Melanoma is the most aggressive form of skin cancer and is notoriously resistant to all current modalities of cancer therapy. A large set of genetic, functional and biochemical studies suggest that melanoma cells become 'bullet proof' against a variety of chemotherapeutic drugs by exploiting their intrinsic resistance to apoptosis and by reprogramming their proliferation and survival pathways during melanoma progression. In recent years, the identification of molecules involved in the regulation and execution of apoptosis, and their alteration in melanoma, have provided new insights into the molecular basis for melanoma chemoresistance. With this knowledge in hand, the challenge is now to devise strategies potent enough to compensate or bypass these cell death defects and improve the actual poor prognosis of patients at late stages of the disease.

Apoptosis and melanoma chemoresistance.

Part 1 Lymphomagenesis: Lymphocyte differentiation Adult T-cell leukaemia/Lymphoma - a model of retrovirus-induced lymphomagenesis Burkitt's lymphoma and Epstein-Barr virus-associated lymphoid malignancies - models for lymphomagenesis T(14 18) translocation. Part 2 Methods: Histological and immunohistochemical methods Genotype. Part 3 Nodal Non-Hodgkin's Lymphomas: The normal lymph node - structure and function Histological classification Staging of NHLs Analytical study of the different subtypes of NHLs - clinical, histological and immunohistochemical aspects NHLs in childhood NHLs associated with HIV infection. Part 4 Extra-Nodal Non-Hodgkin's lymphomas: Malignant lymphomas of mucosa-associated lymphoid tissues Primary gastrointestinal NHLs Pathology of gastro-intestinal NHLs Cutaneous lymphomas NHLs of the Mediastinum NHLs of the lung Bone marrow involvement Blood involvement in chronic (mature) B & T lymphoproliferative syndromes Liver involvement Spleen involvement Extra-cranial head-and-neck NHLs Central nervous system involvement NHLs of bone Urogenital localizations. Part 5 Treatment of Non-Hodgkin's Lymphomas: Methodology and problems in the comparison of results Treatment of lowgrade NHLs The role of radiation therapy Treatment of aggressive lymphomas (intermediate and highgrade) Intensive chemoradiotherapy and bone-marrow transplantation Salvage therapy after failure Treatment of NHLs in childhood.

Non-Hodgkin's Lymphomas

Most patients with plasma cell neoplasia have generalized disease at diagnosis, i.e. multiple myeloma (MM). However, a minority (<5%) of patients with plasma cell malignancies present with either a single bone lesion, or less commonly, a soft tissue mass, of monoclonal plasma cells: solitary bone plasmacytoma (SBP) or extramedullary plasmacytoma (SEP). SBP has a high risk of progression to MM and on magnetic resonance imaging (MRI) examination at least 25% of patients with an apparent solitary lesion have evidence of disease elsewhere (Moulopoulos et al, 1993). In contrast, SEP is nearly always truly localized and has a high cure rate with local treatment. The diagnosis and management of patients with solitary plasmacytoma requires the same range of clinical and laboratory expertise as for patients with MM (UK Myeloma Forum, 2001). The primary treatment for most patients will be radiotherapy, but surgery may also be required, where close liaison among the haematologist, radiotherapist and surgeon is crucial for planning optimum care. Methods A literature search was performed by a professional librarian using MEDLINE and EMBASE from 1996 to March 2002. A search was made for randomized-controlled trials involving plasmacytoma, papers where plasmacytoma was the major focus of the paper and reviews where plasmacytoma was the major focus. The literature was then reviewed by the subgroup of the Guidelines Working Group of the UK Myeloma Forum. Levels of evidence and grades of recommendation are shown in Table I. SBP and SEP are rare diseases and most of the evidence relates to retrospective data from patient series collected over long periods of time. Very few formal clinical trials have been performed. The majority of the recommendations given are therefore based on consensus of expert

/pdf/guidelines-on-the-diagnosis-and-management-of-solitary-5d3n17nxqz.pdf

Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmacytoma.

Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity.

