Ifosfamide based combination in advanced soft tissue sarcoma

1. Combinations of Ifosfamide and doxorubicin can be used in subjects with symptomatic,locally advanced,or inoperable sts where response may render tumorus operable
2. In subjects with metastatic sts addition of Ifosfamide to doxorubicin does not have any advantage.

Cancer treatment reviews(2008)34,p339-347

Metastatic Ca Endometrium

High risk of recurrence in Limited disease

1. deep myometrial invasion,
2. grade 3 disease,
   
3. high-risk cellular histologic types(serous or clear cell)

Solitary metastatic lesions that are amenable to radiation with or without surgical resection.

1. vaginal recurrences who have not received radiation can be treated with radiation,with complete response rates of 40% to 81%
   
2. Small central pelvic recurrences within a radiated field may be cured with pelvic exenteration.
3. Isolated metastasis to the lung parenchyma, brain, or liver

Targetted therapy --

1. mTOR Inhibitors,
2. Bevacizumab,
3. trastuzumab
4. Antagonists to EGFR include small molecule tyrosine kinase inhibitors (gefitinib, erlotinib, and lapatinib) and the anti-EGFR monoclonal antibody cetuximab.
   

Conclusions
Women with metastatic endometrial cancer have an overall poor prognosis, with survival estimates of less than 1 year. Patients who are chemotherapy-naive with a good performance status should be treated with combination chemotherapy. A combination of paclitaxel, doxorubicin, and cisplatin has shown the highest overall response rates to date. In women with multiple medical comorbidities, single-agent chemotherapy may be better tolerated with acceptable results. Hormonal therapy should be considered in women with lowgrade tumors and/or in women with a poor performance status because of the low associated morbidity of treatment.

HIV associated Lymphomas

1. Burkitt lymphoma (BL)
2. Diffuse large B-cell lymphoma (DLBCL) with immunoblastic-plasmacytoid differentiation
3. Primary effusion lymphoma (PEL) and its solid variants
4. Plasmablastic lymphoma of the oral cavity type
5. Large B-cell lymphoma arising in Kaposi sarcoma
6. Herpesvirus (KSHV)–associated multicentric Castleman disease

Preoperative tissue diagnosis -DCIS

1. Wire localisation and open biopsy
2. Image guided FNA/Automated core biopsy
3. Stereotactic -guide directional vaccum assisted biopsy
4. Fiberoptic ductoscopy
5. Ductal lavage

Breast MRI in DCIS

1. MMG is the gold standard
2. 10% completely occult on MMG
3. BMRI - High sensitivity and 3 dimensional view
4. High resolution Mri asses size ,focality and extent of DCIS better than MMG
5. Tends to over asses the size

Factors associated with an increased risk of invasive cancer in DCIS

Clinical Factors

1. Young age
2. Palpable disease Nodular density on mmg
3. Lesions >4cm
4. Pagets disease
5. Nipple discharge
6. Diagnosis by core biopsy
7. Patients undergoing mastectomy

