Metal- and Photocatalyst-Free, Visible-Light-Initiated C3 α-Aminomethylation of Quinoxalin-2(1H)-ones via Electron Donor-Acceptor Complexes.

We report a metal- and photocatalyst-free C3 α-aminomethylation of quinoxalin-2(1H)-ones with N-alkyl-N-methylanilines. The reaction proceeds through the formation of a photoactivated electron donor-acceptor complex between quinoxalin-2(1H)-ones and N-alkyl-N-methylanilines. The present method provides a mild and environmentally friendly protocol that exhibits good atom economy and excellent functional group tolerance to obtain a library of biologically significant C3 α-aminomethylated quinoxalin-2(1H)-ones in good yields.

BF3 ⋠Et2 O-Catalyzed Selective C-4 Alkylation of Isoquinolin-1(2H)-ones Employing p-Quinone Methides.

The direct C-4 alkylation of isoquinolin-1(2H)-one moiety is a challenging transformation in organic synthesis. Here we present a practical and efficient synthesis of C-4 alkylated isoquinolin-1(2H)-ones through conjugate addition of isoquinolin-1(2H)-ones to p-quinone methides for the first time. The process is facilitated by Lewis acid catalysis and this operationally straightforward, mild, metal-free and one-pot transformation provides a wide range of C-4 alkylated isoquinolin-1(2H)-ones at ambient temperature in good to excellent yields.

Metal-Free Aminocarbonylation of p-Quinone Methides with Isocyanides: Synthesis of Sterically Hindered α-Arylated Acetamides.

The synthesis of sterically hindered α-arylated acetamides generally requires a multistep reaction sequence and is also difficult to access due to steric constraints. This protocol allows the synthesis of sterically hindered α-arylated acetamides in moderate to high yields via 1,6-addition of isocyanides to p-quinone methides in the presence of BF3 .OEt2 . The present transformation features transition metal-free conditions, avoiding the use of toxic carbon monoxide, broad substrate scope, mild reaction conditions, and operational simplicity.

Oxone promoted dehydrogenative Povarov cyclization of N-aryl glycine derivatives: an approach towards quinoline fused lactones and lactams.

Oxone promoted intramolecular dehydrogenative imino Diels-Alder reaction (Povarov cyclization) of alkyne tethered N-aryl glycine esters and amides has been explored, thus affording biologically significant quinoline fused lactones and lactams. The reaction is simple, scalable, and high yielding (up to 88%). The method was further extended to prepare biologically important luotonin-A analogues and the quinoline core of uncialamycin.

ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥ 4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial.

BACKGROUND: Treatment with escalated BEACOPP achieved a superior time to treatment failure over ABVD in patients with disseminated Hodgkin lymphoma. However, recent clinical trials have failed to confirm BEACOPP overall survival (OS) superiority over ABVD. In addition, the gain in low-risk patients is still a matter of debate. PATIENTS AND METHODS: We randomly compared ABVD (8 cycles) with BEACOPP (escalated 4 cycles ≥ baseline 4 cycles) in low-risk patients with an International Prognostic Score (IPS) of 0-2. The primary end point was event-free survival (EFS). This parallel group, open-label phase 3 trial was registered under #RECF0219 at French National Cancer Institute. RESULTS: One hundred and fifty patients were randomized in this trial (ABVD 80, BEACOPP 70): 28 years was the median age, 50% were male and IPS was 0-1 for 64%. Complete remission rate was 85% for ABVD and 90% for BEACOPP. Progression or relapses were more frequent in the ABVD patients than in the BEACOPP patients (17 versus 5 patients). With a median follow-up period of 5.5 years, seven patients died: six in the ABVD arm and one in the BEACOPP arm (HL 3 and 0, 2nd cancer 2 and 1, accident 1 and 0). The EFS at 5 years was estimated at 62% for ABVD versus 77%, for BEACOPP [hazards ratio (HR) = 0.6, P = 0.07]. The progression-free survival (PFS) at 5 years was 75% versus 93% (HR = 0.3, P = 0.007). The OS at 5 years was 92% versus 99% (HR = 0.18, P = 0.06). CONCLUSION: Fewer progressions/relapses were observed with BEACOPP, demonstrating the high efficacy of the more intensive regimen, even in low-risk patients. However, additional considerations, balancing treatment-related toxicity and late morbidity due to salvage may help with decision-making with regard to treatment with ABVD or BEACOPP.

L-asparaginase-based treatment of 15 western patients with extranodal NK/T-cell lymphoma and leukemia and a review of the literature.

