ONCOGENES AND ASSOCIATED TUMORS

 1.Growth factor

• PDGF- acts on  PDGF Receptor- Astrocytoma( associated tumor due to mutation)

             mechanism: PDGF binds to PDGF receptor on the astrocytes. Due to mutation, the astrocytes start producing PDGF which again binds to the receptor and the cell grows nd divides continuously. An autocrine loop is formed leading to the tumor formation

                                   

2.Growth factor receptors

• ERBB2[HER2/neu] - Epidermal growth factor receptor- Invasive breast cancers
• RET- neural growth factor receptor- MEN 2A, MEN 2B, Medullary carcinoma of thyroid
• KIT- Stem cell growth factor receptor- GI stromal tumor, testicular seminoma, mast cell diseases, AML

       mechanism: The effect of a single signal is amplified and the cell grows out of control.

                                     

 →HER2/neu overexpression is treated by Trastuzumab

 →When patient has  MEN 2A/2B and has RET mutation, then prophylactically thyroid is removed to avoid medullary carcinoma of thyroid.

3.Signal Transducers

• RAS gene family- GTP binding protein- carcinoma, melanoma, lymphoma                                                                                                                                                                                                           mechanism: Generally, RAS is associated with growth factor receptor in an inactive GDP bound state. when growth factor binds to the receptor, the GDP is replaced by GTP. this complex sends signals to the nucleus which allows cell growth. GTPase activating protein(GAP) will help in conversion of GTP into GDP and stops multiple signals from being passed. Mutated Ras inhibits GAP and multiple signals are sent to the nucleus leading to tumor formation.
•     ABL - Tyrosine kinase - t(9;22) BCR -   CML and some types of ALL.

                                    

4. Nuclear regulators( act on transcription factors)

• c-MYC - Burkitt lymphoma
• N-MYC - Neuroblastoma
• L-MYC - Lung carcinoma                                                                                                                     mechanism: In c-MYC mutation, t(8;14) involving IgH leads to increased production of MYC which will lead to tumor of B cell...Burkitt lymphoma

                                   

5. Cell Cycle Regulators

•  CCND1 - cyclin- Mantle cell lymphoma
• CDK4- cyclin-dependent kinase- Melanoma                                                                                           mechanism: cyclin D/ CDK4 complex phosphorylates the retinoblastoma protein, which promotes progression through the G1/ S checkpoint in cell cycle.     

Mantle zone in the lymph node

                                   

      

AMINOGLYCOSIDE ANTIBIOTICS

Aminoglycosides are bactericidal antibiotics

🠚Aminoglycosides are inactivated under anaerobic conditions. Therefore, anaerobes are resistant to it and facultative anaerobes are more resistant when oxygen supply is deficient . Ex: in big abscesses

🠆These drugs combined with 𝛃-lactams or vancomycin(which affect bacterial cell wall formation) allow the aminoglycosides to penetrate the bacterial cell wall  and exhibit synergism.

MOA

Streptomycin: Binds to 30s ribosomal subunit

other aminoglycosides :Bind to additional sites on 50s subunit and 30s-50s interface

↓

They freeze INITATION process of protein synthesis

↓

Prevent polysome formation & promote their disintegration to non-functional monosomes

↓

Distortion of   mRNA codon recognition 

↓

One or two wrong amino acids are entered in the peptide chain leading to peptides of abnormal lengths are produced

TOXICITIES

1. Ototoxicity: 

Drugs are concentrated in the labyrinthine fluid and slowly removed from it when plasma concentration falls.

a) Cochlear damage:

• No regeneration of the sensory cells occurs, auditory nerve regenerates in retrograde manner
•  Ototoxicity is asymptomatic  and can be detected by audiometry 

b) Vestibular damage 

•  headache first, followed by nausea, vomiting, nystagmus vertigo and ataxia.

2.Nephrotoxicity

Tubular damage resulting in loss of urinary concentrating power, low gfr, nitrogen retention albuminuria and casts.

