproduce else they die. The "life of a cell" is termed the cell cycle. The cell cycle has distinct phases, which are called G1, S, G2, and M. Cells that have temporarily or reversib...

Introduction to cell Biology Oncology Lecture 1 1- Cell reproduction: Cells must reproduce else they die. The "life of a cell" is termed the cell cycle. The cell cycle has distinct phases, which are called G1, S, G2, and M. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase. Phases of the cell cycle Interphase Interphase was once referred to as the “resting phase” of the cell cycle; we now know this statement is incorrect. During interphase the cell is busy. The cell grows in size, new organelles are made, and the DNA of the chromosomes are copied in preparation for mitosis and cytokinesis. Interphase is subdivided into 3 phases: G1, S, and G2. Stages of Interphase: G1 phase During the (G1) phase, the cell grows larger and the number of organelles increases. S phase or synthesis phase During S phase, the cell replicates its DNA. DNA replication only occurs if the cell is programed to proceed beyond G1. At this point the cell possesses twice as much DNA as it normally does and will need to divide. This video from the DNA Learning Center explains the process. G2 phase After more growth occurs in the (G2) phase, the cell is ready to divide and enters mitosis. The G 0 Phase of the Cell Cycle Most cells that differentiate will do so during this phase. Cells arrested in G1 may no longer have the capability of reproducing and are said to be in G0. 1 Certain cells in G0, however, when given some external or internal cues may revert back toG1 and enter the cell cycle again. Nerve and muscle cells are usually arrested in G0. These cells are considered very resistant to X-rays and gamma rays What Controls the Cell Cycle? Regulation of the Cell Cycle by External Events Both the initiation and inhibition of cell division are triggered by events external to the cell when it is about to begin the replication process. An event may be as simple as: - the death of a nearby cell - the release of growth-promoting hormones, such as human growth hormone (HGH). A lack of HGH can inhibit cell division, resulting in dwarfism, whereas too much HGH can result in gigantism. - Crowding of cells can also inhibit cell division. - Another factor that can initiate cell division is the size of the cell; as a cell grows, it becomes inefficient due to its decreasing surface-to-volume ratio. The solution to this problem is to divide. Regulation at Internal Checkpoints It is essential that the daughter cells produced be exact duplicates of the parent cell. Mistakes in the duplication or distribution of the chromosomes lead to mutations that may be passed forward to every new cell produced from an abnormal cell. To prevent a compromised cell from continuing to divide, there are internal control mechanisms that operate at three main cell cycle checkpoints. A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be halted until conditions are favorable. These checkpoints occur near the end of G1, at the G2/M transition, and during metaphase. G1 checkpoint – size and nutrient verification This checkpoint, also called the restriction checkpoint, takes place between the G1 and the S phase. The cell verifies that it is large enough to divide, that its DNA is intact, and if there is enough access to nutrients and stimulating growth factors. If it passes the G1 checkpoint, it irreversibly commits to complete the whole cell cycle and divide. If not, it tries to fix what fails or 2 enter the G phase and wait for more favorable conditions. G2 checkpoint – DNA quality control After the second growth phase, the cell checks that the DNA was completely and correctly replicated during the S phase. If it passes it enters the M phase, and if it fails it tries to correct the errors. If the cell is unable to repair the DNA, it undergoes apoptosis. This prevents it from passing the damaged DNA on to the daughter cells. M checkpoint – nuclear division setup check This checkpoint takes place during the M phase. It is also called the spindle checkpoint because the cell examines whether all sister chromatids are correctly attached to the spindle microtubules that separate them. If not, the cell pauses mitosis until all sister chromatids have been