Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study.

BACKGROUND: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. PATIENTS AND METHODS: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. RESULTS: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. CONCLUSION: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.

Terazosin-induced alterations in catalase expression and lipid peroxidation in the rat seminal vesicles.

Previous studies have shown that alpha1-adrenergic receptor antagonists may alter seminal vesicle contractility and impair fertility in male rats. This study was designed to investigate the effects of terazosin on the catalase expression in the seminal vesicles and the lipid peroxidation of the seminal fluid in normal adult rats. Wistar rats were treated with terazosin (1.2 mg kg(-1) body weight, given orally every second day) for 120 days. Catalase expression was assessed immunohistochemically in tissue sections of the seminal vesicles, and lipid peroxidation was estimated by measuring the malondialdehyde (MDA) levels in the seminal vesicles' fluid. The seminal vesicles in terazosin-treated rats were particularly distended in comparison with those of controls, and their secreting epithelium was suppressed. Cytoplasmic catalase expression in the secreting epithelial cells (% of cells) was increased in terazosin-treated specimens in comparison with controls (76.1 ± 17.1 versus 51.3 ± 25.1, P = 0.005). MDA levels (µm) were also higher in samples from treated subjects in comparison with controls (2.67 ± 1.19 versus 1.39 ± 0.19, P = 0.01). Although the direct effect of terazosin treatment on the seminal vesicles is that of impaired contractility, an indirect effect is that on fertility by increasing lipid peroxidation in the seminal fluid and/or through degrading of hydrogen peroxide that is essential for sperm capacitation.

The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients.

Late-onset cytomegalovirus (CMV) disease is a significant problem with a standard 3-month prophylaxis regimen. This multicentre, double-blind, randomized controlled trial compared the efficacy and safety of 200 days' versus 100 days' valganciclovir prophylaxis (900 mg once daily) in 326 high-risk (D+/R-) kidney allograft recipients. Significantly fewer patients in the 200-day group versus the 100-day group developed confirmed CMV disease up to month 12 posttransplant (16.1% vs. 36.8%; p < 0.0001). Confirmed CMV viremia was also significantly lower in the 200-day group (37.4% vs. 50.9%; p = 0.015 at month 12). There was no significant difference in the rate of biopsy-proven acute rejection between the groups (11% vs. 17%, respectively, p = 0.114). Adverse events occurred at similar rates between the groups and the majority were rated mild-to-moderate in intensity and not related to study medication. In conclusion, this study demonstrates that extending valganciclovir prophylaxis (900 mg once daily) to 200 days significantly reduces the incidence of CMV disease and viremia through to 12 months compared with 100 days' prophylaxis, without significant additional safety concerns associated with longer treatment. The number needed to treat to avoid one additional patient with CMV disease up to 12 months posttransplant is approximately 5.

Microvessel density (MVD) and cyclooxygenase-2 (COX-2)/ beta-catenin interaction are associated with relapse in patients with transitional carcinoma receiving adjuvant chemotherapy with paclitaxel/carboplatin: a hellenic cooperative oncology group (HECOG) study.

BACKGROUND: Cycloxygenase (COX)-2 has been associated with proliferation, apoptosis and angiogenesis in urothelial cancer. The prognostic significance of COX-2 in patients who received adjuvant chemotherapy for urothelial cancer was examined. PATIENTS AND METHODS: Expression of COX-2, p53, ki67, beta-catenin, vascular endothelial growth factor (VEGF) and microvessel density (MVD) were studied retrospectively in 59 patients with urothelial cancer (pT3, pT4, N+) who had undergone surgery. The patients had subsequently received adjuvant chemotherapy. RESULTS: Thirty-eight out of 59 cases (64%) were positive for COX-2. COX-2 was not associated either with progression-free survival (PFS) or overall survival (OS). MVD levels > or =47 were associated with longer median PFS compared with lower levels (not reached vs. 13 months [95% CI: 8-18], p=0.048). The median PFS for patients with beta-catenin nuclear accumulation and COX-2 expression was 6 months (95% CI: 4-7) compared with 19 months (95% CI: 14-23) for neither or only one of these factors (p=0.018). CONCLUSION: MVD may be a useful indicator of relapse in high-risk urothelial cancer treated with adjuvant chemotherapy.

Accuracy of cystoscopy in predicting histologic features of bladder lesions.