Purpose The optimal therapy remains unclear for nasal natural killer (NK)/T–cell lymphoma. The purpose of this study is to analyze the outcome of radiotherapy as the primary treatment for localized stage IE and IIE diseases. Patients and Methods One hundred five patient cases were reviewed. There were 83 stage IE and 22 stage IIE patients. All except three patients received radiotherapy (RT) alone or RT combined with chemotherapy (CT; combined-modality therapy [CMT]). Overall, 31 patients were treated with RT alone, 34 with RT followed by CT, 37 with CT followed by RT, and three with CT alone. Results Five-year overall survival (OS) and progression-free survival (PFS) for all patients were 71% and 59%, respectively. The 5-year OS and PFS were 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. Complete response (CR) was achieved in 91 patients (87%) after RT and/or CT. Initial RT resulted in a superior CR as compared with initial CT, with 54 (83%) of 65 patients achieving CR with initia...

Radiotherapy As Primary Treatment for Stage IE and IIE Nasal Natural Killer/T-Cell Lymphoma

Objectives: To assess the efficacy and toxicity of the most employed therapeutic approaches in the treatment of primary breast lymphoma (PBL). Methods: Ninety-six

Primary breast lymphoma: results of a controlled clinical trial.

Purpose: To evaluate the usefulness of adjuvant radiotherapy to sites of previous bulky disease in patients with advanced diffuse large cell lymphoma (DLCL) who were in complete remission after chemotherapy. Methods and Material: Two-hundred and eighteen patients were initially treated with combined chemotherapy CEOP-bleo (cyclophosphamide, epirubicin, vincristine, prednisone, bleomycin) alternating with DAC (dexamethasone, cytosine arabinoside, and cisplatinum). One hundred and fifty-five patients achieved complete remission. Eighty-eight patients with initial bulky disease were randomly assigned to either received (43 patients) or not received radiotherapy (45 patients). Dose ranged from 40–50 Gy. Results: The median time to treatment failure has not been reached in patients who received radiotherapy. At 5 years 72% of the patients treated with the combined therapy remain alive disease in free compared to only 35% in the control group. Projected survival at 5 years was better in the patients with adjuvant radiotherapy: 81 % compared to 55% in the patients who received no radiotherapy. Toxicity was mild and manageable. No lethal toxicities were observed. Conclusion: This treatment sequence produced durable control disease in patients with disseminated DLCL and bulky disease with acceptable toxicity. The role of radiation therapy in patients with disseminated DLCL will be confirmed in large clinical trials, but we felt that this sequence of treatment could be useful in patients with this clinical condition.

Adjuvant radiotherapy to sites of previous bulky disease in patients stage iv diffuse large cell lymphoma

Solitary bone plasmacytoma (SBP) is a rare presentation of plasma cell dyscrasias. Radiotherapy has been considered the treatment of choice, however, most patients will develop multiple myeloma, 3 to 10 years after initial diagnosis and treatment. No innovations have been introduced in the treatment of SBP in the last 30 years. We began a prospective clinical trial to assess the efficacy and toxicity of adjuvant chemotherapy with low doses of melphalan and prednisone administered to patients with SBP after radiation therapy in an attempt to improve the disease-free survival and overall survival. Between 1982 and 1989, 53 patients with SBP were randomly assigned to be treated with either local radiotherapy with doses ranged from 4000 to 5000 cGy to achieve local control of disease (28 patients) or the same radiotherapy schedule followed by melphalan and prednisone given every 6 weeks for 3 years (25 patients). After a median follow-up of 8.9 years, disease-free survival and overall survival were improved in patients who were treated with combined therapy, 22 patients remain alive and free of disease in the combined treatment group compared to only 13 patients in the radiotherapy group (p < 0.01). Treatment was well tolerated; planned doses were administered in all cases; no delays in treatment or acute side-effects were observed during treatment. Long-term secondary toxicities including secondary neoplasms and acute leukaemia, have not been observed. We felt that the use of adjuvant chemotherapy after adequate doses of radiotherapy in patients with SBP improved duration of remission and survival without severe side-effects. However, as with other studies in SBP, the group was too small to draw definitive conclusions and more controlled clinical trials are necessary to define the role of this therapeutic approach in patients with SBP.

