CVD In General: Definitions

Cardiovascular Disease (CVD): is the general term for heart and blood vessel diseases, including atherosclerosis, coronary heart disease, cerebrovascular disease, and peripheral vascular disease. CVD accounts for one in every two deaths in the US and is the number one killer disease. 90% of CVD is presentaly diagnosed as atherosclerosis (US 5,846,959). 

Cardiovascular Disorders are acute manifestations of CVD and in clude myocardial infarction, stroke, angina pectoris, transient ischemic attacks and congestive heart failure. 

Diagnosis (See also Biomarkers)

Numerous epidemiologic studies have evaluated several inflammatory markers, including C-reactive protein, various cytokines, adhesion molecules and white blood cell count for their clinical usefulness in predicting risk of CVDs.

Prevention

A low fat diet and exercise are recommended to prevent CVD.  

Treatments: See outline

Angina:

Unstable angina: is a cardiovascular disorder in which the heart does not obtain sufficient blood flow and oxygen. It can cause chest discomfort and also lead to heart attack. 

Treatment:  NIH 

Hypertension:

Pathology:

–primary aldosteronism: is a hormonal disorder that leads to high blood pressure. It occurs when your adrenal glands produce too much of a hormone called aldosterone. Your adrenal glands produce a number of essential hormones, including aldosterone. Current guidelines suggest screening only in certain cases. That includes people who have “resistant” hypertension (the medical term for high blood pressure), which means blood pressure that remains high despite a three-medication regimen; and people with hypertension plus low potassium. However, many medical professionals are advocating to change these guidelines and to test people much early as it appears this hormonal disorder is much more common then first thought. 

Treatments:

—beta blockers:  Bystolic (nebivolol): Abbvie/Allergan’s drug. 

BioMarkers/Diagnosis/Pathogenesis/Risk Factors:  See outline

Lymphoma Research Foundation

Skin cancers (i.e., basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma belong to the most frequent tumors. Their formation is based on constitutional and/or inherited factors usually combined with envirnomental facts, mainly UV-irradiation through long term sun exposure. UV light can randomly induce DNA damage in keratinocytes, but it can also mutate genes essential for control and surviellance in the skin epidermis. Various repair mechanisms exist. For example, DNA damaged cells are eliminated by apoptosis (sunburn cells). This occurs under the control of the p53 suppressor gene. Fas-ligand (FasL), a member of the tumor necrosis superfamily, which is preferentially expressed in the basal layer of the skin epidermis, is a key surveillance molecule involved in the elimination of sunburn cells. However, UV light exposure downregulates FasL expression in keratinocytes and melanocytes leading to the loss of its sensor function. Moreover, important control genes can also be direclty affected by UV light. Mutation in the p53 gene is the starting point for the formation of SCC and some forms of BCC. Other BCCs originate through UV light mediated mutations of genes of the hedgehog signaling pathway which are essential for the maintainance of cell growth and differentiation. Once the keratinocytes or melanocytes have been transformed they reexpress FasL which may allow the expanding tumor to evade the attack of immuen effector cells.

Non-Melanoma Skin Cancers:

The two major forms of skin cancer are squamous cell carcinoma (SCC) and basal cell carinoma, the most common form of skin cancer. They form the upper and lower layer of the epidermis respectively. Both are classified as “nonmelanoma” and rarely spread to other parts of the body. Whereas melanoma typically begins as a mole and can occur anywhere on the body. Squamous cell carcinoma may appear as a firm red bump, a scaly patch, or open sore, or a wart that may crust or bleed easily. Basal cell carcinoma may appear as a small white or flesh-colored bump that grows slowly and may bleed.

Cutaneous Squamous cell carcinoma (SCC):

Keratinocyte dervied carinoms such as cutaneous squamous cell carinoma (SCC) include the most common class of these malignancies. Sugical excision is the most common first line treatment for cutaneous SCC. However, SCC reoccurrence is commonAlhtough both topical cheotherapeutic and immunomodulatory agents have demonstrated potential in the local treatment of superficial SCCs, cream and gel formations fail to acheive adequate penetration into deeper SCCs. Nanoparticles formed from the block copolymer poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG) has been shwon to increase the duration, bioavailability and efficacy of locally adminsitered chemotherpay drugs which minimizes the systemic toxicity associated wtih coventional chemotherpaies. (Hu, “Nonsurgical treatment of skin cancer with local delivery of bioadhesive nanoparticles” PNAS 118, 2021). 

Head and neck squamous cell carcinoma (HNSCC)/Squamous cell carcinoma of the head and Neck HNSCC): reamin a substantial burden to global health. Despite improvements in treatments, many patietns develop disease recurrence. Fewer than 505 of pateints will surive beyong five years. (British J of Cancer, 2022, 126: 1186-1195).

–Detection/Staging:

A distinct staging for p16 positive HNSCC as determiend by immunostaining, a widely used clinical biomarker for infeciton with HPV, has been introduced due to its strong prognostic value in patients with squamous cell carcinomas (SC) of the oropharynx. About 30-35 of oropharyngeal tumours are attributable to HPV and are also linked to a significantly better outcome compred to pteints diagnosed with HPV negative, i.e., p16-negative disease. Unlike other cancers, reliable biomarkers for therapy planning and to monitor treatment resonse in patients with p16 negative HNSCC do not exist. Instead, initial diagnosis, as well as monitoring of HNSCC, are based solely on clinical findings and imaging with known sensitivity and specificity caveats. (British J of Cancer, 2022, 126: 1186-1195). 