attached in the right way. Frequency of cell division varies by cell type − Embryo, cell cycle < 20 minute − skin cells, divide frequently throughout life 12-24 hours cycle − liver cells, retain ability to divide, but keep it in reserve divide once every year or two − mature nerve cells & muscle cells, do not divide at all after maturity, permanently in G0 Mutations in cells can be triggered by: − UV radiation − chemical exposure − radiation exposure − heat − cigarette smoke − pollution − age − genetics 3 2- Radiation damage to DNA DNA Strand Breaks 1) Single strand breaks: − Can take place at the phosphodiester bond, or at the bond between the base and the sugar. − A large proportion of the single strand breaks are caused by hydroxyl radicals (OH ). 2) Double strand breaks: − Involves breakage of both strands at points less than 3 nucleotides apart. − Production by single particle crossing both strands? − Production by two independent events? − Can be measured by various techniques (e.g., sucrose gradient centrifugation) − Double strand breaks have shown a direct proportionality to radiation dose. X-ray dose of ~1 Gy produces about 1000 single strand breaks and about 50-100 double strand breaks in a typical mammalian cell. This dose causes about 50% cell death. DSBs are not necessarily lethal. 3- DNA repair − Repair of damage to DNA is of central importance to all cells, and is an ongoing process. − Existing repair mechanisms eliminate most radiation-induced lesions. Restores viability But viable cells may still harbor mutations or chromosomal aberrations − Distinguish repair as Error-free: restores DNA to its original state Misrepair: non-lethal errors are incorporated and passed on to daughter cells. This could lead to genomic instability and carcinogenesis. − DNA repair is governed by a multitude of genes, and executed by DNA repair enzymes. Mutants deficient in DNA repair genes have helped elucidate these complex systems and their control 4 Basis of cancer and its systemic therapy (Oncology Lecture 2) 1- What is Cancer A tumor is an uncontrolled growth in a specific cell type. A malignant tumor (cancer) is an uncontrolled cell growth that acquired many potentials such as angiogenesis, immortality, invasiveness, and metastatic potentials. Staging and early detection of cancer Many staging systems are used to classify cancer into several stages which is important for prognosis and to guide the treatment strategy. The most commonly used system is the TNM staging system. There is a specific TNM staging criteria for each type of cancer. However, as a general rule the following applies: − T stands for Tumor stage (T1, T2, T3 or T4) where T1 is the earliest stage (smallest tumor) and T4 is the most locally advanced stage. − N stand for Nodal stage (N0, N1, N2, or N3) where N0 represents no spread to LNs, N1 is the earliest or minimal spread and N3 is the most advanced nodal spread. − M stands for Metastatic stage (M0 or M1) where M0 represents no distant metastatic spread and M1 represents distant metastatic spread (also commonly named stage IV disease). A simpler stage grouping system classifies cancer into 3 stage groups: − Local: where cancer is localized into the organ of origin − Regional: where cancer has spread to the regional LNs or nearby structures. − Distant: Where cancer has spread to distant organs. Early detection of cancers − One of the most important factors for cancer prognosis is the stage in which cancer is discovered. This means that early detection of most cancers can improve the cure rates. − Paying attention to any persistent symptom or sign that is progressive and doesn’t respond to routine treatment can help in early detection of many cancers (e.g., persistent progressive cough or chest symptoms could indicate lung cancer). − Examples of successful strategies of early detection include: 1. Regular annual Mammography or breast examination for early detection of breast cancer. 2. Pap smear and HPV for early detection of cervical cancer. 3. Abdominal ultrasound screening for hepatocellular carcinoma in cirrhotic patients. 4. Low dose CT chest for chronic heavy smokers to detect early lung cancer. 5. Colonoscopy, sigmoidoscopy, and stool-based tests for colorectal cancer 6. Digital rectal exam and PSA level for prostate cancer. 