Important implication of aminoglycosides induced nephrotoxicity is reduced clearance of the antibiotic resulting in higher and more persistent levels in blood which leads to ototoxicity

                                             

3. Neuromuscular blockade

All aminoglycosides reduce Ach release from motor nerve endings.

They interfere with :

• Mobilization of centrally located synaptic vesicles to fuse with terminal membrane.
•  decrease the sensitivity of muscle end plate to Ach.

GENTAMICIN

• Highly active against aerobic gram -ve bacilli ( E.coli, Klebsiella pneumoniae, Enterobacter, H.influenzae, Brucella etc.)
•  gentamicin is ineffective against M.TB and other mycobacteria

Uses

1. Treatment of respiratory infections in immunosuppressed patients, patients in resuscitation wards or on tracheostomy or on ventilator, ICU

• They should not be used for community acquired pneumonias, as they are caused by aerobic gram +ve cocci and anaerobes
• They are used to treat peritonitis

2. Pseudomonas , Klebsiella, Proteus infections: burns, UTI, septicemia

      Topical use for infected burns and for conjunctivitis is permissible

3.Meningitis caused by gram negative bacilli:            3rd generation cephalosporins +                          aminoglycosides                                                          

4. SABE : Gentamicin( 1 mg/kg 8hrly i.m.) combined with penicillin/ ampicillin/ streptomycin

                             

STREPTOMYCIN

• It has narrow anti-bacterial spectrum
• Gram -ve bacilli (Brucella , Yersinia, Francisella , Nocardia, Shigella, Vibrio)

Uses

1.TB- It acts on extracellular bacilli. it penetrates tubular cavities but does not cross CSF.

It is always used in addition to other  1st line anti- TB drugs.

Resistance is developed rapidly when Streptomycin is used alone in TB - most patients have relapse. In case of streptomycin resistant infection, it must be stopped at the earliest because the infection flourishes if the drug is continued due to streptomycin dependence. Non- tubercular mycobacteria is unaffected by streptomycin.

2.Plague- it is rapidly curative in positive patients

3.SABE- Streptomycin+ penicillin/ampicillin/vancomycin

4.Other conditions like UTI, peritonitis, septicemia

Hypersensitivity reactions like rashes, fever exfoliative dermatitis may occur. It has the lowest nephrotoxicity.

                                             

ANTI -TUBERCULAR DRUGS

Tuberculosis is a chronic granulomatous disease and a major health problem in developing countries. About 1/3 of world's population is infected with mycobacterium tuberculosis.

A total of 1.5 million people died from TB in 2018 (including 251 000 people with HIV). Worldwide, TB is one of the top 10 causes of death and the leading cause from a single infectious agent (above HIV/AIDS).

An estimated 58 million lives were saved through TB diagnosis and treatment between 2000 and 2018.

                                        

   Classification of anti-tubercular drugs

                            

Rifampin, Isoniazid, Pyrazinamide, Ethambutol (RIPE) drugs are the first line drugs used for the treatment of TB.

                                  

ISONIAZID(H)

• It acts on extracellular and intracellular tb (bacilli within macrophages).
• It is active in acidic and alkaline medium

     MOA

 

                                                        INH(prodrug)

                                                                ↓

                                                 enters                                                                           mycobacteria

                                                                ↓

                         catalase-peroxidase enzyme                              converts it into active form(Kat-G)

                                                                ↓

                                                          active INH

                                                      ↙            ↘                                                

                   forms adduct with NAD     forms an                                                                         adduct                                                                            with                                                                                NADP                                           ↓                                                      ↓

   Inhibition of DHFRase             Inhibits InhA,                                                                 KasA genes 

                                 ↓                                     ↓                                      

                Inhibition  of  

DNA synthesis                                          Mycolic                                                                   acid                                                                 synthesis inhibited                                                     which are unique                                                           components of                                                           mycobacterial                                                                 cellwall                      

                                    

Adverse Effects

 

• Peripheral neuritis, paresthesias, numbness, convulsions, mental disturbance.These effects are due to interference with production of active coenzyme pyridoxal phosphate from pyridoxine and its increased excretion through urine.