The detection of circulating cel-free tumour DNA (ctDNA) as a marker of minimal residual disease following curative-intent surgery holds promise for identifying patients at an increased risk of relapse, who may benefit form adjuvant radio_chemo)therapy or facilitate close monitoring with repeat resection, if needed. (British J of Cancer, 2022, 126: 1186-1195).

–Treatment:

Standard therapy for locally advanced HNSCC involves surgical resection of the primary tumour and regional lymph node metastses, radiotehrapy with or without chemotherapy or a combination of modalities. (British J of Cancer, 2022, 126: 1186-1195).

Melanoma: 

Melanoma is increasing at a rate faster than any other cancer. It is the most virulent of skin cancers and highly metastatic, almost uniformly fatal within 5 years of diagnosis. The development of melanoma begins with the malignant transformation of normal human epitheial melanocytes (NHEM) located within the basement membrane of the skin. There is a correlation between the thickness of the primary melanoma and its capacity to metastasize to the draining lymph node basin(s). Once melanoma has metastasized by either route, the overal survival for patients greatly diminishes. Wherein patients with thin primary tumors are cured by surgery, patients diagnosed with metastatic melanoma (AJCC stage IV) have an overall poor prognosis, with 6 out of every 7 skin cancer deaths due to metastatic melanoma.

Treatments:

–monoclonal antibodies

—-Anti-GP240: US2005/0214307A1 provides immunoconjugates of an antibody which recognizes GP240 antigen found on melanoma cancer cells. In one embodiment, the antibody is coupled with a toxin such as gelonin, recin A chain and abrin A chain.

—-Anti-PD-1 (Program death receptor-1: Keytruda which is developed by Merk has been approved by the FDA for treatment of melanoma. 

–Nucleic Acid based approaches

—-Imlygic (talimogene laherparepvec): is indicated for the treatment of meloma recurrent after initial surgery. Imlygic is a live, attenuted herpes simplex virus type 1 carrying the human GM-CSF coding sequences. Viral replcation subsequent to injection directly into the tumor is believed to trigger cell lysis and it is believed tht the release of tumor derived antigens along with the GM_CSF may also promote an antitumor effect. (Gary Wash “Biopharmaceutical benchmarks 2018” Nature Biotechnology, 36(12), 2018)

Lymphomas

Cutaneous T cell Lymphoma: 

Prostate cancer is the most prevalent cancer diagnosed and the second leading cause of cancer-related death among men in the United States. The prostate is a 20-gram gland, which is located at the base of the bladder and surrounds the urethra and consists of five lobes; the anterior, posterio, median and right and left lateral lobes. Since the prostate is a gland, the most common type of cancer is called adenocarcinoma.

MetasMetastatic castration-resistant prostate cancer (mCRPC) is a form of advanced prostate cancertatic castration-resistant prostate cancer (mCRPC) is a form of advanced prostate cancer. When prostate cancer no longer responds to androgen deprivation therapy (also known as ADT or hormone therapy) and spreads to other parts of the body, it is known as mCRPC. This means that the cancer cells have become resistant to the effects of ADT and may spread to other parts of the body. The most common sites of metastasis for prostate cancer include the bones, lymph nodes, liver, and lungs. The development of mCRPC signifies a more aggressive form of prostate cancer that requires specialized treatment approaches.

Symptoms:

Common Symptoms: 

Symptoms of Prostate cancer include (1) Frequent urination, especially at night, (2) Difficulty starting or stopping urination, (3) Weak or interrupted urinary stream, and (4) Blood in urine or semen. Advanced prostate cancer may present itself wiht pain in the hips, upper thights or lower back. 

Distinguish other Conditions: 

The prostate can grow larger as men age, sometimes pressing on the bladder or urethra and causing symptoms similar to prostate cancer. This is called benign prostatic hyperplasia. This is not cancer and can be treated if symptoms become bothersome. A third problem that can cause urinary symptoms is prostatitis. This inflammation or infection may also cause a fever and in many cases is treated with medication.

Risk Factors:

After age 70, studies suggest that anywhere from 31% to 83% of men have some form of prostate cancer, though there may be no outward symptoms. Family history increases a man’s risk: having a father or brother with prostate cancer more than doubles the risk. African-American men and Caribbean men of African descent are at high risk and have the highest rate of prostate cancer in the world.

Too much sex or masturbation, contrary to popular belief, has not been shown as a risk factdor. But Researchers are still studying whether alcohol use, STDs, or prostatitis play a role in the development of prostate cancer.

A diet which is too low in fruits and vegetables may also play a role. 

Diagnosis: 

The incidence of prostate cancer is increasing, in part due to increased surveillance efforts form the application of routine testing such as prostate-specific antigen (PSA).

If a physical exam or PSA test suggests a problem, your doctor may recommend a biopsy. A needle is inserted either through the rectum wall or the skin between the rectum and scrotum. Multiple small tissue samples are removed and examined under a microscope. A biopsy is the best way to detect cancer and predict whether it is slow-growing or aggressive.

A normal PSA level is considered to be under 4 nanograms per milliliter (ng/mL) of blood, while a PSA above 10 suggests a high risk of cancer. But there are many exceptions:

• Men can have prostate cancer with a PSA less than 4.
• A prostate that is inflamed (prostatitis) or enlarged (BPH) can boost PSA levels, yet further testing may show no evidence of cancer.

Treatment: 

Surgery:

For most men, prostate cancer is a slow-growing, organ-confined or localized malignancy that poses little risk of death. The most common treatment for prostate cancer are surgical procedures such as radical prostatectomy, where the enitre prostate is removed. The vast majority of death form prostate cancer occur in patients with metastasis. Despite significant improvement of hormonal, chemical and radiation therapies, there is no cure for locally advanced or metastatic prostate cancer.

