Small rings in the bigger picture: ring expansion of three- and four-membered rings to access larger all-carbon cyclic systems.

The release of the inherent ring strain of cyclobutane and cyclopropane derivatives allows a rapid build-up of molecular complexity. This review highlights the state-of-the-art of the ring expansions of three- and four-membered cycles and is organised by types of reactions with emphasis on the reaction mechanisms. Selected examples are discussed to illustrate the synthetic potential of this elegant synthetic tool.

Improving the Quality of Host Country Ethical Oversight of International Research: The Use of a Collaborative 'Pre-Review' Mechanism for a Study of Fexinidazole for Human African Trypanosomiasis.

Developing countries face numerous barriers to conducting effective and efficient ethics reviews of international collaborative research. In addition to potentially overlooking important scientific and ethical considerations, inadequate or insufficiently trained ethics committees may insist on unwarranted changes to protocols that can impair a study's scientific or ethical validity. Moreover, poorly functioning review systems can impose substantial delays on the commencement of research, which needlessly undermine the development of new interventions for urgent medical needs. In response to these concerns, the Drugs for Neglected Diseases Initiative (DNDi), an independent nonprofit organization founded by a coalition of public sector and international organizations, developed a mechanism to facilitate more effective and efficient host country ethics review for a study of the use of fexinidazole for the treatment of late stage African Trypanosomiasis (HAT). The project involved the implementation of a novel 'pre-review' process of ethical oversight, conducted by an ad hoc committee of ethics committee representatives from African and European countries, in collaboration with internationally recognized scientific experts. This article examines the process and outcomes of this collaborative process.

Intermediate stage Hodgkin lymphoma in partial remission after three or four courses of doxorubicin, bleomycin, vinblastine dacarbazine: no benefit of one course of intensive chemotherapy before irradiation.

The H97-I trial (1997-2004) for Hodgkin lymphoma at intermediate stage (HL-I) included 269 patients who were randomized to receive three or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). The 197 patients who reached complete remission (CR) (73.2%, p = 0.41 between arms) received radiotherapy (RT); their 10-year progression-free survival (PFS) rate was 87.7 ± 3.0%, similar to that of the 180 patients of a historical control group (HCG) in CR after three ABVD cycles before RT. The 59 patients who reached post-ABVD partial remission (PR) received one course of intensive chemotherapy (i.v., mg/m(2), vindesine 5, adriamycin 90, BCNU 140, etoposide 600, methylprednisolone 600) before RT. In spite of this additional intensive chemotherapy, their PFS rate (78.4 ± 6.3%) remained significantly lower (p = 0.03) than that of the 197 patients who reached post-ABVD CR, and was similar to that of the 60 patients of the HCG in PR after three ABVD cycles who did not receive additional chemotherapy before RT.

Reduced versus full doses of irradiation after 3 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine in early stage Hodgkin lymphomas: results of a randomized trial.

BACKGROUND: The combination of 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and a tailored, extended irradiation schedule has been used to treat patients with early Hodgkin lymphoma (HL) in the authors' group since 1981. The randomized H97-E trial (1997-2004) was designed to assess the impact of a slightly reduced irradiation dose on the freedom from treatment failure (FFTF) rate. METHODS: Patients with supradiaphragmatic HL at clinical stages I and II who had

Twenty-year disease and treatment-associated mortality rates of patients with Hodgkin lymphoma of clinical stages IIIB and IV prospectively treated with 3-month anthracycline-based chemotherapy followed by extended high-dose radiation.