5 2- Aim and intent of cancer therapy: Radical: This is the main strategy of therapy used aiming to cure cancer (The commonest is surgery as in breast cancers and sarcomas, etc… but radiation can also be gives as a radical treatment in head and neck cancers and chemotherapy can be used to cure hematological malignancies. Adjuvant (after surgery): In patients at relatively high risk for recurrence after surgery, another line of treatment may be given to decrease the risk of recurrence. Neoadjuvant (before surgery): In patients with large or locally advanced cancers, a line of treatment may be used to reduce the size of the tumor before surgery Palliative: In metastatic patients, treatment is given to relieve cancer related symptoms and improve survival. 3- Basics of multidisciplinary management of cancer Cancer is a complex disease that always needs several specialties to complete adequate treatment. Using one treatment strategy (e.g., surgical resection alone) is not sufficient to cure most cancer patients. Therefore, cancer is best treated in the setting of a multi-disciplinary team (MDT) or a tumor board where physicians from different specialties meet and discuss what is the best treatment plan or strategy for each patient. A typical MDT should include a surgical oncologist, a medical oncologist, a radiation oncologist, a radiologist, and a pathologist. Additional specialties like a nutritionist, a molecular biologist, a psychiatrist, and a social worker might also be needed. 4- Systemic therapy for cancer 4-1-Definition and rationale: − Systemic therapy refers to any type of cancer treatment that targets the entire body and circulates throughout the blood stream to destroy cancerous cells in multiple locations. − Once the medications enter the blood stream, they disperse and destroy abnormal cells in various locations. As a result, systemic therapy is often used to treat cancers that have spread to distant sites (metastatic). 6  − Usually, a combination of several systemic treatment options may be combined to ensure all malignant cells are destroyed. −− Types of systemic therapies include: A. Chemotherapy B. Targeted therapies C. Immunotherapies D. Hormone therapies A- Chemotherapy The goal of cancer therapy is to achieve a cure or at least remission. Cytotoxic Chemotherapy is the most common and oldest form of systemic cancer treatment. It can be administered through different methods: intravenous infusions, IV shot or oral as pills. Although chemotherapy can impact cancerous and noncancerous cells throughout the entire body, it usually causes more damage to cancer cells, hence the concept of the therapeutic ratio. Chemotherapy is most effective in treatment of rapidly dividing cells. The most chemo- sensitive cancers are: Leukemias, Lymphomas, Germ cell tumors, and to lesser extent breast and ovarian cancers. I. Types of Cytotoxic drugs: Alkylating agents Anti-metabolites Natural products/Plant alkaloids Antitumor Antibiotic 7  Pharmacology Lecture -1: Pharmacology of Chemotherapeutic agents Classification and Mechanisms of action Alkylating Agents: a. Transfer of alkyl groups to various cellular constituents. Alkylation of DNA within the nucleus probably represents the major interaction leading to cell death. b. Member examples: □ Cyclophosphamide □ Chlorambucil □ Platinum compounds: cisplatin, carboplatin, oxaliplatin Antimetabolites a. Antifolates: methotrexate □ Inhibit/antagonize folic acid metabolism b. Fluoropyrimidines: fluorouracil, capecitabine □ Inhibition of DNA synthesis c. Purine Antagonists: Fludarabine □ inhibits several enzymes of de novo purine nucleotide synthesis 8 Natural Product Cancer Chemotherapy Drugs d. Vinca Alkaloids □ inhibit the process of tubulin polymerization, which disrupts assembly of microtubules, especially those involved in the mitotic spindle apparatus inhibition of cell division cell death. e. Taxanes: pactitaxel □ high-affinity binding to microtubules with enhancement of tubulin polymerization f. Epipodophyllotoxins: Etoposide □ forms a complex with topoisomerase II, the enzyme responsible for cutting and religating double stranded DNA, and DNA, leading to inhibition of DNA synthesis and function g. Camptothecins: Irinotecan and topotecan □ inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and re- ligating single DNA strands. Inhibition