–Robot Assisted Radical Prostectomy:

Compared to a surgeon-led prostate removal, this method involves smaller cuts, more accurate prostate removal, and less nerve damage. That means fewer negative side effects like erectile dysfunction and urinary problems. Other benefits include less blood loss, less post-op pain, and a quicker recovery. 

–-Focal Laser Ablation:

A common breast cancer treatment that’s still new to prostate cancer, focal laser ablation is a quick procedure that uses a laser to remove a tumor on the prostate instead of removing the entire prostate. 

–-Cryotherapy:

When prostate cancer cells are frozen, they die. Cryotherapy is often used when other treatments don’t work, or if cancer comes back after a different treatment. To avoid damaging healthy tissue, doctors use an ultrasound to find and isolate the cancerous tissue, then insert metal gas-filled probes to freeze it. New technology has helped sidestep some of the side effects men had after treatments in the past, but sexual dysfunction remains an issue.  

–High Intensity Focused Ultrasound (HIFU):

In this noninvasive treatment, an ultrasound transducer uses high-energy sound waves to create heat and kill cancerous prostate tissue found by MRIs. Also called MRI-guided focused ultrasound (MRgFUS) and focused ultrasound (FUS), it earns the high-intensity title because it can heat cancerous tissue to 200 F in just 20 seconds. 

Hormone therapy (also known as androgen deprivation therapy or ADT) are commonly employed to eliminate or control the cancer cells. ADT works by suppressng the production of testosterone, a hormone that fuels the growth of prostate cancer cells.

Androgens, such as testosterone, play a crucial role in the growth and function of the prostate gland. Androgens also play a role in the growth and survival of prostate cancer cells by interacting with androgen receptors present on the cells. When the prostate cancer cells are still sensitive to androgens, prostate cancer treatment (eg, hormone therapy) aims to either suppress androgen production or block androgens from acting on the receptors to impede the growth of prostate cancer cells. However, as time goes by, certain cancer cells can acquire resistance to this therapy, allowing the cancer to progress.

Hepatocyte growth factor receptor/stimulating factor (HGF/SF) is known to be involved with the formation of metastases once a tumour is present, expecially in the case of prostate cancer. Thus one treatment regimen to to counteract HGF/SF.

Vaccines:

–APCs loaded with Antigen:

Provenge:

A new form of immune therapy has shown a significant survival benefit in men who have metastatic androgen-independent prostate cancer, when compared to patients receiving placebo. The treatment is called Provenge and is manufactured by Dendreon Corp. of Seattle. Provenge is called a vaccine, but unlike most vaccines, it is used not to prevent illness but to treat an already existing condition. The vaccine combines a protein that is found in most prostate cancer cells with a substance that helps the immune system recognize the cancer as a threat. The vaccine must be custom made for each patient individually. First, patients have their blood run through a machine for several hours in order to extract antigen presenting cells (APCs). These cells are then mixed with a protein called prostatic acid phosphatase (PAP) that is commonly found on most prostate tumors. The PAP is fused with another immune-stimulating substance called GM-CSF. The mixture is then returned to the patient in a one-hour infusion. This process is repeated three times over the course of a month. The basic idea is to alert the immune system that cells containing prostatic acid phosphatase, (i.e., prostate cancer cells) should now be attacked as if they were a foreign invader.

PARP Inhibitors:

Cells have a built-in enzyme called poly-ADP-ribose polymerase, or PARP, that repairs damaged DNA. But damaged cancer cells that can’t heal themselves die, and that’s the goal. PARP inhibitors like olaparib (Lynparza) and rucaparib (Rubraca) stop PARP from repairing cancer cells in cases where your prostate cancer has spread and hormone treatments have stopped working. 

Targetted Radiation:

A prostate-specific membrane antigen, or PSMA, is a protein on the surface of a prostate cancer cell. Targeted radiation therapy connects a radioactive compound with the molecule that hunts down PSMA, and attaches to and kills cancer cells. Recent trials have prolonged the lives of men with advanced prostate cancer. More research is needed for men with earlier stages of the disease.  

Where PSMA and targeted radiation therapy fall short with men at various stages of prostate cancer, 177Lu-PSMA-617 covers more ground. The process is the same: A molecule finds and attaches to a protein on the surface of the cancer cell, then radiation kills the cancer cell and its DNA so it can’t grow back. When other treatments haven’t worked, 177Lu-PSMA-617 has successfully killed cancer cells. 

Chemotherapy:

When prostate cancer spreads – for example, to the bones – or hormone therapy doesn’t work, chemo has been successful in killing cancer cells on its own or combined with other therapies. The side effects can be rough, and chemo can kill healthy cells too. New forms of treatment like radium Ra 223 dichloride (Xofigo) destroy cancer cells with reduced alpha particle radiation and don’t harm healthy bone tissue as much.

Radiation:

–Xofigo:

This medication is an alpha particle-emitting radioactive therapeutic agent. It’s classified as a radiopharmaceutical. If your prostate cancer is resistant to medical or surgical treatments that lower testosterone and has spread to bones with symptoms, but not to other parts of the body, doctors may suggest this treatment option.

Ovarian: Ovarina cancer is the fith leading cause of cancer death among US women and has the highest mortality rate of all gynecologic cancers. Some 24,000 new cases are estimated in the US each year according to the American Cancer Society. Due to lack of effective screening tools and therapy, the mortality of ovarian cancer has not declined in the past two decades. Most cases are diagnosed at an advanced state with survival rates of only 19-30%. If diagnosed at an early stage, there is up to 74% chance of survival. The high mortality rate is also attributable to the lack of specific symptoms among patients in the early stages.

