Fluoropyrimidine-Associated Toxicity in Two Gastrointestinal Cancer Patients: Potential Role of Common DPYD Polymorphisms.

While the majority of patients can be treated safely with fluoropyrimidine, some experience severe fluoropyrimidine-associated toxicity. The frequency and severity of these adverse events vary from patient to patient and are partially explained by genetic polymorphism into the dihydropyrimidine dehydrogenase (DPYD) gene. Carriers of the rare allelic variants DPYD*2A, DPYD*13, and DPYD D949V are more likely to experience severe adverse reactions during fluoropyrimidine-based therapy. However, these 3 genetic variants explain only a small percentage of the overall drug toxicity, and more frequent ones such as homozygous or compound heterozygous DPYD V732I can play a key role.

Clinical relevance of the dose of cytarabine in the upfront treatment of primary CNS lymphomas with methotrexate-cytarabine combination.

BACKGROUND: The combination of high doses of methotrexate (MTX) and cytarabine (araC) is the standard chemotherapy for patients with primary CNS lymphoma (PCNSL). The addition of an alkylating agent could improve MTX-araC efficacy because it is active against quiescent G0 cells and increases antimetabolites cytotoxicity. A pilot experience with high doses of MTX, araC, and thiotepa (MAT regimen) was performed to investigate feasibility and efficacy of adding an alkylating agent. With respect to MTX-araC combination, araC dose was halved to minimize toxicity. Herein, we report tolerability, activity, and efficacy of MAT regimen and compare these results to those previously reported with MTX/ara-C combination. METHODS: Twenty HIV-negative patients with PCNSL treated with MAT regimen and whole-brain irradiation and selected according to eligibility criteria of the International Extranodal Lymphoma Study Group (IELSG) #20 trial were analyzed. RESULTS: Patient characteristics of MAT and MTX-araC series were similar. G4 hematologic toxicity was common after MAT chemotherapy, with dose reductions in 60% of patients, infections in 20%, G4 non-hematologic toxicity in 15%, and one (5%) toxic death. Response after chemotherapy was complete in four patients (clinical response rate, 20%; 95% confidence interval, 3%-37%) and partial in three (overall response rate, 35%; 95% confidence interval, 15%-55%). Fifteen patients experienced failure and 16 died (median follow-up, 26 months), with a 2-year overall survival of 24% ± 9%. CONCLUSIONS: MAT and MTX-araC combinations showed similar tolerability, whereas araC dose reduction was associated with a remarkably lower efficacy, hiding any potential benefit of thiotepa. Four doses of araC 2 g/m(2) per course are recommended in patients with PCNSL.

Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients Aged ≥ 75 Years With Non-small-cell Lung Cancer (NSCLC): An Italian, Multicenter, Retrospective Study.

INTRODUCTION: Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly population. Over the past few years, immunotherapy with monoclonal antibodies named checkpoint inhibitors (ICIs) greatly improved the clinical management of a significant proportion of patients with metastatic NSCLC. However, pivotal trials excluded older patients, although, given the favorable clinical profile of ICIs, this treatment may be revealed to be a most valuable option also for these patients. To this aim, a multicenter retrospective analysis was performed on patients aged ≥ 75 years with NSCLC treated with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy. MATERIAL AND METHODS: Inclusion criteria were: diagnosis of locally advanced or metastatic NSCLC (stage IIIB or IV, according to the American Joint Committee on Cancer (AJCC) classification system, version 8.0); age ≥ 75 years; treatment with anti-PD-1/PD-L1 monoclonal antibodies in first or subsequent lines of treatment; absence of epidermal growth factor receptor-activating mutations or anaplastic lymphoma kinase and ROS-1 rearrangements. The primary endpoints of the study were the efficacy, in terms of overall response rate, progression-free survival, and overall survival, and safety, by means of evaluations of the incidence of immune-related adverse events. RESULTS: Eighty-six patients were considered for the final analysis; 71 (82.6%) were male. The mean age was 78.5 years (range, 75-86 years; SD, 3.12 years). Of the 86 patients, 69 (80.2%) of patients had a performance status of 0 or 1. The overall median progression-free survival was 5.6 months (range 1-36 months; SD, 7.5 months,) whereas the median overall survival was 10.1 months (range, 1.7-34.8 months; SD, 8 months). At the Cox regression analysis, the only parameter significantly associated with survival was the smoking status (P = .008). No difference in survival was found between patients younger and older than 80 years. CONCLUSIONS: In the present real-world retrospective cohort, efficacy and toxicity profiles of ICIs in older patients with advanced NSCLC were comparable with those observed in younger patients enrolled in clinical trials.

Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy: Treatment Patterns From the PROXIMA Prospective Registry.

PURPOSE: There is a major clinical need to devise an optimal treatment sequence for the multiple therapy options available for patients with metastatic castration-resistant prostate cancer (mCRPC). In the absence of prospective clinical trials, sequencing information can be derived from large, real-world registry studies. PATIENTS AND METHODS: PROXIMA (Treatment Patterns in Patients With Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy) is a large, global, prospective registry study evaluating real-world treatment patterns of patients with mCRPC who experience disease progression during or after docetaxel therapy. Patients were enrolled worldwide between 2011 and 2014. Treatments were determined by the treating physicians and recorded in categories of chemotherapy, hormonal therapy, targeted therapy, immunotherapy, and palliative therapy. Treatment sequencing patterns, response to treatment, and types of progression were recorded and analyzed. Progression-free survival and overall survival with different treatment modalities were analyzed using Kaplan-Meier method. RESULTS: Treatment patterns were evaluated in 903 patients. Therapy selection was influenced by region. Hormonal therapy (57.5%) and taxane chemotherapy (26.4%) were the most frequently administered first subsequent treatments after docetaxel. Tumor responses to first subsequent treatment were observed in 22.6% of evaluable patients. Overall survival and progression-free survival did not differ significantly across different treatment modalities. CONCLUSION: Identifying an optimal treatment sequence is vital for improving the care of patients with mCRPC. The PROXIMA registry provided a representative sample of global data on real-world treatment patterns for patients with mCRPC previously treated with docetaxel. These data can be used to devise optimal therapy sequences and inform treatment decisions.

Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the feasibility and toxicity of CHOP-14, with rituximab (R-CHOP-14), supported by pegfilgrastim, in untreated diffuse large B-cell lymphoma (DLBCL). DESIGN AND METHODS: This study included 50 patients with DLBCL with a median age of 55 years (range: 22-70). Sixty-two percent had an International Prognostic Index score >1, 40% had bulky disease and 52% had stage IV disease. CHOP was administered every 14 days, preceded on day 1 by rituximab (375 mg/m2) and followed on day 3 by pegfilgrastim (6 mg per cycle). Toxicity was calculated over 277 cycles administered; feasibility was calculated over 227, since the first cycle in each patient was not susceptible to delay or dose-reduction. RESULTS: Therapy was delivered on time in 92% of cycles, with the relative dose intensity being 95% for doxorubicin and cyclophosphamide. Grade 4 neutropenia developed in 19% of cycles and neutropenic fever in 4% of cycles (16% of patients), with a median duration of 3 days (range: 2-10). The program was completed in 40 of 50 patients (80%); reasons for withdrawal included progression in three patients, interstitial pneumonia in four, prolonged severe neutropenia in two and septic shock in one patient. Severe adverse events occurred on 12 occasions (4% of cycles), involving 11 patients (22% of total); the most frequent severe adverse event was interstitial pneumonia which occurred in seven patients (14% of total). In three cases, Pneumocystis carinii pneumonia was documented; no cotrimoxazole prophylaxis had been given and a correlation with hypogammaglobulinemia was observed. The complete remission rate was 74%; the 2-year event-free and overall survival rates were 72% and 68%, respectively. INTERPRETATION AND CONCLUSIONS: A single dose of pegfilgrastim per cycle of R-CHOP allowed on-time delivery of this chemotherapy in DLBCL, with a low incidence of febrile neutropenia; the risk of P. carinii pneumonia makes cotrimoxazole prophylaxis essential in this setting.

Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patient's quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens. PATIENTS AND METHODS: Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis. RESULTS: Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment. CONCLUSION: Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatin-based chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. GemVin could be offered to advanced NSCLC patients who express concern about toxicity.

The VAD-DCEP sequence is an effective pre-transplant therapy in untreated multiple myeloma.

BACKGROUND AND OBJECTIVES: Standard treatment for patients with multiple myeloma is debulking chemotherapy with non-alkylating agents followed by a regimen to mobilize peripheral blood stem cells (PBSC) and the transplantation of the mobilized, autologous PBSC. The aim of this study was to evaluate the efficacy of a new regimen and compare it with that of a previous regimen. DESIGN AND METHODS: In a large cohort of 106 patients (group I) we administered a new pre-transplant program which includes 2 courses of pulsed-VAD (vincristine, adriamycin, dexamethasone) followed by 2 courses of DCEP (dexamethasone, cyclophosphamide, etoposide and cis-platinum). We compared the efficacy of this new VAD-DCEP sequence, in terms of mobilizing capacity, toxicity and anti-myeloma activity in comparison with that of the previous VAD-high-dose cyclophosphamide program (group II, 40 patients). RESULTS: In group I 81/106 (76.4%) patients yielded >or= 4x10(6)/kg CD34+ cells, as did 30/40 (75%) in group II but with a significantly higher toxicity in this latter group. In detail, 9 patients in group I (8.5%) had WHO grade III neutropenia versus 35 in group II (87.5%), 5 patients of group I (4.7%) had grade III thrombocytopenia versus 12 patients in group II (30%), and 8 patients in group I (7.5%) experienced an infections fever versus 9 patients in group II (22.5%). Therefore, nearly all patients in group II had to be admitted to hospital (39/40, 97.5%). There was a higher percentage of responses (CR+VGPR+PR) in group I than in group II: 73% versus 50% (p=0.02). INTERPRETATION AND CONCLUSIONS: the VAD-DCEP sequence has an adequate mobilizing capacity, without significant toxicity, and a good anti-myeloma activity, and therefore represents a safe and effective therapeutic approach for multiple myeloma patients at the onset of their disease.

Granulocyte colony-stimulating factors used in clinical practice: PoloNord Registry-Based Cohort Italian Study.

AIMS AND BACKGROUND: Granulocyte colony-stimulating factors are widely used to reduce myelotoxicity of chemotherapy and to allow its regular administration. National and international guidelines regulate their use. The aim of the study was to evaluate the use of pegfilgrastim and filgrastim/lenograstim in clinical practice, adherence to ASCO and ESMO guidelines, chemotherapy-related complications and adverse reactions. MATERIALS AND METHODS: Data from 645 consecutive patients and 3,150 chemotherapy administrations, receiving granulocyte colony-stimulating factors, as primary/secondary prophylaxis or therapeutic use, for the first time during a line of chemotherapy, were recorded from 08/2008 to 08/2011, in 10 Lombardy Italian cancer centers. Patients and chemotherapy administrations data were examined in a multiple logistic regression analysis model. RESULTS: Adherence to guidelines: primary prophylaxis, pegfilgrastim and filgrastim/ lenograstim 66%/47% (P = 0.002); secondary prophylaxis, 19.0%/26.8%; but 56.8%/ 53.6% including patients at high risk of febrile neutropenia with grade 3-4 neutropenia. Correct timing start (administration 24-72 h after chemotherapy): pegfilgrastim and filgrastim/lenograstim, 93.2%/61.5% (P <0.0001). CONCLUSIONS: Results suggest the more correct administration of pegfilgrastim as primary prophylaxis and timing start, compared to filgrastim/lenograstim. In secondary prophylaxis, the use of granulocyte colony-stimulating factors is extended beyond guideline recommendations to support patients at high risk of febrile neutropenia and to guarantee dose intensity. These outcomes suggest both the need of educational activities and the development of predictive tools to better define high risk patients and the use of granulocyte colony-stimulating factors.