PURPOSE: To correlate individual endoscopist impressions of the nature (benign/malignant) of a urothelial lesion and, in the case of malignancy, "clinical" grade and stage of bladder lesions with the histologic findings after transurethral biopsy/resection. Furthermore, we compared the assessments of trainees and experienced urologists. PATIENTS AND METHODS: We considered 146 patients submitted to cystoscopy and transurethral excision of tumors or biopsy of suspect regions. Clinical and pathologic diagnoses were compared, and the agreement between reports was assessed by calculating kappa statistics. RESULTS: Complete agreement between the cystoscopic and histologic diagnoses was found in 131 of 146 cases. Both specialists and trainees had a tendency to overdiagnose bladder cancer, and they were not effective in predicting the precise stage: complete agreement with the pathologic stage was observed in 66.1% and 64.5% of cases, respectively. Grade was assessed correctly in 55.1% and 54.3% of the cases. The two teams of surgeons expressed complete agreement in the prediction of stage in 78.7% of cases (kappa 0.658) and of grade in 73.2% of cases (kappa 0.584). CONCLUSIONS: Our study confirms the diagnostic value of cystoscopy, given the high recognizability of the malignant nature of a lesion by both specialists and trainees. However, cystoscopy is less satisfactory for the characterization of the stage and grade of a cancer. The comparative assessment of the endoscopic and pathologic findings could prove useful to assess the effectiveness of training in endoscopy.

Correlation of in vitro cytotoxicity and clinical response to chemotherapy in ovarian and breast cancer patients.

During the last years, a number of assays have been developed aiming at predicting the most effective chemotherapy regimen for each individual, avoiding possible toxicity of ineffective drugs. In the present study we have used an in vitro chemosensitivity/chemoresistance assay in order to evaluate cytotoxic treatment in ovarian and breast cancer patients. The assay was applied in 77 ovarian and breast cancer samples and the observed in vitro responses to various chemotherapeutic drugs or combinations of drugs were then correlated to the in vivo responses and the overall clinical data of the examined patients. Direct comparison was possible for 25 cases. The overall positive predictive value of the assay was 50% and the negative predictive value was 57%. However, it was observed that the positive predictive value for ovarian patients was 69% and that the negative predictive value for breast patients was 100%. Therefore this study indicates that although in vitro chemosensitivity/chemoresistance is a valuable assay, further analysis and implications of other factors are required for a general evaluation of cytotoxic treatment for patients with ovarian and breast cancer.

The efficacy of amineptine in the treatment of depressive patients with irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) often suffer from depression. In view of this, the effect of amineptine on the psychopathological condition of depressive patients with IBS was studied. Forty patients who satisfied the criteria for irritable bowel syndrome and had a Hamilton 24-item score above 15 were randomly assigned to receive either amineptine 200 mg/day or placebo in a double-blind clinical trial. Patients on amineptine were more improved at the end of the trial than patients on placebo (total Hamilton score). Amineptine was more effective on depressive mood, retardation, and cognitive dysfunction. Although these findings should be interpreted with caution because the baseline scores were higher in the amineptine than in the placebo group, they provide some evidence that amineptine may be a useful tool for the management of depressive patients with IBS.

Delusional depression: further evidence for genetic contribution.

To quantify the contribution of genetic factors in the pathogenesis of delusional depression, the incidence of major depression in the first degree relatives of 77 delusional, 76 nondelusional depressive patients, and 153 age- and sex-matched controls was calculated in a case-control study. The morbid risk for psychiatric disorders, including major depression and bipolar I disorder, did not distinguish the two proband groups. The segregation analysis showed that the model of multifactorial inheritance fits best to our results. Heritability was estimated on the basis of a threshold model for multifactorial inheritance, and a high contribution of genetic factors for both subgroups was found.

Lymphocytic thyroiditis in fine-needle aspirates: differential diagnostic aspects.

This study assessed the morphological criteria for the diagnosis of various types of lymphocytic thyroiditis in fine-needle aspirates. Of 950 aspirates, 121 revealed lymphocytic thyroiditis, including Hashimoto's thyroiditis (partly confirmed by serological or histological examination) and focal thyroiditis adjacent to neoplasms. The diagnosis of Hashimoto's thyroiditis was easy when the aspirated material was adequate and contained oxyphilic cells; in the fibrous type, diagnosis was rather difficult. Focal thyroiditis may be confused with Hashimoto's thyroiditis, especially when adjacent to neoplasm. Surgical exploration should be performed in cases of severe lymphocytic thyroiditis revealed by fine-needle aspiration with repeatedly negative antibody titers in order to exclude neoplasm.

Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study.