Symptoms:

Patients afflicted with ovarian cancer most often present with non-specific complaints, such as abnormal vaginal bleeding, gastrointestinal symptoms, urinary tract symtpoms, lower abdominal pain, and generalized abdominal distension.

Diagnosis:

Ovarian cancer may be diagnosed, in part, by collecting a routine medical history and by performing physical examination, x-ray examination and chemcial and hematological studies. Hematological tests include analyses of serum levels of CA125 and DF3 proteins and plasma levels of lysophosphatidic acid (LPA). Palpation of the ovaries and ultrasound techniques, particularly including endovaginal ultrasound and color Doppler flow ultrasound techniques, can aid in detection of ovarian tumors and differentiation of ovarian cancer form benign ovarian cysts (US 2006/0029956A1).  Administration of adjuvant chemotherpay consisting of a platinum compound (cisplatin or carboplatin) and a taxene remains the standard treatment for advanced stage folloiwng an optimal primary debulking surgery.

Mesothelia is a rare and aggressive cancer. One of the primary mesothelioma causes is asbestos exposure. The cancer develops in the mesothelium, a protective membrane that lines three body cavities: the thoracic cavity (pleura), abdominal cavity (peritoneum) and the heart sac (pericardium). In the case of testicular mesothelioma, the cancer develops in the tunica vaginalis, the membrane surrounding the testicles.

The cancer develops when asbestos fibers are inhaled or ingested into the body where they can become lodged in organs or cavities, causing inflammation or infection and cellular damage. Overtime, the cancerous cells begin to divide uncontrollably, causing the membranes in the affected location to thicken. Fluid then begins to build up in the spaces between membrane layers and tumors begin to form, causing impaired bodily function.

A mesothelioma patient will generally not demonstrate symptoms of mesothelioma until 20 to 50 years after initial exposure to asbestos. Symptoms often resemble illnesses such as influenza and pneumonia, and in the case of pericardial mesothelioma, symptoms can resemble other cardiac conditions. This can make mesothelioma diagnosis difficult though informing a doctor of prior asbestos exposure can alert them of the possibility of an asbestos-related disease.

What is the typical prognosis for a patient with mesothelioma?

A mesothelioma patient’s prognosis, or the probable course and outcome of a disease’s influence on the body, is influenced by numerous factors. Since a mesothelioma diagnosis often occurs once the cancer has progressed to later stages of development, prognosis is typically poor. However if a patient is diagnosed before the cancer has spread or elects to undergo treatment to combat the cancer, their prognosis may improve. Factors that may influence prognosis include: the stage of a patient’s mesothelioma at the time of diagnosis, type of mesothelioma, size of the tumor, location of the tumor and whether it may be surgically removed and the age and overall health of the patient.

It is important to note that each patient may experience some or all of these stages in a different order or for varying amounts of time. Even though these stages are natural reactions to a mesothelioma prognosis, some patients may need help dealing with them.

Is there a cure for mesothelioma?

While a cure for mesothelioma does not currently exist, treatment options such as surgery, chemotherapy and radiation are available for patients to help combat the cancer. Extensive studies and mesothelioma clinical trials are in progress internationally and cancer specialists and doctors are constantly working towards the discovery of a cure.

Lung Cancer is the leading cause of cancer death among both men and women globally. Tobacco smoking is the most prominent cause of lung cancers but not the only cause. The majority of lung cancers include small cell lung cancer (SCLC) and the three non-small cell lung cancer (NSCLC) types. NSCLC tumours are highly heterogenous and despite advances in therapy, the overall 10 year survival rate remans low at 8%.

Lung cancer is the leading cause of cancer mortality worldwide, with about 1.8 million deaths in 2020. About 85% of cases are non-small cell lung cancer (NSCLC), with lung adenocarcinoma and lung squamous cell carcinoma being the prevalent sybtypes. The majority of patietns present with stage III-IV disease, with limited treamtent options and survival rates. (Gilligan, “Residual ctDNA after treatment predcits early relapse in patients with early-stage non-small cell lung cancer” March 2022, Annals of Oncology). 

Diagnosis: 

Usually lung cancer is initially viewed on chest X-rays or CT scans which is then confirmed with a biopsy. Four major histology types categorized by the size and appearance of malignant cells. 

Recent research has shown that cirulating tumour DNA (ctDNA) in blood can be used as a liquid biopsy, providing a minimally invasive diagnostic tool to assess tumour burden in cancer patients. Fragmetns of DNA are rleeased into the circulation as cell free DNA through apoptosis, necrosis or active release. In cancer patients, DNA is also released form tumour cells and this ctDNA may represent a small fraction of the total cell free DNA. (Gilligan, “Residual ctDNA after treatment predcits early relapse in patients with early-stage non-small cell lung cancer” March 2022, Annals of Oncology).

Treatment

Traditional Treatment Therapies:

NSCLC was the leading cause of cancer death in 2000, claiming more than 1 million lives. Traditional therapeutics towards SCLC lung cancer is chemotherapy and/or radiotherapy while patients with NSCLC a surgical resection of the primary tumour with or without a combination of chemotherapy and chest radiotherapy. Common chemotherapy regimens include cisplatin, platinum or carboplatin in combination with one or more of gemcitabine, paclitaxel, docetaxel, etoposide, vinorelbine, topotecan, or irinotecan. However, the average 5-year survival rate of lung cancer patients is less than 15%. The survival rate has not improved over the past decade, mainly because the tumors become resistant to traditional chemotherapy and the cancer is able to expand and metastasize. In addition, chemotherapy nonspecifically kills normal proliferating cells in addition to cancerous cells.