of this enzyme results in DNA damage Antibiotic chemotherapy: h. Anthracyclines: □ inhibition of topoisomerase II □ generation of free radicals and oxygen free radicals □ high-affinity binding to DNA through intercalation, blockade of the synthesisof DNA and RNA □ binding to cellular membranes to alter fluidity and ion transport i. Mitomycin □ DNA alkylation j. Bleomycin □ binding to DNA, which results in single and double-strand breaks following free radical formation, and inhibition of DNA biosynthesis 9  Pharmacology Lecture 2 B- Targeted therapy □ Targeted therapy is a type of cancer treatment that targets proteins that control how cancer cells grow, divide, and spread while sparing healthy normal cells. This makes targeted therapies generally less toxic than conventional chemotherapy. □ Most targeted therapies are either small-molecule drugs or monoclonal antibodies. - Small-molecule drugs are small enough to enter cells easily, so they are used for targets that are inside cells. - Monoclonal antibodies, also known as therapeutic antibodies, are proteins produced in the lab. These proteins are designed to attach to specific targets found on cancer cells. Some monoclonal antibodies mark cancer cells so that they will be better seen and destroyed by the immune system. Other monoclonal antibodies directly stop cancer cells from growing or cause them to self-destruct. Still others carry toxins to cancer cells. □ Biomarker testing is a way to look for genes, proteins, and other substances (called biomarkers or tumor markers) that can provide information about cancer. Each person’s cancer has a unique pattern of biomarkers. Biomarker tests can help physician select a cancer treatment for patient. Some cancer treatments, including targeted therapies and immunotherapies, may only work for people whose cancers have certain biomarkers. For example, people with cancer that has certain genetic changes in the EGFR gene can get treatments that target those changes, called EGFR inhibitors. □ Cancer cells can become resistant to targeted therapy. For this reason, they may work best when used with other types of targeted therapy or with other cancer treatments, such as chemotherapy and radiation. C- Immunotherapy □ The immune system detects and destroys abnormal cells and most likely prevents or curbs the growth of many cancers. Cancer cells have ways to avoid destruction by the immune system; for example, cancer cells may: - Have genetic changes that make them less visible to the immune system. - Have proteins on their surface that turn off immune cells. - Change the normal cells around the tumor so they interfere with how the immune system responds to the cancer cells. □ Immunotherapies are a group of drugs that aim at activating the patient’s immune system to fight cancer □ They include immune checkpoint inhibitors (That stops the cancer-induced immunosuppressive signals), cancer vaccines, cytokine therapies (like interferons and interleukins). 10 D- Endocrine therapy Some cancers depend on hormones to grow. Because of this, treatments that block or alter hormones can sometimes help slow or stop the growth of these cancers. Treating cancer with hormones is called hormonal therapy, or endocrine therapy. Hormone therapy is mostly used to treat certain kinds of breast cancer and prostate cancer that depend on sex hormones to grow. A few other cancers can be treated with hormone therapy, too. 1) Glucocorticoids □ Are used in combination with cytotoxic agents in treating of lymphomas and myeloma and to induce a remission in acute lymphoblastic leukemia. □ Glucocorticoids are also helpful in reducing oedema around a tumor. □ They have antiemetic activity too. □ Hydrocortisone, Prednisone, Dexamethasone, Prednisolone 2) Female sex hormones □ Progestins suppress endometrial cancer cells (e.g. Medroxyprogesterone) 3) Hormone antagonists □ Estrogen antagonists (e.g. Tamoxifen) suppress breast cancer cells. It binds competitively to estrogen receptors □ Aromatase inhibitors are used in postmenopausal women with advanced breast carcinoma. They inhibit the production of estrogen inside the body □ Androgen antagonists suppress prostate cancer cells e.g. cyproterone & flutamide 4) Thyroid hormones Stop the growth of thyroid tumors after surgery or radiation therapy for thyroid cancer. 