        Therefore pyridoxine is given 10mg/day prophylactically to prevent neurotoxicity.

         INH neurotoxicity is treated by pyridoxine 100mg/day.

•  Another side effect is hepatotoxicity and INH must be stopped at the first sign of   hepatotoxicity.
•  It may cause drug-induced lupus and anion gap metabolic acidosis.

      This drug penetrates the CNS freely and is a key chemotherapeutic agent in Tubercular Meningitis with proven potent bactericidal activity.

RIFAMPIN (R)

1. It is a bactericidal drug. 
2. Active against M.Leprae and  MAC(Mycobacterium Avium Complex).
3. It affects extracellular and intracellular bacilli.

MOA

                                                           Rifampin

                                                                       ↓

                                binds to 𝛃-sub unit of DNA                                     dependant RNA polymerase

                                                                       ↓

                                            blockage of                                                            polymerization function

                                                                ↓

                                                inhibition of DNA                                                            synthesis

Adverse Effects

• Hepatitis:If jaundice develops then rifampin should be discontinued
• cutaneous:flushing, pruritus, rash, redness
• flu-like symptoms: chills, fever, headache, malaise, bone pain
• nausea ,vomiting ,diarrhoea

 

Uses

• Used in treatment of TB
• Used in treatment of leprosy
• Prophylaxis for meningococcal and H. influenzae meningitis
• 2nd /3rd choice drug for MRSA

  ETHAMBUTOL (E)

1.  Ethambutol blocks arabinosyl transferase, inhibiting carbohydrate formation at the cell wall.
2. It is bacteriostatic. 

Adverse Effects

•  optic neuritis (loss of visual acuity, red green color blindness).
• hepatotoxicity is seen.

  PYRAZINAMIDE (Z)

 

1. Pyrazinamide may cause hyperuricemia and needle shaped uric acid crystal formation. 
2. It precipitate gout attacks. 
3. can be hepatotoxic. 

                                                     

                                   

                        

                                                

Snippet from pathology:

HODGKIN'S LYMPHOMA

It is a type of cancer that originates from a specific group  of white blood cells called B lymphocytes.It arises within lymph nodes and also involves extra-nodal lymph nodes secondarily. 

                                

                                     

Incidence

Hodgkin's disease had a bimodal distribution of age-specific incidence rates with two peaks in the age groups of 15-34 years and older than 55 years.

It is more prevalent in young adult males than in females.

                                           

Etiology

Its main etiology is from Ebstein barr virus(EBV). This virus causes increased production of the transcription factor NF-𝜿𝛃( responsible for proliferation) in the B cells and decreased production of I-𝜿𝛃 (responsible for inhibition of NF-𝜿𝛃) which ultimately leads to increased proliferation of cancer cells.

REED STEENBERG CELLS

• Presence of these cells is the classical feature of hodgkin lymphoma.
• These cells have 2 nuclei with prominent nucleoli.
• OWL EYE appearance of cells.
• They have CD15 and CD30 markers on their surface.
• Aneuploidy(more than normal number of copies) of 2p chromosome.

Variants of RS cell

Lacunar cell- it has all the features of a RS cell with a pericellular cytoplasm or lacuna in which it lies. This lacuna is formed by the artificial shrinkage of the cytoplasm .

It releases TGF-𝛃 responsible for deposition of fibrous tissue.

Polypoid type / lymphohistiocytic cell / popcorn cell

In this type the nucleus has irregular indentations.

CD15 and CD30 are absent.CD20 is present.

Pleomorphic RS cells

They have pleomorphic or atypical nuclei

                                        

Presence of RS cells along with inflammatory cells is considered as hodgkin's lymphoma . This is because in some conditions like infectious mononucleosis and immunoblastic lymphoma RS-like cells are found.