BACKGROUND: Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are highly aggressive diseases with a poor outcome. PATIENTS AND METHODS: We report a multicentric French retrospective study of 15 patients with relapsed, refractory, or disseminated disease, treated with L-asparaginase-containing regimens in seven French centers. Thirteen patients were in relapse and/or refractory and 10 patients were at stage IV. RESULTS: All but two of the patients had an objective response to L-asparaginase-based treatment. Seven patients reached complete remission and only two relapsed. CONCLUSION: These data, although retrospective, confirm the excellent activity of L-asparaginase-containing regimens in refractory extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Therefore, L-asparaginase-based regimen should be considered as a salvage treatment, especially for patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia should be tested in prospective trials.

Assessment of cetirizine, an antihistamine, to prevent cutaneous reactions to nevirapine therapy: results of the viramune-zyrtec double-blind, placebo-controlled trial.

We conducted a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of cetirizine to assess the ability of antihistamines to prevent nevirapine-associated rash in patients infected with human immunodeficiency virus type 1. Patients initiating treatment with nevirapine were randomized to receive either cetirizine, 10 mg q.d. (104 patients), or placebo (96 patients) during the first 6 weeks of therapy. Rash occurred in 22 (11%) of 200 patients; 10 (9.6%) were in the cetirizine group and 12 (12.5%) were in the placebo group (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.31-1.81; P=.5). Five of 22 rashes were cases of hypersensitivity syndrome. The rate of nevirapine discontinuation due to rash was similar in the 2 groups (7.7% and 6.25% in the cetirizine and placebo groups, respectively; P=.4). Multivariate analysis showed no treatment-group effect but indicated that age >40 years (OR, 3.83; 95% CI, 1.4-10.46; P=.008) was associated with an increased risk of rash. Cetirizine has no preventive effect on nevirapine-associated rash.

Late autologous transplantation in chronic myelogenous leukemia with peripheral blood progenitor cells mobilized by G-CSF and interferon-alpha.

In chronic myelogenous leukemia (CML), autologous stem cell transplantation could be a promising new approach for patients with no cytogenetic response after interferon alpha (IFN-alpha) therapy. We report data on 28 CML patients autotransplanted in chronic phase with peripheral blood progenitor cells mobilized with G-CSF (5 microg/kg/day x 5 days) given subcutaneously while continuing IFN-alpha therapy. At mobilization, 23 patients (82%) were in complete hematological remission (CHR), 16 (57%) achieved a minor cytogenetic response (mcr). We obtained, after stimulation, a median of 37.4 x 10(9)/l (6.9-108) white blood cells, 7.2 x 10(8)/kg (2.2-16.6) mononuclear cells, 39 x 10(4)/kg (4.8-403.5) CFU-GM and 4.2 x 10(6)/kg (0-58.6) CD34+ cells. Six patients received GM-CSF after transplantation. All patients engrafted, with no significant influence stemming from the Sokal index score and pretransplantation IFN-alpha therapy duration. The first cytogenetic evaluation after transplantation showed 11 (39%) major cytogenetic response (Mcr), and nine (32%) mcr with no significant correlation between these responses, the Sokal index score, and pretransplantation IFN-alpha therapy duration, although there was a significant impact from GM-CSF administration (P=0.01). After transplantation, 26 patients received IFN-alpha alone or associated with hydroxyurea. The median follow-up was 12 months after transplantation and 57 months after diagnosis. At the time of follow-up, nine patients were in CHR, six remained stable in chronic phase, three presented an mcr and one remained in Mcr. At the last follow-up, 22 patients were alive. We conclude that the results of this strategy are encouraging in poor IFN-alpha responders but that other prospective studies that try to maintain the cytogenetic responses obtained immediately after transplantation are needed.

CD4+ CD56+ cutaneous neoplasms: a distinct hematological entity? Groupe Français d'Etude des Lymphomes Cutanés (GFELC).

We report seven cases of particular cutaneous tumors selected from the register of the French Study Group on Cutaneous Lymphomas. The patients (three men, four women) were aged 37-86 years. They initially presented with cutaneous nodules or papules. Three cases presented with regional lymph nodes. Stagings were negative, except for one patient with bone marrow involvement. Histological features were relevant with pleomorphic medium T-cell lymphoma, but these cells exhibited a distinguishing phenotype. They were positive for CD4, CD56, and also CD45, CD43, and HLA-DR. All other T-cell and B-cell markers were negative. The myelomonocytic markers (CD13, CD14, CD15, CD33, CD117, myeloperoxidase, and lysozyme) were negative excepted CD68, which was clearly positive in four cases and weakly in two cases. Others natural killer cell markers (CD16, CD57, TiA1, granzyme B), TdT, and CD34 were negative. Polymerase chain reaction studies did not detect any B or T clonal rearrangement. The cytogenetic studies, performed in five cases, showed a del(5q) in two cases. All patients were treated successfully by polychemotherapy, but relapsed quickly in the skin, between 4 and 28 months. Five patients developed bone marrow involvement, with leukemia in three cases, and they died in 5-27 months. One patient died at 17 months with skin progression. The seventh patient is alive at 33 months, with cutaneous progression. The origin of these cells is unclear. Despite expression of CD4 or CD56, we failed to demonstrate a T-cell, natural killer cell origin. However, CD4 and CD56 are not specific for T or natural killer lineages. Although these two markers are also known to be expressed by monocytic cells, classic myeloid antigens were negative. These seven cases, together with other rare similar cases already reported, seem to represent a distinct entity likely developed from hematological precursor cells.