11 Oncology Lecture 3 Adverse effects of cancer systemic therapy − Side effects result from lysis of normal cells, and they vary according to the type of drug, the dose, the route of administration and individual response. − Rapidly dividing cells are more affected i.e. bone marrow cells, digestive tract, hair follicles and reproductive tract cells. − Adverse effects of cancer systemic therapy may be classified according to their time of occurrence as follows: Immediate adverse effects: Occur during or within thirty minutes of administration, the most common include: − Local site reactions e.g. Local irritation, thrombophlebitis, extravasation into surrounding subcutaneous tissues (with subsequent ulceration). − Flushing. − Hypotension. − Hypersensitivity. − Anaphylaxis. Short term adverse effects: Occur within hours to days of treatment administration, e.g.: − Gastrointestinal side effects e.g. Mucositis, Nausea and vomiting, Anorexia, Constipation or diarrhea. − Hematopoietic side effects….Myelosuppression i.e. Neutropenia, Anemia and thrombocytopenia. − Tumor lysis syndrome….It occurs when cancer treatments cause the destruction (or lysis) of a large number of rapidly dividing cancer cells, overwhelming the body’s ability to excrete the end products of cell death. Medium to long term adverse effects: Occur later than seven days of treatment administration and may be cumulative, e.g.: − Alopecia − Liver dysfunction − Nephrotoxicity − Cardiac toxicity − Neurological toxicity e.g. Peripheral neuropathy − Pulmonary toxicity e.g. pulmonary Fibrosis − Gonadal damage (may induce Infertility) − Second malignancies. 12  Adverse effects are common in patients receiving any cancer therapy. Successfully managing these adverse effects is important because it improves quality of life. A- Cytopenias − Cytopenias are common in patients with cancer due to a direct effect of the cancer (especially in blood and bone marrow cancers such as leukemias, lymphomas, and multiple myeloma) and from effects of cancer therapy, especially conventional cancer (chemotherapy) drugs. 1- Anemia − Anemia remain as one of the serious and frequent problem of cancer mainly cancer of the gastrointestinal, liver, head and neck, ovarian ,cervix and leukemia. This is mainly caused by cytokines produced by these cancer diseases. These cytokines caused impairment of erythropoietin (EPO) synthesis, reduce erythrocytes life span and prevent normal iron utilization. Other direct effect of tumor that cause anemia is bone marrow replacement which is associated with inhibition of the body ability for the production of RBC. As the common side effect of chemotherapy especially with the myelosuppressive type. − The treatment of anemia will include red blood cell transfusion, corticosteroids, VitB12 and Epoetin alfa (recombinant human erythropoietin, rHuEPO). 2- Thrombocytopenia − The main causes leading to occurrence of thrombocytopenia are: Chemotherapy drugs. Solid cancer, Blood cancer (Leukemia), Spleen cancer. Hemorrhage which will lead to increases loss of platelets. − Grades of thrombocytopenia The normal range of the platelets is between 150,000 and 450,000 cells per microliter of blood (i.e., 150-450×109/ L) while thrombocytopenia could be classified into three levels as follows: Mild thrombocytopenia if platelets count < 150 and ≥ 100 × 109/ L. Moderate thrombocytopenia if platelets count < 100 and ≥ 50 × 109/ L. Severe thrombocytopenia if platelets count < 20 × 109/ L. - Options for thrombocytopenia treatments The selection for thrombocytopenia treatment will mainly depends on the etiology and severity of thrombocytopenia. If thrombocytopenia incidence is because of spleen enlargement then splenectomy will be beneficial. if the cause is due to chemotherapy then the decision to either continue the treatment with low chemotherapy doses or use of alternative drugs or use of platelets growth factors (i.e., thrombopoietic growth factor) which stimulate megakaryocytes to produce platelets should be made. 13  In the case of severe thrombocytopenia< 20,000/microL platelet transfusions is needed. but there are some limitations to its use which are: the availability of the blood products since it must be freshly taken and used within 5 days, cost, transfusion reaction and diseases transmission 3. Neutropenia - A decreased granulocyte concentration is common in patients with cancer. 