BACKGROUND: In 1981, the authors developed an original strategy combining 3 cycles of doxorubicin (adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) or ABVD-like chemotherapy and extended high-dose radiation for treating patients with clinical stages IIIB and IV Hodgkin lymphoma (HL). In the current study, the authors analyzed the 20-year results of this treatment as applied to 213 patients according to 2 successive trials. METHODS: All patients who responded to chemotherapy received extended high-dose radiation. The rates of complete remission (CR), freedom from disease progression (FFP), HL-specific survival (HLSS), second tumors and cardiac events, freedom from treatment-associated mortality (FFTM), overall survival (OS), and event-free survival were calculated. RESULTS: In December 2006, the median follow-up of the surviving patients exceeded 13 years; 102 patients (48%) achieved a CR after chemotherapy and 178 patients (84%) did so after radiotherapy. The rates of FFP (61%, quasi-stable after 6 years) and HLSS (81.6%, stable after 12 years) were found to be significantly higher in patients who achieved a CR after chemotherapy. The incidence of hematologic malignancies was 10.9% (with 10 of 12 events occurring within the first 7 years). The rates of solid tumors (32.4%), cardiac events (33.4%), and FFTM (65.6%) did not reach any plateau by 20 years and were found to be significantly associated with patient age. The 20-year OS rate was 48%. CONCLUSIONS: This combined modality treatment gave long-term results similar to those obtained using 6 to 8 cycles of ABVD. Response to the initial brief chemotherapy administration was found to be predictive of the FFP and HLSS rates. The low rate of FFTM was the result of extended high-dose radiation. The results of the current study should help to design future trials for treating patients with advanced stages of HL.

Early versus late intensification for patients with high-risk Hodgkin lymphoma-3 cycles of intensive chemotherapy plus low-dose lymph node radiation therapy versus 4 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine plus myeloablative chemotherapy with autologous stem cell transplantation: five-year results of a randomized trial on behalf of the GOELAMS Group.

BACKGROUND: The 5-year freedom from treatment failure (FFTF) rate, with treatment failure defined as the lack of post-treatment complete remission (CR), recurrence, or death, ranges from 60% to 70% after 6 to 8 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which is the reference treatment for patients with advanced Hodgkin lymphoma (HL). In this randomized, phase 2 study, the authors tested 2 intensive chemotherapy regimens in 158 patients with clinical stage (CS) IIB through IV HL accompanied by high-risk factors who were recruited between May 1997 and December 2004. METHODS: High-risk CS IIB, III, and IV were defined by the presence of > or =5 involved lymphoid areas, and/or a mediastinal mass ratio > or =0.45, and/or > or =2 extra lymph node sites affected by the disease (for CS IV). In Arm V, 82 patients received 3 courses of combined vindesine (5 mg/m(2)), doxorubicin (99 mg/m(2)), carmustine (140 mg/m(2)), etoposide (600 mg/m(2)), and methylprednisolone (600 mg/m(2)) (VABEM) followed by low-dose lymph node irradiation. In Arm A, 76 patients received 4 cycles of ABVD followed by myeloablative combined carmustine (300 mg/m(2)), etoposide (800 mg/m(2)), cytarabine (1600 mg/m(2)), and melphalan (140 mg/m(2)) and underwent autologous stem cell transplantation. RESULTS: After 3 cycles of VABEM, the CR rate was 89% versus 60% after 4 cycles of ABVD. However, after the completion of treatment, the CR rates for Arms V and A were similar (89% and 88%, respectively). The 5-year FFTF rates for Arms V and A also were similar (79% and 75%, respectively) along with the 5-year overall survival rates (87% and 86%, respectively). CONCLUSIONS: Early intensification (Arm V) and late intensification (Arm A) were equally effective for treating patients with high-risk/advanced HL.

Predictive and discriminating three-risk-group prognostic scoring system for staging Hodgkin lymphomas.