Improved outcome in solitary bone plasmacytomata with combined therapy.

Treatment of stage IA non-Hodgkin's lymphoma (NHL) of Waldeyer's ring remains controversial, probably because of the small number of patients and the scarcity of controlled studies. Between 1981 and 1991, 316 patients with stage I NHL of Waldeyer's ring were randomised for treatment with radiotherapy alone (extended fields), 101 patients; combined chemotherapy with a regimen of CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) or CHOP-like (epirubicin instead of doxorubicin), 106 patients; and combined therapy (radiotherapy followed by the same combination chemotherapy), 109 patients. Median follow-up was 6.8 years. Complete response was achieved in 93, 87 and 97%, respectively. Relapses were least frequent in patients treated with combination therapy. The 5-year rate for failure-free survival was 48% for radiation therapy, 45% for the patients who were treated with chemotherapy, which was statistically significantly less than the 83% for patients treated with combined therapy (P < 0.001). Overall survival was also better in the combined therapy arm: 90%, statistically different to 58% for the patients treated with chemotherapy alone and 56% for patients treated with radiation therapy (P < 0.001). Toxicity was mild and late side-effects were not observed in any patients. From these results combined therapy should be considered as the best therapeutic approach in patients with localised NHL of Waldeyer's ring.

Treatment of non-Hodgkin's lymphoma of waldeyer's ring: Radiotherapy versus chemotherapy versus combined therapy

:Objectives: We evaluate the long-term results of a randomized clinical trial in patients with advanced stages (III and IV) of follicular lymphoma using chemotherapy or combined therapy (chemotherapy following by adjuvant radiotherapy in patients with nodal bulky disease). Material and methods: Between 1981 and 1995, patients with follicular lymphoma were treated with combined chemotherapy, mostly anthracycline-based regimens; patients who achieved complete response were randomly assigned either to receive adjuvant radiotherapy to sites or to nodal bulky disease or not (control group). Results: Four hundred and sixty-nine patients were randomized; in an intent-to-treat analysis all were evaluable for efficacy and toxicity. Actuarial curves at 20 yr showed that event-free survival (EFS) and overall survival (OS) in the control group were 41% [95% confidence interval (CI) 36–56%) and 71% (95% CI 65–78%), respectively; these were statistically different from results for the patients who received adjuvant radiotherapy: 68% (95% CI 62–72%) and 89% (95% CI 79–96%), respectively (P < 0.01). Acute and late toxicity were minimal; only four patients (< 1%) developed myelodysplastic syndrome/acute leukemia. Cardiac toxicity was 2%, but one case was lethal. Thirty-six patients (8%) died secondary to unrelated causes, in complete remission. Conclusions: The use of adjuvant radiotherapy in patients with poor-prognosis follicular lymphoma increases EFS and OS with minimal toxicity. We feel that follicular lymphoma should be treated curatively because < 80% of patients will be in first complete response at < 20 yr. The use of adjuvant radiotherapy will be considered in the first line of treatment in this set of patients.

http://www.lymphomation.org/chemoandradiostage3.pdf

Combined therapy in advanced stages (III and IV) of follicular lymphoma increases the possibility of cure: results of a large controlled clinical trial.

Serafin Delgado

Papers

Primary breast lymphoma: results of a controlled clinical trial.

Adjuvant radiotherapy to sites of previous bulky disease in patients stage iv diffuse large cell lymphoma

Improved outcome in solitary bone plasmacytomata with combined therapy.

Treatment of non-Hodgkin's lymphoma of waldeyer's ring: Radiotherapy versus chemotherapy versus combined therapy

Combined therapy in advanced stages (III and IV) of follicular lymphoma increases the possibility of cure: results of a large controlled clinical trial.