1. Nodular sclerosis classical HL 

•      It is the most common type of hodgkin's lymphoma in the world.
•      Equal incidence in males and females
•      It consists of lacunar type of reed steenberg cells. Because of these cells variable amount of fibrous tissue is present in the involved lymph node.

2.Mixed cellularity classical HL

• It is the most common type in India
• It consists of RS cells, plasma cells , eosinophils and lymphocytes.
• Some amount of fibrosis and focal area of necrosis is present in the lymph nodes.

3.Lymphocyte rich HL

•    It is seen in elderly individuals .
•    It consists on lymphohistiocytic cells .
•    Since there are more number of lymphocytes in this type this condition has a better prognosis.

4. Lymphocyte depleted HL

•      In this type of HL the lymph node is depleted of lymphocytes so it has the worst prognosis.
•     Atypical histiocytes called hodgkins cells are seen.

                             

Nodular lymphocyte predominant HL has the best prognosis.

Clinical features include:

Painless, rubbery lymph node enlargement, mostly cervical lymph nodes.

Other symptoms are fever,night sweats and weight loss.

   

STAGING

                   

MULTIPLE MYELOMA

It is a cancer of plasma cells, which are type of white blood cells in the bone marrow. Plasma cells are responsible for producing antibodies which help in fighting infections. It is also called Kahler's disease. When plasma cells become cancerous, they proliferate and accumulate in the bone marrow and produce abnormal antibodies which cause complications. It produces osseous as well as extra-osseous manifestations.

                                             

Incidence

• mostly affects elderly individuals(50-60 yrs) and incidence increases with age
• more common in males than females

Etiology

-it can occur due to radiation exposure

-occupational exposure to petroleum products

-mutations

• 13q deletion
• translocation t(11;14)
• overexpression of MYC and RAS growth promoting oncogenes
• mutation in p53 gene(tumor suppressor gene) present on chromosome 17p

Pathogenesis

The neoplastic plasma cells adhere to bone marrow stromal cells(BMSC) with the help of adhesion molecules CD4,VLA4,ICAM-1

                                                                          ↓

Both MM cells and BMSC cells secrete growth factors and anti-apoptotic factors( factors which prevent programmed cell death) like IL-6 ,IGF-1,BCL-2

                                                                           ↓

These secretions mediate tumor cell growth, proliferation, survival, drug resistance and migration

                                                                           ↓

BMSC cells also secrete RANK ligand which bind to RANK receptors on the osteoclasts promoting their differentiation and resorptive activity

                                                                            ↓

                                              This causes lytic lesions of the bone

                                              

                                              

                                                                             

The most common affected bones are vertebrae, skull , ribs and pelvis and long bones of limbs. Radiographically these lesions appear punched out, rounded and 1-2cm in size.

The marrow is hypercellular and the myeloma cells constitute  greater or equal to 10% of marrow cellularity.

                                                                                                                                

Extra osseous lesions include:

• Blood: anemia,neutropenia, inc.↑↑ESR, ↑ serum calcium,↑IL-6
• Myeloma kidney: when the abnormal light chains of the antibodies are excreted in urine they are called Bence Jones proteins which cause renal tubular damage. These proteins combine with Tamm horsfall proteins and form tubular casts in the DCT.
• Myeloma neuropathy
• Systemic amyloidosis
• Liver and spleen involvement

Clinical features include:

• bone pain
• susceptibility to infections( due to neutropenia)
• anemia
• bleeding tendencies (due to thrombocytopenia)
• renal failure
• POEMS syndrome: occurs in 1% of the cases 

                                Polyneuropathy

                                Organomegaly

                                Endocrinopathy

                                Multiple myeloma

                                Skin changes

                                           

Diagnosis

• bone marrow clonal plasmacytosis >10%
• presence of M proteins in serum or urine
• related organ and tissue impairment:

                              C-increased calcium level

                              R-renal insufficiency

                              A-anemia

                              B-bone marrow lesions

• biomarkers-

                               S - 60% or more clonal plasma cells in bone marrow

                               Li- light chains

                               M- MRI