BACKGROUND: Several 3-stage Ann Arbor classification-derived prognostic systems were constructed since 1980 to identify the prognosis of Hodgkin lymphoma (HL). Modern statistical tools were applied to 955 patients treated between 1981 and 1996 to build a 3-stage prognostic scoring system (PSS). METHODS: Each variable associated with 10-year overall survival (10-year OS) was assigned to 2 (0 or 1) or 3 (0, 1 or 3) values. By summing the values attributed to each variable, 3 stages were defined. 10-year OS, 5-year event-free survival (5-year EFS), and freedom from progression (5-year FFP) rates of the PSS and of other existing systems were then compared. RESULTS: Four variables were associated with 10-year OS: age (<40 = 0, >or=40 = 1), number of involved lymphoid areas (1-2 = 0, 3-4 = 1, >or=5 = 2), visceral disease (no = 0, yes = 1), and systemic symptoms (no = 0, yes = 1). Scores 0 and 1, 2 and 3, and >or=4 were attributed to 59.7%, 30.9%, and 9.4% of the patients who had 10-year OS rates of 93.5, 75.7, and 53.4% and 5-year EFS / 5-year FFP rates of 91.2%/90.3%, 78.1%/76.3%, and 54.1%/52.6%, respectively. The discrimination and prediction abilities of the PSS were better than those of the other systems tested; moreover, the PSS adequately identified the few patients with a worse prognosis without resorting to the International Prognostic Score for advanced stages. The PSS was also highly predictive for 489 patients treated between 1997 and 2002. CONCLUSION: PSS is a useful alternative to the existing prognostic systems for evaluating HL patients.

Fifteen-year secondary leukaemia risk observed in 761 patients with Hodgkin's disease prospectively treated by MOPP or ABVD chemotherapy plus high-dose irradiation.

Between 1972 and 1988, 869 adult patients received MOPP (mechlorethamine, vincristine, procarbazine and prednisone; 462 patients) or ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine; 373 patients) and subsequent high-dose irradiation for Hodgkin's disease. Nine patients developed a leukaemia after MOPP and four after ABVD; 11 patients were diagnosed as acute non-lymphoblastic leukaemia (ANLL) and two as acute lymphoblastic leukaemia (ALL). Both cases of ALL were observed after ABVD and were associated with a 11q23 translocation. The 15-year actuarial risk of secondary leukaemia was 2.4% for the whole group of patients, 3.4% after MOPP and 1.3% after ABVD. For the MOPP subgroup, the risk of leukaemia was significantly associated with the extent of irradiation: 2.4% for limited irradiation and 13.9% for extended irradiation (P < 0.001). For the ABVD subgroup, this risk remained low (1.3%) whatever the type of irradiation. Concerning ANLL, the MOPP regimen was significantly associated with a higher risk: 3.4% versus 0.7% for ABVD (P

Comparison of initial characteristics and long-term outcome of patients with lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma at clinical stages IA and IIA prospectively treated by brief anthracycline-based chemotherapies plus extended high-dose irradiation.

Lymphocyte-predominant Hodgkin lymphoma (LPHL), according to the Revised European-American Lymphoma classification, was considered on a retrospective basis as a specific clinical entity with a large majority of patients at clinical stage (CS) IA or IIA. Of the 500 patients with CS IA/IIA Hodgkin lymphoma (HL) prospectively treated between 1981 and 1996 by one or 3 courses of anthracycline-based chemotherapies combined with high-dose extended irradiation, disease in 42 patients was reclassified as LPHL. These 42 patients, none of whom had mediastinal involvement (MI), were compared with the 458 patients with classical HL (cHL), 144 without MI and 314 with MI. Surprisingly, the male-female ratio, age, first site involved, hemoglobin level, lymphocyte count, and sedimentation rate of patients with LPHL and cHL without MI were identical and significantly different from those of patients with cHL with MI. Moreover, 15-year HL mortality rates were similarly low in patients with LPHL (2.4%) and cHL without MI (0.7%). Overall survival rates were also similar (86% and 82%) and as high as 100% and 95% in patients treated before the age of 40 years. This study demonstrated that LPHL and cHL without MI shared the same presenting characteristics and the same excellent long-term prognosis after a brief anthracycline-based chemotherapy plus high-dose extended irradiation.

Three cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or epirubicin, bleomycin, vinblastine, and methotrexate (EBVM) plus extended field radiation therapy in early and intermediate Hodgkin disease: 10-year results of a randomized trial.