Unpredictability in Treatmnet of NSCLC:

A great majority of therapies for NSCLC failed in clinical trails. In non-small-cell lung cancer alone, between 1990 and 2005, a total of 1,631 new drugs were sutdied in phase II. Only sevel of these new agents gained FDA approval. OSI Pharmaceuticals, LLC v. Apotex Inc. (USPTO Patent Trial and Appeal Board IPR201601284)

Anti-EGFR compunds: Activation of the EGFR triggers a cascade of events leading to cell reprudction, and inhibiting EGFR can be beneficial in treating tumor cells. 

–Erlotinib (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy-4-quinazo-linamine): is and FDA anti EGFR compound. It is protected by US Patent No: 6,900,221. 

PD-1 (programmed death receptor-1): Bristol Myers Squibb Company has obained FDA approval for Opdivo (nivolumab) injection, for intravenous use, for the treatment of maetastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

Keytruda (Merck) which is an anti-PD-1 blocking antibody is approved for patients with metastatic non-small cell lung cancer whose tumors express PD-1 and who have disease progression after platinum containing chemotherapy. 

Possible Treatments in Future: Recent evidence showed that cancer in general may be sustained by a small subpopulation of cancer stem cells (CSCs).

–CD133 has been identified as a surface marker of CSCs and methods of treating subjects by adminsitering compositions antgaonistics to this polypeptide have been proposed (WO 2010/126452). 

–Inhibitors of farnesyltransferase (FTIs) have been demonstrated to be effective in treating Ras-dependent tumors in animal models. 

Leukemia is a group of cancers that typically starts in the bone marrow and results in high number of abnormal white blood cells. 

Acute Lymphoblastic Leukemia (ALL)

ALL is an acute form of leukemia (cancer of the white blood cells) characterized by the overproduction and accumulation of ancerous, immature white blood cells (lymphoblasts). In ALL, lymphoblasts are overproduced in the bone marrow and continuously multiply, causing damage and death by inhibiting the produciton of normal cells such as red blood cells, other white blood cells and platelets. ALL is most common in childhood with a peak incidence at 2-5 years of age, and another peak in old age. 

Cuases: The efinitive cause of most cases of B cell ALL is not known, although in many cases, the disease results from acquired genetic alterations in the DNA of a single cell, causing it to become abnormal and multiply continously. (Hagal, WO 02/059264) 

Symptoms: include fever, increased risk of infection, shortness of breath, chest pain, cough, vomiting, and changes in bowel or bladder habits, increased tenedcy to bleed (due to thrombocytopenia) and signs indicative of anemia such as pallor, tachycardia (high heart rate), fatigue and headache. These sytpoms are indicative of a reduced production of functional blood cells, because the leukemia wastes the resources of the bone marrow, which are normally used to produce new fuunctioning blood cells. 

Diagnosis: begins with physical examination, complete blood count and blood smears. Bast cells are seen on blood smear in the majority of casesA bone marrow biopsy is conclusive proof of ALL. Pathological examination, cytogenetics such as the presence of the Philadelphia chromosome and immunophenotyping establish whether myloblastic (neutrophils, eosinophils or basophils) or lymphoblastic (B or T lymphocytes) are the problem. 

Acute Myeloid Leukemia (AML)

AML is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal whtie blood cells that accumulate in the bone marrow and interferes with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. It accounts for about 1.2% of cancer deaths in the US

Symptoms: include fatigue, shortness of breath, easy bruising and bleeding, and increased risk of infection. The syptoms are caused by replacement of normal bone marrow with leukemic cells, which causes a drop in red blood cells, platelets and normal white blood cells. A lack of normal white blood cell production makes the patient susceptible to infections, while the leukemic cells themselves have no infeciton fighting capacity. A drop in red blood cell count (anemia) can cause fatigue, paleness and shortness of breath. A lack of platelets can lead to easy brusing or bleeding with minor trauma. 

Some patients with AML may experience swelling of the gums because of infiltration of leukemic cells into the gum tissue. Rarely, the first sign of leukemia may be the development of a solid luekmic mass or tumor outside of the bone marrow, called a chloroma. 

Detection: An abnormal result on a complete blood count is a first sign of AML. An excess of abnormal white blood cells (leukocytosis) is a common finding. AML can also present with isolated decreases in platelets, red blood cells or even with a low white blood cell count (leukpenia). A presumptive diagnosis of AML can be made via examination of a peripheral blood smear when there are cirulating leukemic blasts. A definitive diagnosis usually requires an adequate bone marrow aspiration and biopsy. 

Marrow or blood is exmained via ligh microscopy as well as flow cytometry to diagnose the presence of leukemia and to differentiate AML from other types of leukemia such as acute lymphblastic luekemia (ALL) and to also classify the subtye of disease. 

Treatment: varies among subtypes. AML is treated initial with chemotherapy aimed at inducing a remission. Patients may go on to receive additional chemotherapy or a hematopoietic stem cell transplant. 

Chronic Myelogenous Luekemia (CML) 

The Philadelphia chromosome is a genetic abnormality in chromosome 22 in luekemia cells. The gene is the ABL1 gene of chromosome 9 justaposed onto the BCR gene on chromosome 22 coding for a hybrid protein; a tyrosome kinase signalling protein which is always “turned on” as a result of the abnormality, causing the cell to divide uncontrallably. 