9 - A granulocyte concentration < 500/microL (0.5 × 10 /L) markedly increases the risk of infection. - Measures to protect against infection, including hand washing and protective isolation, are important. - Oral non-absorbable antibiotics are sometimes given prophylactically. When a prolonged interval of low granulocytes is anticipated, prophylactic antifungal and antiviral drugs are sometimes given. Afebrile patients - with neutropenia require close outpatient follow-up for detection of fever and should be instructed to avoid contact with sick people or areas frequented by large numbers of people (eg, shopping malls, airports). - Although most patients do not require antibiotics, patients with severe immunosuppression are sometimes given trimethoprim/sulfamethoxazole (one double-strength tablet/day) as prophylaxis for Pneumocystis jirovecii. − In transplant patients or others receiving high-dose chemotherapy, antiviral prophylaxis (acyclovir 800 mg orally twice a day or 400 mg IV every 12 hours) should be considered if serologic tests are positive for herpes simplex virus. Febrile neutropenia − Fever> 38.5° C on two or more occasions in a patient with neutropenia is a medical emergency. − An extensive evaluation for potential infection sources should be made and include immediate chest x-ray and cultures of blood, sputum, urine, stool, and any suspect skin lesions. Examination includes possible abscess sites (eg, skin, ears, sinuses, perirectal area), skin and mucosa for presence of herpetic lesions…. − Typically, systemic broad-spectrum antibiotics, antifungal and sometimes antiviral drugs are give B- Diarrhea − Diarrhea is defined as the frequent passage of loose stools(more than three unformed stools in 24 hours) with urgency. − Causes: Several types of malignant tumors like Gastroentero-pancreatic and lung neuroendocrine tumors(NETs) and colo-rectal cancer are the most frequent diarrhoea-associated tumors(20% of the cases). Diarrhea is a common side effect of many chemotherapy agents, targeted therapy and immunotherapy drugs, 14  Radiation therapy, especially if the abdomen and/or pelvis is included in the radiation field. Surgery: resection of part of the digestive tract. Others, Clostridium difficile diarrhea, Enteral feeding (Tube feeding, either by nasogastric tube, gastrostomy or jejunostomy), Coeliac plexus block. − Management of chemotherapy -related diarrhoea Patients with grade 1 or 2 diarrhoea: − Oral hydration − Dietary modifications (e.g. eliminating all lactose-containing products and high-osmolar dietary supplements) − Loperamide should be started at an initial dose of 4mg followed by 2mg every 4 hours or after every unformed stool(not to exceed 16mg/day). Patients with high grade diarrhea − Hospital admission and involves i.v. fluids; − Octreotide at a starting dose of 100–150 mg s.c. three times a day (tid) or i.v. (2550mg/h) if the patient is severely dehydrated, with dose escalation up to 500mg s.c. tid until diarrhoea is controlled − Administration of antibiotics (e.g. fluoroquinolone). − These patients should be evaluated with complete blood count, electrolyte profile and a stool work-up evaluating for blood, Clostridium diff icile, Salmonella, Escherichia coli, Campylobacter and infectious colitis C - Mouth lesions Causes − Such as inflammation and ulcers are common in patients receiving chemotherapy drugs and/or radiation therapy. − Ulcers can cause pain and preclude sufficient oral intake, leading to under nutrition and weight loss. Management − Rinses with analgesics and topical anesthetics (2% viscous lidocaine 5 to 10 mL every 2 hours) before meals. − A bland diet without citrus food or juices, and avoidance of temperature extremes may allow patients to eat and maintain weight. If not, a feeding tube may be helpful if the small intestine is functional. − For severe mucositis and diarrhea or an abnormally functioning intestine, parenteral alimentation may be needed. − Sometimes these lesions are complicated by infection, often with Candida albicans. Candidiasis is usually treated with nystatin oral suspension 5 to 10 mL 4 times a day or fluconazole 100 mg orally once/day. 15  Pharmacology Lecture-3 Pharmacotherapy of some chemotherapy-related complications A) Management of Cancer-Induced Constipation (CIC) 1- Prevention Non pharmacological management : − Ensuring privacy and comfort. − Increased fluid intake. − Increase dietary fiber intake (with adequate fluid intake and mobility). − Encourage activity within patient limits. − Attempts at defecating 30 - 60 minutes following a meal to take advantage of the gastro-colic reflex. Pharmacological − Treatment of underlying causes (examples) − Hypercalcemia: hydration and bisphosphonate. − Painful anorectal conditions: medical / surgical management. − Medications: discontinue / switch to an alternative. 