From 1990 to 1996, a total of 386 adult patients with early/intermediate Hodgkin disease (HD) were randomly assigned to receive 3 cycles of adriamycin, bleomycin, vinblastine, dacarbazine (an alkylating agent), and methylprednisolone (ABVDm, arm A) or epirubicin, bleomycin, vinblastine, methotrexate, and methylprednisolone (EBVMm, arm E), a combination without alkylating agent. Responding patients received extended field radiation therapy (RT). Postchemotherapy complete remission and 10-year freedom from progression rates were higher in arm A (79.5% and 91.4%) than in arm E (70.4%, P =.04, and 80%, P <.002). HD mortality (HDM), treatment-related mortality (TRM), and overall survival (OS) were similar in both arms (A, 2.1%, 7.5%, and 90.4%; B, 3.9%, 5.5%, and 90.3%). However TRM and OS rates were lower in patients aged 40 years or older (P <.005), reflecting the increasing incidence of background fatal events with increasing age. Finally, event-free survival (EFS) was higher in arm A (84.6%) than in arm E (74.9%, P <.02). In patients aged younger than 40 years in arm A (74%), 10-year EFS and OS rates were 88.9% and 95.4% with HDM and TRM rates as low as 0.7% and 3%. Three courses of ABVDm plus RT are the best available option for treating early or intermediate HD.

Treatment of patients with advanced or bulky Hodgkin disease with a 12-week doxorubicin, bleomycin, vinblastine, and dacarbazine-like chemotherapy regimen followed by extended-field, full-dose radiotherapy: long-term results of the Groupe Ouest et Est des Leucémies et Autres Maladies de Sang H90-A/B Multicenter Randomized Trial.

BACKGROUND: This Phase II study was performed in patients with advanced or bulky Hodgkin disease (HD) to evaluate the results of a 7-drug chemotherapy (CT) regimen that was administered over 12 weeks according to 2 randomized modalities followed by high-dose lymph node irradiation. METHODS: From 1990 to 1996, 162 patients with HD at clinical stages (CS) I-III with bulky disease (mediastinal mass ratio >or= 0.45 and/or unilateral or bilateral pelvic plus lumboaortic disease; 86 patients) or CS IV (76 patients) were randomized to receive the same cumulated dose of a CT regimen consisting of epirubicin (240 mg/m(2)), bleomycin (60 mg/m(2)), vinblastine (20 mg/m(2)), vincristine (4 mg/m(2)), cyclophosphamide (4000 mg/m(2)), etoposide (900 mg/m(2)), and methotrexate (180 mg/m(2)) plus methylprednisolone (1500 mg/m(2)) over 12 weeks either every 4 weeks (Arm Y, 79 patients) or every 3 weeks (Arm Z, 83 patients). Patients with disease in complete remission (CR) or partial remission after CT received extended-field lymph node irradiation (involved areas, 40 grays [Gy]; noninvolved areas, 30 Gy). RESULTS: Forty-two percent of patients achieved a post-CT CR, and 86% of patients achieved a CR after the completion of irradiation (there was no difference between Arm Y and Arm Z). Thirty-five patients developed recurrent disease; most of those patients were in post-CT partial remission. The 10-year freedom from first progression rate was 63.9% (there was no difference between Arm Y and Arm Z). Thirty-eight patients died: 24 patients from HD, 3 patients from CT-related early sepsis, 1 patient from radiation-induced pneumonitis, 6 patients from a second malignancy, and 4 patients from causes unrelated to treatment. The overall 10-year survival rate was 76.7%. Survival was slightly higher among patients in Arm Y (83.3%) compared with patients in Arm Z (70.2%; P = 0.12). CONCLUSIONS: No differences were found when the same amount of CT was delivered in three courses or in four courses. In 1997, because most recurrences of the H90-A/B trial occurred in patients who achieved a post-CT partial remission, the authors decided to reinforce the intensity of the initial CT and designed a new randomized study comparing two modalities of more intensive CT plus consolidative radiotherapy (H97-LM trial).