Angioimmunoblastic-like T-cell non Hodgkin's lymphoma: outcome after chemotherapy in 33 patients and review of the literature.

We analyzed 33 patients with AILD T-NHL in a retrospective multicentric study. The median age was 62 yr (35-84 yr) (19 patients over 60 yr). Advanced disease (n = 31) and B-symptoms were consistently found (n = 29) and 20 patients had bone marrow involvement. The main laboratory abnormalities were: anemia (n = 13), hypereosinophilia (n = 13), lymphopenia (n = 14), hypergammaglobulinemia (n = 17), elevated lactate dehydrogenase (LDH) level (n = 24). First-line therapy was chemotherapy (ChT) alone (n = 25) or ChT after steroids (n = 8). Most patients received a CHOP-like regimen for a median number of 6 cycles and 3 patients received interferon alpha (IFN alpha) as consolidation after chemotherapy. With a median follow-up of 46 mo, 60% achieved a complete response but the outcome was poor with a relapse rate at 56%, a median survival referring to the total population was of 36 mo (2-108+ mo) and an overall survival at 5 yr of 36%. Two patients received high-dose chemotherapy (with total body irradiation) and autologous progenitor-cell transplantation for chemosensitive relapse and were free of disease at, respectively, 76 and 24 mo+. In conclusion AILD T-NHL still has a poor prognosis compared to other NHL. The role of intensive therapy and IFN alpha still remains to be evaluated.

Feasibility of tandem autologous stem-cell transplantation (ASCT) in induction failure or very unfavorable (UF) relapse from Hodgkin's disease (HD). SFGM/GELA Study Group.

BACKGROUND: Despite high-dose therapy and ASCT some patients with aggressive HD fail to achieve long-term survival. PATIENTS AND METHODS: Forty-three patients with induction failure (n = 19) or very unfavorable (UF) relapse (n = 24) from HD were included in a multicentric study of tandem ASCT. They planned to receive two course of IVA75 with GCSF and blood stem cell collection. ASCT1 was conditioned with CBV + mitoxantrone (30 mg/m2) and ASCT2 (cytarabine 6 g/m2 melphalan 140 mg/m2 and total body irradiation at 12 Gy or busulfan 16 (n = 4) than 12 mg/kg). After salvage therapy, response > 50% was observed in 63% of the patients (six patients were included for refractory relapse). Four patients had no ASCT for disease progression; seven patients had only ASCT1 (disease progression, n = 3) and thirty-two patients (74%) received the two ASCT. RESULTS: Hematologic recovery was normal after ASCT1 but delayed platelet recovery was observed after ASCT2 with busulfan in the conditioning regimen. Two VOD with one fatal occurred with busulfan at 16 mg/kg and one hemorrhagic cystic, no further grade 4 toxicity was observed with the reduced doses of busulfan (12 mg/kg). After ASCT2, 83% of these UF patients were in remission and 20% relapsed within the first year. On an intent-to-treat analysis, 22 of 43 patients are in continuous CR (including 8 patients with induction failure). For the whole population (n = 43) and for patients receiving the two ASCT (n = 32), the two-year survival from the date of progression were respectively at 65% and at 74%. CONCLUSION: Double ASCT is feasible in very UF relapse from HD and may lead to some prolonged remission.

Epstein-Barr virus-associated lymphoproliferative disease during methotrexate therapy for psoriasis.

BACKGROUND: Epstein-Barr virus (EBV)-associated lymphoproliferative disorders have recently been observed during treatment of rheumatoid arthritis and dermatomyositis with low-dose methotrexate. OBSERVATION: A patient with psoriasis developed a B-cell lymphoproliferative disorder during long-term treatment with low-dose methotrexate. The lymphoid cells expressed EBV latent membrane protein 1, and the EBV viral genome was present as demonstrated by in situ hybridization. Evaluation for EBV clonality showed that the lymph node contained clonal EBV DNA. Polymerase chain reaction studies confirmed that the B-cell lymphoproliferative disorder was mainly monoclonal, suggesting that the disorder arose from a single EBV-infected B-cell clone. CONCLUSIONS: Lymphoproliferative disorders associated with Epstein-Barr virus in which the clinicopathological presentation is similar to those occurring in patients after transplantation may be observed in patients with psoriasis treated with methotrexate. While it is impossible to rule out a fortuitous occurrence of an EBV-associated lymphoproliferative disorder and psoriasis treated with methotrexate in the same patient, EBV appears to be critical in the pathogenesis of the lymphoproliferative disorder in this patient.