Treatments: 

–Tyrosine kinase inhibitors: 

—-Imatinib (Glivec): was approved by the FDA in 2001 for the treatment of chronic myelogenous leukemia (CML), a rare form of cancer that affects certain type of white blood cells. Since approval, its use has been approved for pateitns with several types of gastrointestinal tumors. The drug has been described as a miracle drug in that it has a phenomenal success rate. Its development started in the late 1950s when researches notice that cancer cells chromosomal abnormality in that individuals with CML had an atypical small chromosome #22 which was called the “philadelphia chromosome”. The long arm had transferred to chromosome 9. Ten years later scientists determined the actual genes involved in the translocation labeled as human c-abl oncogene located in the region of chromosome 9 that translocates to become part of the Philadelphia chromosome. Then, the scientists idnetifed a breakpoint cluster region in which all of chromosome 22 breaponts seemed to occur in CML pateitns. Later scientists from the Whitehead Institute in Cambridge infected bone marrow cells with a retrovirus encoding the fusion gene and demonstrated that the presence of an iactive bcr-abl gene initials CML like symptoms. Later researches identified the fuction of the bcr-abl fusion gene: production of an abnormal tyrosine kinase protein that is not properly regulated. This proliferation resutls int he overproduction and accumulation of immature white blood cells, which is the ahllmoark of CML. Research at Ciba-Geigy (which later become Novartis) identified kinase blocking inhibitors using computer models to predict which molecule structures might fit the ATP binding site of the fusion protein. One compound was particularly pormosing. kills cancer cells by turning of tyrosine kinase. It is marketed by Novartis. It is on the World Health Orgnization List of essential medicines. 

Colorectal cancer (CRC): is a term used to refer to colon and rectal cancers. The major differences between the two are the sites where the malignant growths occur and the fact that treatments may differ based on the location of the tumors. Colon cancer is the second leading casue of cancer deaths in the US. Each year over 100,000 new cases are diagnosed, and 50,000 patients die from the disease. In large part this death rate is due to the inability to diagnose the disease at an early stage. CRC is one of the most frequently diagnosed cancers and cancer related mortality remains unacceptably high despite improvements in understanding the events leading to malignant transformation of the colorectal epithelium. The lifetime risk of developing CRC is about 1 in 18 person (Cancer Statistics 2009: A Presentation from the American Cancer Society, 2009).

How CRC starts: 

Colorectal carcinogenesis occurs as a multstep process that requires sequential or concomitant damage to several genes within and across cellular generations. The pathogenesis of CRC is characterized by a well defined sequence of events – from aberrant crypt proliferation or hperplasia over benign adenomas to carcinoma in situ and, finally, metastatic carcinoma.

Classification: Pathologists classify abnormal mucosal growth into 4 categories with increasing severity: 1) low-grade intraepithelial neoplasia (LIEN) or adenoma, which occurs in more than 30%, 2) high-grade intraepithelial neoplasia (HIEN) or advanced adenoma, occuring in more than 2%, 3) carcinoma in situs, where the cancerous growth is still confined to the mucosa, and 4) CRC, where the cancerous growth has invaded the submucosa.

Diagnosis: 

Cologuard

CRC is diagnosed with an incidence rate of about 1% in persons over the age of 55 years with an average risk of the disease. Current technologies to detect CRC include:

1) in vitro diagnostics where a specimen is taken from the test person and analyzed for one or mroe biomarkers. Exemplary tests include guaic fecal occult blood test (gFOBT) or immunological fecal occult blood test (iFOBT).

2) imaging methods without interventional capabilites such as X ray.

3) imaging methods with interventional capabilities such as colonoscopy.

Treatment: 

The prognosis for a case of colon cancer is vastly enhanced when malignant tissue is detected at the early stage known as polyps. Simply removal of malignant polyps (polypectomy) through colonoscopy is now routine, and curing the condition from this procedure is effectively guaranteed. Noramlly a malignant colon cancer will not cause noticeable symptoms (e.g., bowel obstruction, abdominal pain, anemia) until it has reached an advanced and far mroe serious stage of malignancy. At these stages, only risky and invasive procedures are available, including chemotherapy, radiation therapy, and colonectomy.

Adjuvant chemotherapy, radiation therapy and immunotherapy have shown some usefulness in the treatment of primary and advanced colorectal carcinoma. Chemotherapy alone has limiations in that the cancer cells often become resistant to a broad spectrum of structurally unrelated chemotherapeutic agents. In immunotherapy, immunoglobulin molecules are preferably specific for an antigen expressed on the cancer cells. For example, in the case of colorectal cancers, radiolabelled antibodies specific for A33 antigen have shown promise for targeting colon cancer cells (US2002/0187144A1).

Antibodies

Monoclona antibody (mAb) A33 recognizes a cell surface differentiation antigen (A33) of normal human gastrointestinal epithelium that is expressed in 95% of primary and metastatic colorectal cancerl cells, but is absent in most other normal tissues and tumor types. Consequently, the A33 antigenic system is the focus of several clinical studies in patients with colon cancer. Damasceno (Protein Expression and Purification 37 (2004) 18-26)

The anti-epidermal growth factor receptor (EGFR) mAbs cetuximab and panitumumab are effective in a subset of RAS/BRAF wild-type metastatic colorectal cancers (mCRCs). However, the onset of secondary resistance limits their clinical benefit. After EGFR blockage, about 20% of CRCs develop mutations in the EGFR extracellular domain (ECD) that impair antibody binding and are associated with clinical relapse. EGFR extracellular domain that impair antibody binding and are associated with clinical replace can be targeted more efficiently with antiboies that bind multiple regions of the EGFR ECD. Arena, Science Translational Medicine, 8(324) 324ra14). 