Histopathological factors

1. High grade DCIS
2. Presence of comedo necrosis
3. Periductal Inflammation

Monoclonal Antibodies the current scenario

1. Paul Ehrlich introduced the concept of the “Magic bullet” (1900)
2. Pressman and Korngold in 1953 demonstrated that antibodies selectively targeted tumor cells and provided a means of exploiting the immune system by recognizing and directing antitumour responses against defined targets.
3. The therapeutic efficacy of these first generation monoclonal antibodies was limited largely due to their immunogenicity as these were generated from polyclonal antiserum from immunized animals. Recognized as foreign by the innate immune system it was rapidly cleared eliciting inflammatory effects.
4. 1970s -Multiple Myeloma -elaborated immunoglobulins .
5. Neils Jerne, George Kholer and Caesar Milstein in 1975 decided to use the immunoglobulin secreting machinery of the plasma cell for creating monoclonal antibodies. They fused myeloma cells that had lost their secretory capacity with previously immunized healthy B cells with intact secretory potential--The hybridoma--and generated large quantities of monoclonal proteins with high purity and monospecificity for a single epitope. In theory these constructs after binding to the antigen are eliminated by the immune system. Conjugates of these proteins were thought to provide the proverbial “magical bullet” for the treatment of various types of cancer.
6. Antibody based therapeutics elicit cell kill by modulating the immune system to target tumor cell (Cell mediated cytotoxicity Complement dependent cytotoxicity, and immunomodulation) or components of the signal transduction pathways with unconjugated antibodies and those Mo Antibodies not capable of eliciting an immune response are still rendered effective by conjugating them with cytotoxic payloads.1) Immunodrug conjugates- Focused delivery of antibody drug conjugates allows higher dose intensity with minimum normal tissue toxicity e.g.- Gemtuzumab for AML.2) Immunotoxins – Tumor localizations of antibodies targeting internalized antigens coupled with plant/bacterial toxins e.g. antiCD22 Immunotoxins for Burkitt lymphoma xenograft models.3)Radio immuno conjugates –e.g. Ibritumomab and Tositumomab for NHL.5)Immumnocytokine Conjugates- IL2 immuno conjugates enhance T cell mediated immune response to enhance a vascular leak to permit better localization of the antibody. Pre targeted multistep antibody conjugates have been developed with the idea of sparing the toxicity of systemic chemotherapy or the slow delivery of of an immunoconjugate – e.g. ADEPT-Antibody dependent Enzyme Pro drug Therapy.
   Unconjugated antibodies are another class of agents that are finding increasing application in the treatment of solid tumors. 1) Trasutzumab- A humanized antibody which recognizes HER-2 neu ,a member of the EGFR family and which is expressed in more than 25%of all breast cancers. Used in the adjuvant setting it reduces recurrence by 50% after a year of use.2) Cetuximab – This chimeric antibody binds to the domain 3 of the EGFR inhibiting the activation of the tyrosine kinase reception and finds use in the colorectal and squamous cell cancers.3) Panitumab –Blocks the binding of EGFR &TGFa is approved for the treatment of metastatic colorectal cancer relapsing after adjuvant therapy. 4) Rituximab and Alemtuzumab are humanized anti CD20 & anti CD 52 antibodies used in the management of NHL in the adjuvant setting.
   Since the advent of hybridoma technology by Kohler and Milstein, antibody therapy has witnessing a flurry of activity leading to few molecules that have reached the clinic and many more in the pipeline. Judicious application of the clinical and preclinical data is needed for the process to continue and more antibodies are needed to effectively tackle malignant tumors.

F317 MUTATIONS IN CML

1. Encountered in subjects with CML resistant to Dasatinib
2. Sensitive eto other TKI
3. Prognosis depends on the stage

(Blood-2008:112-4839-4852)

Chemotherapy for early stage NSCLC(Completely resected)

CALGB-9633

1. NSCLC Stage-1b(T2No)
2. Complete resection /Resection followed by Adj chemo -Paclitaxel+Carboplatin
3. Survival was not significantly different in both the arms
4. Significant survival benifit for subjects with tumour size > 4cm

This brings about the following questions

1. Is the benifit of adjuvant chemo transient.
2. Should we propose adjuvant chemo as standard.
3. Is the combination of Pacli and Carboplatin the standard.
4. Role of biomarkers .
5. Should this data be incorporated in to the NCCN guidelines.

(JCO- Vol-26(31) Nov 2008.

Solid Cancers after Hemopoietic Stem Cell Transplantation

Transplant recipients have been reported to have an increased risk of solid cancers.but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. 1-- Overall, patients developed new solid cancers at twice the rate expected based on general population rates. the risk reached 3-fold among patients followed for 15 years or more after transplantation.
2-- Among patients irradiated at ages under 30 years, the relative risk of non-SCC was9 times that of nonirradiated patients,while the comparable risk for older patients was 1.1
3--Chronic graft-versus-host disease and male sex were the main determinants for risk of SCCallogeneic transplant survivors.Those irradiated at young ages, face increased risks of solid cancers,

(Blood. 2009;
113:1175-1183)

1. 
   

NON HEMATOLOGICAL AUTOIMMUNE COMPLICATIONS OF CLL

1. Angioedema
2. Bullous pemphigoid/paraneoplastic pemphigius
3. Churg Strauss Syndrome
4. Imune thyroiditis
5. Nephrotic Syndrome
6. Polyneuropathy
7. Sjorgens syndrome
8. SLE
9. Raynauds
10. Rheumatoid Arthritis
11. Ulcerative Colitis
12. Vasculitis
    

NEW AGENTS FOR CLL

1. Monoclonal Antobodies -- Luimixilimab -Anti CD23 , Ofatumab - Moab binding to a different epitope other than rituximab
2. Immune modulators -- Lenalidomide
   
3. Cyclin dependent kinase inhibitors -- Flavoperidol ,SNS O32
   
4. BCL-2 Family Member Inhibitors --- Oblimersen ,Obatoclax
5. Protein kinase inhibitor -- Enzastaurine
6. Hsp90 inhibitor ---BII B201
7. SRC kinase inhibitors -- Dasatinib
8. Small modular immune pharmaceutics -TRU -16
   

HDT&PBSCT in Peripheral T Cell Lymphomas

Summary

1. Current data does not support the routine use of transplant in all patients with Peripheral T Cell lymphoma.
2. Certain histological subtypes (AILT) achieving CR after treatment may benifit and prospective randomized trials need to confirm this hypothesis.

ASH 2008 p-39-40