Unusual Microsporum canis infections in adult HIV patients.

Tinea capitis in men, even if infected with HIV, is infrequent. Microsporum species nail infections are extremely rare. In most cases Microsporum canis infection is usually easy to treat with antifungal agents. We describe two HIV-infected men with an unusual M. canis infection. Both patients had tinea capitis, presenting as alopecia in one and scaling of the scalp in the other. One patient also had tinea unguium caused by M. canis. Ketoconazole was ineffective in both patients; terbinafine was tried in one patient without benefit; itraconazole was effective in both, but treatment took many months and only one patient was cured.

Primary thrombocythaemia associated with systemic mastocytosis: a report of five cases.

Mastocytosis is an uncommon disease characterized by a proliferation of tissue mast cells involving various organs, particularly the bone marrow. Though rare, the association of mastocytosis and haematological malignancies is well established. However, the frequency of mastocytosis reported in patients with essential thrombocythaemia is relatively low. We report five cases of such an association. Our five patients were undergoing evaluation for thrombocyte when the bone marrow biopsy revealed the presence of mastocytosis. The pathogenetic significance of this association is poorly understood. The different hypotheses are discussed.

[Urinary schistosomiasis in the Saharan mountain plateau of Air (Republic of Niger)]. / La schistosomose urinaire dans le massif Saharien de l'Aïr (République du Niger).

In two villages of the Aïr (Republic of Niger) the authors have found a Schistosoma haematobium overall prevalence of 24.1% at Timia and 43.5% at El Meki. At El Meki, the distribution of prevalences by age group accords to that which is usually found. The maximum is found in the 5-14 years age group and highest in men than in women. At Timia, the prevalence among young pupils is low, this seems to be due to the application of sanitary education measures. At El Meki, Bulinus truncatus rohlfsi, present in a permanent pool ("guelta") is the intermediate host of schistosomes. The role of this snail in the transmission of urinary schistosomiasis at Timia has not been demonstrated. The role of Bulinus senegalensis, found in both villages has yet to be proved.

Ultrasonographic assessment of the regression of bladder and renal lesions due to Schistosoma haematobium after treatment with praziquantel.

The effect of praziquantel on urinary tract lesions due to Schistosoma haematobium was assessed by ultrasound in an endemic village in Niger. Ten months after treatment with praziquantel, bladder and renal lesions among the 149 patients were assessed. The parasitological cure rate was 87%. Ultrasonography proved to be an excellent tool to assess pathological changes. It is reliable, quickly performed, well accepted by the community and permits the definition of a "regression-rate" of the pathological lesions. Ten months after treatment, the "regression-rate" of bladder lesions was 68% and of renal lesions was 73%. The presence of bladder lesions had a negative influence on the regression of renal lesions. Nearly all renal lesions, without bladder lesions, regressed within the ten months period of observation. This study permitted the identification of a group of persons whose bladder lesions did not regress and who were possibly more vulnerable to the development of bladder cancer, thus requiring long-term follow-up.

[Echographic study of the morbidity due to urinary bilharziasis in a hyperendemic village in Niger]. / Etude échographique de la morbidité due à la bilharziose urinaire dans un village hyperendémique nigérien.

Three hundred and seven patients, 130 children and 207 adults, from a hyperendemic village, underwent an ultrasonography of bladder and kidneys. Prevalence of bladder lesions is 79.3% in children and 61.9% in adults, prevalence of hydronephrosis is 36.1% in children and 9.7% in adults. These study confirms the importance of urologic lesions from schistosomiasis in the irrigation schemes of the Niger river. There is no relationship between frequency and importance of lesions and urinary egg count.

[Morbidity due to bilharziasis caused by S. haematobium. Relationship between the bladder lesions observed by ultrasonography and the cystoscopic and anatomo-pathologic lesions]. / Morbidité due à la bilharziose à S. haematobium. Relation entre les lésions vésicales observées en échographie et les désordres cystoscopiques et anatomo-pathologiques.

Twenty-seven patients with proved urinary schistosomiasis and echographic bladder lesions were selected for cystoscopic examination and biopsy. All patients had specific lesions at cystoscopic investigation. Histologic examination confirmed diagnosis 26/27 cases. Ultrasonography appears as a very efficient method for detection of schistosomiasis bladder pseudo-tumors.