Antivirals in medical biodefense.

The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha- and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.

[Histopathologic risk factors in patients with non-seminomatous germ tumors of the testis in clinical stage 1. Retrospective study of 75 patients]. / Fattori istopatologici di rischio in pazienti con tumore germinale non seminomatoso del testicolo in stadio clinico 1. Uno studio retrospettivo su 75 pazienti.

OBJECTIVES: This retrospective study was performed to evaluate histopathologic prognostic risk factors in 75 patients on clinical stage 1 nonseminomatous germ cell cancer of the testis (NSGCTT). METHODS: From September 1976 to February 2000 we operated on 75 patients for NSGCTT on clinical stage 1 disease. Average age was 29.5 years (range 16-71). After orchiectomy, therapeutic options included retroperitoneal lymph node dissection (RLND) for 44 patients (58.6%), surveillance for 26 (34.6%) and neoadjuvant chemotherapy for 5 (6.6%). Testis primary tumor samples were assessed for studying prognostic risk factors that included vascular and/or lymphatic invasion (IV/IL+), percentage of embryonal carcinoma (%EC) and absence of yolk sac tumor (YS-). RESULTS: All patients were alive and disease-free. The average age follow-up was 84.5 months (range 1-254). Relapses occurred in 11 (14.6%) patients after an average follow-up of 9.09 months (range 3-24). Prognostic risk factors were detected as follows: IV/IL+ in 17 cases (22.7%), (50-80%) EC in 23 (30.6%), CE% > 80 in 23 (30.6%), YS- in 55 (72%). In 8 (10.6%) patients there was not any prognostic risk factor. Disease relapse related to prognostic risk factors was detected as follows: 18.1% for VI/LI, 90.9% for EC% > 50 (27.2% for 50-80% EC and 63.6% for CE% > 80) and 90.9% for YS-. Relapsing rates between patients with EC% > 80 and 50-80% EC resulted statistically significant (p = 0.02, odds ratio = 12.25). Relapsing rates between patients on surveillance and those who underwent RLND was next to be significant (p = 0.05, odds ratio 3.68). CONCLUSIONS: EC% > 80 is a prognostic risk factor for disease relapse in patients with clinical stage 1 NSGCT who are selected in a high risk group requiring RPLND or neoadjuvant chemotherapy as therapeutical option.

Primary extranodal lymphomas of Waldeyer's ring, stage IE and IIE.

We reviewed 45 cases of Waldeyer's ring lymphomas (25 stage IE, 20 IIE): 73% had high-grade histology according to Kiel's classification. Fourteen patients received radiotherapy alone and 31 chemotherapy, combined with radiotherapy in 28. Complete remission rate was 95% and relapse rate 32%. At 8 years overall disease-related survival (DRS) and event-free survival (EFS) were 69% and 57% respectively. Combined treatment provided both significantly better DRS (82% vs 42%) and EFS (76% vs 25%) than radiotherapy alone. Most of the patients with high-grade histology (26/33) received the combined treatment and this subgroup achieved a long-term EFS of 78%. Both DRS and EFS were also significantly longer in patients under 60. At multivariate analysis favorable prognostic factors were lower age for DRS and combined treatment for EFS.

Extragonadal germ cell tumor: a clinical study.

Among 18 patients with primary extragonadal germ cell tumors (8 seminoma and 10 non- seminoma), the disease involved the mediastinum (7), the retroperitoneum (8), multiple lymph nodal sites (2) and the pinealis gland (1). Seventeen patients received cisplatin-based chemotherapy as part of the initial treatment. Fifteen patients (83%) achieved complete remission (6 seminoma and 9 non-seminoma): 12 of them are relapse-free after a median follow-up of 82 months (range 13-138). Five-year overall survival was 65%. No statistically significant survival difference was found between mediastinal and retroperitoneal tumors or patients with seminoma and nonseminoma.

AFP and HCG in germ cell tumors.

The high specificity and sensitivity of testicular tumor markers make them particularly useful in the management of these neoplasms. Basal value represents an independent prognostic variable, influencing the choice of therapy. An increase in marker level before chemotherapy could also acquire a powerful prognostic significance. The decay curve pattern is indicative of the radicality of surgery. Also during chemotherapy the behavior of markers conditions further therapeutic strategies.

High-dose chemotherapy supported with autologous bone marrow transplantation (ABMT) in germ cell tumors: a phase two study.

In this paper, the first Italian multicentre experience with high-dose chemotherapy and ABMT in germ cell cancer is presented. Twenty-eight patients underwent treatment with a carboplatin-etoposide w/o ifosfamide high-dose combination. Seventeen patients were in progression of disease, 9 were responsive to salvage treatments or failed to achieve CR to front line, and 2 had stable disease (both with an elevated marker level) at the time of transplantation. Five patients, all of whom were in sensitive relapse at transplantation, are alive and disease-free at > 17 months' follow-up. Two patients died 15 days after ABMT, one of veno-occlusive disease and one of rapid uncontrolled tumor progression. In highly pretreated patients this schedule seems to provide an option of cure for a cohort of patients failing to achieve CR to standard salvage regimens for germ cell cancer. Definitive conclusions may eventually be drawn with a more homogeneous group of patients. This type of approach should continue to be taken in sensitive relapse patients only, as responses in progressive cases are very transient, with virtually no cures. The question of whether high-dose programs are better than standard chemotherapy will in any case be answered only in a randomized prospective trial.