2. Current Pharmacological therapy : Step 1 : Oral laxative: products are the mainstay and first line in treating constipation in cancer provided that there is no suspected organic bowel obstruction. Oral laxative osmotic (lactulose or polyethylene glycol) and / or stimulant (senna, bisacodyl or sodium picosulfate) laxatives. Step 2 : Rectal laxatives: Osmotic (glycerin suppositories) or stimulant (bisacodyl suppositories/enema or sodium phosphate enema). Step 3 : Methylnaltrexone: A peripherally-acting μ- opioid receptor antagonist (PAMORA) for severe intractable opioid- induced constipation(OIC) in cancer patients not responded to titrated dosed of laxatives. Promising emerging therapy for CIC: − chloride secretion activators: Lubiprostone : − guanylate cyclase-c activators: Linaclotide and plecanatide 22 B) Management of patients with fever and neutropenia. Patients with fever and neutropenia should be quickly investigated by: − History and physical examination − Complete blood picture − Cultures − Other investigations such as chest X ray or special tests according to the situation. Most patients with fever and neutropenia are hospitalized unless they are low risk patients. Patients should receive empiric antibiotic therapy (all are given iv) that covers Pseudomonas such as: − Cefepime − Meropenem − Imipenem − Ceftazidime (a third-generation cephalosporin) − Piperacillin/Tazobactam Typical regimens include cefepime or ceftazidime 2 g IV every 8 hours immediately after samples for culture are obtained. Antibiotic combinations may be used if antibiotic resistance is suspected. − If diffuse pulmonary infiltrates are present, sputum should be tested for P. jirovecii, and if positive, appropriate therapy should be started. If fever resolves within 72 hours after starting empiric antibiotics, they are continued until the neutrophil count is > 500/microL. If fever continues, antifungal drugs should be added and sometimes antiviral drugs. Reassessment for infection, often including CT of the chest and abdomen, is done. Additional therapies in special situations include: − Cellulitis and skin infection requires adding an agent covering Gram positive organisms such as cloxacillin. − Vancomycin or linezolid is added if MRSA infection is suspected or in cases of infection of a vascular access site (peripheral cannula or a central line). − An antibiotic covering anaerobes such as metronidazole, meropenem, or piperacillin/tazobactam in cases with abdominal or perirectal pain − An antifungal such as fluconazole in presence of oral thrush − Amphotericin B is a broad-spectrum antifungal that can treat several types of invasive fungal infections but can cause sever renal toxicity and infusion reactions. Side effects are less with liposomal amphotericin. − Antivirals such as acyclovir in cases with mucosal vesicles or ulceration Granulocyte concentrations can be increased by giving molecularly cloned myeloid growth factors such as granulocyte (G) or granulocyte/macrophage (GM) colony stimulating factors (CSFs) such as filgrastim, sargramostim, and peg-filgrastim. To shorten the duration of neutropenia. G-CSF 5 mcg/kg subcutaneously once/day up to 14 days and longer-acting forms (eg, pegfilgrastim 6 mg subcutaneously single dose once per chemotherapy cycle) may be used to accelerate WBC recovery. These drugs are begun at the onset of fever or sepsis or, in afebrile high-risk patients, when neutrophil count falls to < 500/microL. 23 C) Chemotherapy-Induced Nausea and Vomiting (CINV) − Emetogenic activity − High emetic risk (HEC, Highly Emetogenic Chemotherapy) ➔ vomiting in > 90% of patients − Moderate emetic potential ➔ 30-90% of patients − Low emetic potential ➔ 10-30% of patients − Minimal potential ➔