Anti-PD-1 mAb: A small study showed incredible results against rectal cancer. All patietns had mismatch repair-deficient locally advanced rectal cancer and were given dostarlimab, an anti-PD-1 monoclonal antibody, every three weeks for six months. After at least six months of follow-up, all 14 pateints ahceived remission, with no evidence of tumors on medical scans and tests, digital rectal exam or biopsy. 

Useful Links:  National Cancer Institute (Staging)

Currently used International Federation of Gynaecology and Obstetrics system of aging (FIGO staging) is based on anatomical extent of the disease and on clinical evaluation. When there is doubt as to which stage a particular cancer should be allocated, the earlier stage is mandatory.

Detection/Staging

In patients with histologically (biopsy, endo-cervical curettage and/or cone biopsy) confirmed cervical carcinoma, a staging procedure is required that involves colposcopy, vaginal and rectal examination, cystoscopy and recto-sigmoidoscopy, to assess the extension to the surrounding structures (parametria, baldder and rectum). Suspected bladder and/or rectal involvement should be confirmed histologically.

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) are usually preformed to determine lymphadenopay and parametrial spread, respectively.

To rule out small nodal disease, particularly in para-aortic region where external radiation may offer a survival advance, Positron emission tomography (PET) scanning is the preferred approach. PET was shwon to be significanly superior to CT/MRI (sensitivity: 92% vs. 60%) in identifying metastatic lesions.

Treatment of Cervical Cancer by Stages:

–Stage Ia microinvasive disease:

Interest in defining this sub-stage of cervical cancer is motivated by the desire to preserve fertility and prevent the potential complications of radical treatment.

–Stage Ia1 cervical cancer: defined as minimal microscopic invasion (depth <3mm, width <7mm) can be managed conservatively. Treatment options are –conization, in women wishing to retain their reproductive potential, assuming complete excision of the lesion, –simple hysterectomy, in women who do not wish to retain fertility.

Some believe that presence of lymphovascular invasion requires radical treatment.

–Stage Ia2 cervical cancer: depth 3-5 mm, with <7mm have the risk of nodal disease of about 7% and accordingly, unless there are strong reasons for conservative treatment, the patient can be treated by primary radical hysterectomy, modified radical hysterectomy with pelvic lymphadnectomy or primary radiotheraphy.

–Stage Ib-IIa cervical cancer:there is no standard treatment. Most patients are treated by either radical surgery or radical radiotheraphy. Combinations of surgery and radiotherpahy are also used.

–stage Ib1 and early stage IIa disease: radical hysterectomny with pelvic lymphadnectomy (pelvic lymph nodes are carefully dissected to remove as many of the nodes as possible)

–Stage Ib2 disease: treatment of bulky stage Ib tumors (primary tumors greater than 4 cm) is difficult and whatever primary treatment is chose, the recurrence rate is higher when compared to stage Ib1 disease. While some centers are performing primary surgery as for stage Ib1 disease followed by tailored postoperative radiation with or without chemotheraphy, others are in favor of pirmary radiation therapy.

The rate of pelvic relase is significantly higher among patients with stage Ib2 disease who had radiation alone (30%) compared to those who had surgery plus adjuvant radiation (20%).

Neoadjuvant ehmotheraphy is a possible alternative in treatment. The rational is that apart form eradicating micrometastases, it would debulk the tumor and thus improve the outcome of subsequent surgery or radiotherpahy.

-Stage IIB-IVa cervical cancer: radiotheraphy has long played a mjaor role in the treatment of locally advance cervical cancer. Standard treatment for advanced cervical cancer is radical external beam radiation theraphy plus brachytheraphy. It is important that appropirate dosing is administered to the central tumor and the pelvic side wall nodes.

There is strong evidence that chemotheraphy should be incorporated into radiation treatment of patients with advanced cervical caner. Today, concurrent cisplatin-based chemo-radiation is considered the treatment of choice in locally advanced, metastatic and recurrent cervical cancer. The addition of chemotheraphy has significantly improved cumulative rates of survival at 8 eyars (67% vs. 41%)

National Cancer Society National Cancer Institute World Health OrganizationIARC

BMJclinical Evidence AP John Institute 

Cervical cancer is the second most common cancer in women worldwide. Cervical cancer accounted for an estimated 11.070 new cases and 3870 deaths in the USA for 2008. Nearly 1/3 of patients who present with invasive cervical cancer will die of their disease. Cervical Cancer is named for the part of the body in which it begins. Cancers of the cervix also are named for the type of cell in which they begin. Most cervical cancers are squamous cell carcionmas. Squamous cells are thin, flat cells that form the surface of the cervix.  In many developing countires, hwere mass screening programs are not widely available, the clinical problem is more serious. Woldwide, the number of new cases is estimated to be 471,000 with a four year survival rate of only 40%. A large body of epidermioloigcal and molecular biological evidence has established human papillomavirus (HPV) infection as a causative factor in cervical cancer. HPV is found in 85% or more of squamous cell invasive lesions, which represent the most common histoloigcal type seen in cervical carcinoma. Additional cofactors have also been identified, including oncogenes that have been activated by point mutations and chromosomal translocations or deletions. In light of this, cervical cancer remains a highly preventable form of cancer when pre-invasive lesions are detected early. Tytological examination of Papanicolaou-stained cervical smears (also referred to as Pap smears) is currently the principle method for detecting cervical cancer. The effectiveness of Pap smear screening varies depending not only upon the quality of the sampel being used, but also upon subjective parameters that are inherent to the analysis.