CA 15.3 determination in patients with breast cancer: clinical utility for the detection of distant metastases.

In 81 healthy women, 26 pregnant women, 25 patients with fibrocystic disease and 144 breast cancer patients, the overall diagnostic sensitivity and specificity of the CA 15.3 test was 27 and 97%, respectively. The positive and negative predictive values were 93 and 43%. In 150 node-negative patients taking part in a chemoprevention trial CA 15.3 was assayed at baseline and every 4 months for a median follow-up of 24 months (range 4-48). In these patients, 5 had local recurrences, 1 had a regional recurrence, 9 had distant metastases and 3 developed cancer in the contralateral breast. Among the patients with recurrences, those with distant metastases showed the highest ratio of CA 15.3 increase (8/9); in local and regional recurrences, this ratio was lower (2/6). The patients with contralateral breast cancer had no significant increase in CA 15.3. Patients in whom metastases were detected showed an increase in CA 15.3 4-48 months before clinical or instrumental detection of the metastases.

An Italian experience of high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in germ cell tumours. Suggestions for future direction.

In this paper an Italian cooperative trial investigates the role of a high-dose regimen with carboplatin, etoposide and ifosfamide in germ cell tumours. Twenty-eight patients underwent one or two transplants. Seventeen with progressive disease. Nine in sensitive relapse and two with stable disease after salvage therapy. Toxicity was generally moderate: two deaths occurred at day 15 from ABMT (one from VOD and one from tumour growth). Five patients are alive and disease free at least 10 months follow-up. In highly pre-treated patients this high-dose combination seems to give an option of cure for relapsed patients. Early transplantation is suggested.

High dose chemotherapy with carboplatin, VP 16 +/- ifosfamide in germ cell tumors: the Italian experience.

This schedule has shown an interesting activity with nearly 40% of the patients achieving CR. Moreover 4 patients experienced an inversion rate (CR with ABMT when they never achieved this status before). In terms of toxicity, this schedule seems feasible with 2/28 toxic deaths, which is in the lower part of the range of major solid tumors ABMT programs. But even if the rationale is proper, a better patients' selection is required. The CCR (continuous Complete Remission) rate is overimposable to other main studies previously published, but all our CCR were obtained in responding patients (Sensitive Relapses or unresectable PR). We may suggest that earlier transplantation is advisable when less tumor bulky is present and less clonal eterogeneity. The exact maximum tolerated dose of Carboplatin/VP 16/Ifosfamide programs has not yet clearly pointed out. The lack of major life-threatening episodes and neuro/nephrotoxicity may allow us to explore higher Carboplatin doses. Anyway the ultimate answer to the utility of ABMT trials must come from a randomized study in responding patients.

Recombinant alpha-interferon and vinblastine in metastatic renal cell carcinoma: efficacy of low doses.

Twenty-six patients with metastatic renal cell carcinoma (RCC) were treated in a phase I-II trial with recombinant interferon alpha-2b (alpha-IFN) and vinblastine (VBL) in combination. Patients received IFN at a starting dose of 3 x 10(6) IU/m2 subcutaneously three times a week and VBL 0.1 mg/kg intravenously every 3 weeks, with dose modification for toxicity. All patients were evaluable for toxicity; 18 patients were evaluable for efficacy. An objective response rate of 44% was observed (eight of 18 patients, with one complete response and seven partial responses). The median duration of response was 5 months. The actuarial survival of responding patients was significantly longer than that of nonresponding patients. In general, the toxicity was tolerable; the subjective toxicity and fever were similar to that reported for the same doses of IFN alone. Only a mild neurotoxicity, usually mixed polyneuropathy, occurred with increased frequency. Alpha-IFN and VBL administered at low doses in combination demonstrated the highest response rate so far reported in RCC without significant toxicity.

Micro-chromatographic measurement of hemoglobin A1 in uremia.

In an investigation of the reliability of the measurement of HbA1 by microcolumn chromatography for monitoring glucose metabolism in chronic renal failure, measurements were made in 96 uremic patients. Thirty-one patients were undialyzed, 42 patients including 10 with primary diabetes mellitus were on hemodialysis, and 23 patients were on continuous ambulatory peritoneal dialysis (6 with primary diabetes mellitus). Significantly raised HbA1 values were observed in all groups, whether their glucose tolerance was normal or decreased. Azotemia was not statistically correlated either with HbA1 values, or with glucose tolerance. Dialyzed primary diabetic patients showed HbA1 levels which were significantly higher than those in non-diabetics, but some overlap was evident. The results suggest that the increased values of HbA1 in uremic patients depend on the plasma concentration of either glucose which leads to the formation of glycosylated Hb or of urea which leads to the formation of carbamylated Hb. These are indistinguishable by microcolumn chromatography. Therefore this method cannot be recommended for evaluation of glucose metabolism in uremic patients.