Epidemiologic surveys of histoplasmin and paracoccidioidin sensitivity in Brazil

Esta publicacao visa a tornar acessiveis os resultados obtidos em inqueritos epidemiologicos sobre histoplasmose e paracoccidioidomicose, realizados no Brasil, atraves das reacoes intradermicas de histoplasmina e paracoccidioidina. Ela justifica-se porque os resultados aqui relacionados, em grande parte, nao foram publicados em revistas cientificas. Os resultados que conseguimos colecionar sao apresentados nas tabelas: 1-sobre histoplasmose e 2-sobre paracoccidioidomicose. Ao todo sao relacionados 88 inqueritos sobre histoplasmose e 58 sobre paracoccidioidomicose. No final da publicacao sao feitos comentarios sobre os itens a serem obedecidos em inqueritos desta natureza

Candidin: comparison of two antigens for cutaneous delayed hypersensitivity testing

Candidina, constituida de suspensao de celulas leveduriformes mortas, e comumente usada em provas intradermicas de hipersensibilidade retardada, principalmente na avaliacao da competencia imunologica do paciente, quando usada conjuntamente com outras provas intradermicas do mesmo tipo. considerando-se o estudo histopatologico de reacao positiva com este tipo de antigeno, e possivel obter uma reacao positiva nao especifica na leitura da prova intradermica. Esta pesquisa apresenta os resultados obtidos a partir da comparacao entre antigeno de suspensao celular e o antigeno polissacacaridico, ambos obtidos a partir das mesmas amostras de Candida albicans...

Histoplasmin reaction: comparison of a polysaccharide antigen to the filtrate antigen

O estudo envolve a comparaçäo entre o antigeno polissacaridico de Histoplasma capsulatum com a histoplasmina classica em inquerito epidemiologico, atraves de provas intradermicas de hipersensibilidade do tipo tardio, realizado em 115 individuos da regiäo de Santo Amaro. Os resultados revelaram 46 por cento de provas positivas com a histoplasmina classica e 51,30 por cento de resultados positivos com o antigeno polissacaridico em sua maior concentraçäo. A principal conclusao da pesquisa: e possível utilizar o antigeno polissacaridico como histoplasmina, em substituiçäo ao antigeno filtrado

Eritromicina tópica na acne vulgar / Topical erythromycin in acne vulgaris

Estuda-se uma soluçäo de eritromicina base a 2%, em veículo de álcool etílico e propilenoglicol, em 41 pacientes portadores de acne vulgar II e III. Os 32 pacientes que concluíram o tratamento de 90 dias mostraram ótima evoluçäo, obtendo resultados satisfatórios (bons e excelentes) em 90,6%, regulares em 6,3% e inalterados em 3,1%. Os efeitos colaterais verificados como descamaçäo, ardor, prurido e eritema foram desprezíveis, näo obrigando à interrupçäo do tratamento

Distribuiçäo geográfica e morbidade da paracoccidioidomicose no Estado de Säo Paulo / Geographical distribution and morbidity of paracoccidioidomycosis in the State of Säo Paulo, Brazil

A incidência de paracoccidioidomicose "doença" nos Munícipios e nas Grandes Unidades do Estado de Säo Paulo é analisada segundo a procedência de 937 doentes. Dos 571 Munícipios do Estado de Säo Paulo, 212 apresentaram casos de moléstia. Estes 212 Municípios estäo distribuídos sôbre todas as Grandes Unidades do Estado indicando a endemicidade da doença em toda a área estadual. A pesquisa indicou que existem diferenças marcantes entre os Municípios quanto à incidência da paracoccidioidomicose "doença". As diferenças näo säo täo marcantes quando calculadas as incidências para as Grandes Unidades do Território paulista. Os principais fatores determinantes da paracoccidioidomicose doença, referentes ao parasita, ao hospedeiro e ao meio ambiente säo discutidos. Os dados da pesquisa conduzem à conclusäo de que a "reservária" ou "nicho ecológico" da paracoccidioidomicose pode situar-se em pequenas áreas, talves menores do que as dos Municípios