The recurrence rate of cervical cancer is between 10% and 20% for FIGO stages Ib-IIa and 50-70% in locally adevanced cases (stages IIb-IVa). Patients with recurrent disease or pelvic metastases have a poor prognosis with a 1 year survival rate between 15% and 20%. (see Chemotherapy for recurrent cervical cancer, Pectasides et al. Cancer Treatment Reviews (2008)).

Causes/Etiology: 

Infection with high risk types of human papillomavirus is the main cause of cervical cancer. HPV DNA is double-stranded, containing 7,900 base pairs, which are arranged in a circle. The genome consists of 8 open reading frames, 6 early genes (E1, E2, E4, E5, E6 and E7) encoding the early protein and 2 late genes (L1 and L2) encoding the late protein. E1 protein aids in viral replication utilizing the host replication machinery. E5, E6 and E7 proteins are considered to be associated with virus immune evasion. 

HPV infection starts with the contact of the virus with the basement membrane, which is often exposed by micro-abrasions on the cervical surface. Suitable receptors increase the probability of hrHPV infection. Studies have found several receptors involved in this process. Interaction between the virus’ capsid protein and the cell receptors promotes virus capsid conformational changes, thus aiding the cell entry process.

HrHPV infection promotes immune cell migration to the dermis. In the squamous epidermis, macrophages, Langerhans cells (LC), KCs, T lymphocytes, dendritic cells (DC), natural killer cells (NK) and B lymphocytes play important roles during the immune response to infection. HrHPV infection could cause the immune system to become more tolerant to the infection, thus creating a microenvironment susceptible to further infection and facilitating CIN progression. The mechanisms that have been proposed and proved are as follows: Firstly, HPV remains silent for a long time; its duplication and assembly do not cause cytolysis or the cytopathic death of the host cells. Secondly, hrHPV inhibits interferon (IFN) synthesis through E6 and E7 oncoproteins interfering with IFN signaling pathways. Thirdly, HPV infection induces regulatory T cell (Treg) infiltration and interleukin (IL)-10 or transforming growth factor β (TGF-β) production. Fourthly, the infected cells express low levels of MHC class I, resulting in impaired CTL function. Fifthly, they could induce an accumulation of ineffective CD4 and CD8 T lymphocytes in stage II/III CINs.  See Song

Prevention: 

Vaccination as well as screening are the primary ways to prevent cervical cancer. The preventive vaccination against HPV16 and 18 has now become widely used. Antigen-specific immunotherapy is one of the effective methods to elicit immune responses to hrHPV. Listeria monocytogenes (LM) has been used to eliminate palpable, vascularized tumors in several mouse models due to its ability to generate CD8+ tumor-infiltrating lymphocytes. Two vaccines, LM-LLO-E7 and LM-ActA-E7, have been created by a truncated listeriolysin O (LLO) fused to E7 and a fragment of the ActA protein fused to E7, respectively. These vaccines overcome central tolerance by expanding low avidity CD8+ T cells specific for E7. See Sounders

symptoms: 

certical cancer usually originates in the transformation zone of the cervix, and spreads to regional lymph nodes. Clinical presentation depends mainly on the location and extent of disease.

Precancerous changes or very early stage disease are usually asymptomatic and are detected on a cervical smear.

Symptoms usually appear when the tumour causes spontaneous or contact bleeding, or pain if lymph nodes are involved. Other symptoms include serosanguineous foul smelling vaginal discharge or backache.

Diagnosis: 

When a lesion is visible with the naked yee, conisation is contraindicated, and a cervical biopsy will usually provide the diagnosis. Conisation is indicated when frank invasion cannot be ruled out by a colposcopically directed biopsy, or when colposcopy is unsatisfactory and the results of a smear test show a high grade lesion.

Pathology:Squamous (thin, falt cells that form the surface of the cervix) cell carcinoma accounts for about two thirds of all cervical cancers. Adenocarcinoma has many histological variations and is found in 15-25% of cases. Unusual histological variants include clear cell carcinoma, neuroendocrine carcinoma, and adeno-squamous carcinoma.

Tumour grade (wee differentiated, moderately differentiated, and prooly differentiated), depth and width of invasion, and presence (or absence) of invasion of lymphovascular space are prognostic factors that should be adequately assessed.

Recurrent disease: 

Recurrent cervical cancer is almost always incurable and less than 5% of patients who develop recurrence are alive at 5 years.

pateints who develop pelvic recurrence after radical hysterectomy may be salvaged with chemoradiotheraphy if they have not previously been irradiated.

Central pelvic recurrences after radiation or chemoradiotherpahy may udnergo curative surgery with pelvic exenteration in the absence of metastatic disease.

Most recurrences occur in the first two years after primary treatment. The recurrence rate is between 10% and 20% for FIGO stages Ib-IIa and 50-70% in locally advanced cases (stages IIb-IVa). Both persistent and locally recurrent pelvic tumors are characterized by an advanced malignant progression and often exhibit an anatomically complex topography rendering curative treatmetn very difficult and rarely successful. The role of chemotherpahy in patients with recurrent or metastatic disease is merely palliative. There is no standard but when chemotheraphy is indicated, cisplatin administered in dosage of 50-100 mg/m every 3 weeks seems to be a reasonable option.

Physical examination includes rectovaginal examination, nodal assessment (especially supraclavicular) and cervical smears. Examination should be performed every six months and after 5 years annually. Pain, vaginal bleeding, and gastrointestinal or genitourinary dysfunction must be investigated.

Treatment: see ouline