Although the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are highly effective immunosuppressants, they are associated with serious side effects. There is great interest in immunosuppressive regimens that permit reduction or elimination of CNIs, while maintaining adequate immunosuppression and acceptable acute rejection rates. Patients (n = 536) receiving their first renal allograft were randomized to one of three immunosuppressant regimens: daclizumab, mycophenolate mofetil (MMF), corticosteroids (CS) and low-dose CsA (target trough levels of 50-100 ng/mL), weaned from month 4 and withdrawn by month 6; daclizumab, MMF, CS and low-dose CsA; or MMF, CS and standard-dose CsA. Mean GFR 12 months after transplantation (primary end point) was not statistically different in the CsA withdrawal and low-dose CsA groups (both 50.9 mL/min/1.73 m(2)) vs. the standard-dose CsA group (48.6 mL/min/1.73 m(2)). At 12 months, the incidence of biopsy-proven acute rejection was significantly higher in the CsA withdrawal group (38%) vs. the low- or standard-dose CsA groups (25.4% and 27.5%, respectively; p < 0.05). In summary, a regimen of continuous low-dose CsA with MMF, CS and daclizumab induction is a clinically safe and effective immunosuppressive regimen in renal transplant recipients.

Influence of psychological and clinical factors on postoperative pain and narcotic consumption.

Demographic, psychological and clinical factors influencing postoperative pain and narcotic analgesic requirements in 162 patients undergoing elective operations under general anesthesia were studied. Eysencks Personality Questionnaire, Foulds Hostility Questionnaire, Zung's Anxiety-Depression (self-rating) Scales and the 43 Item Life Events Inventory by Holmes and Rahe were used. Clinical correlates such as surgical department, outcome of the operation, patient's knowledge of the diagnosis, were studied. Using multiple regression analysis the following results were obtained: postoperative pain levels increase with higher score of extroverted hostility (p = 0.038), abdominal surgery (p = 0.004), longer stay at hospital postoperatively (p = 0.15) and higher educational status (p = 0.13). Postoperative narcotic requirements increase with increased postoperative pain levels (p = 0.039) and preoccupation with pain postoperatively (p = 0.025), preoperative analgesic drug use (p = 0.017), abdominal surgery (p = 0.009) and longer stay at hospital preoperatively (p = 0.016). Also the department in which the patients were hospitalized influenced narcotic consumption.

Depression among general hospital patients in Greece.

We estimated the prevalence of depression in 150 medical and surgical inpatients. Forty-three patients (29%) scoring at 14 or above on the Beck Depression Inventory (BDI) were classified as depressed. An excess of women and white-collar workers and more stressful life events during the last 12 months were found among the depressed patients. Of the 21 BDI items, 6 differentiated the 43 medical-surgical depressed patients from a group of 43 psychiatric inpatients with a diagnosis of primary or secondary depression (Feighner's criteria). Medically ill depressed patients scored higher in social withdrawal, work inhibition and irritability but lower in loss of libido, sleep disturbance, and lack of satisfaction. Our results show rates of depression in a medical inpatient population in Greece comparable with those in other studies. The use of BDI may help assessment of depression in general hospital patients.

Psychological factors influencing the surgical patients' consent to regional anaesthesia.

To investigate the preoperative attitude of surgical patients to regional anaesthesia, 162 subjects scheduled for elective surgery were studied. On the day before operation, patients were interviewed by an anaesthesiologist, using a semi-structured schedule. Topics investigated were sociodemographic variables and clinical correlates, such as past anaesthetic experience, information about anaesthesia and surgery, as well as questions and fears related to anaesthesia. Subjects were assessed for personality characteristics and emotional symptoms by Eysenck's Personality Questionnaire (EPQ), Zung's Self-rating Anxiety and Depression Rating Scales, Schalling-Sifneos' Personality Scale and the 43-item Life Events Inventory of Holmes and Rahe. Seventy-one patients (44%) consented to regional anaesthesia. Consent to regional anaesthesia was associated with advanced age, low neuroticism and high extroversion score in the EPQ, as well as longer duration of illness. The deniers of consent asked more questions and expressed more fears about anaesthesia. It is suggested that the patients' characteristics influence their preference, acceptance or refusal of regional anaesthesia.

GHQ-28 as an aid to detect mental disorders in neurological inpatients.

The prevalence of mental disorders (DSM-IIIR criteria) among 107 neurological inpatients was estimated, as well as the extent to which disorders were detected by neurologists. The validity of the scaled version of the General Health Questionnaire (GHQ-28) was evaluated using Receiver Operating Characteristic (ROC) analysis and DSM-IIIR as external criteria. Of the 107 patients who submitted to a structured psychiatric interview (SCID-R), 56 (52.3%) showed evidence of a mental disorder. Major depressive episode (n = 16), generalized anxiety disorders (n = 13) and dysthymia (n = 12) were the most frequent diagnoses. The neurologists recognized only 13/107 cases (12.1%). Significantly more women than men exhibited some form of mental disorder. The validation of GHQ-28 in the series of 107 neurological inpatients indicated that the best trade-off between sensitivity and specificity was the cut-off score of 5/6. The high occurrence of mental disorder, in association with the low rate of detection by the neurologists, points to the need for special attention to be paid to this problem by staff and experts.

Delusional depression: phenomenology and response to treatment. A prospective study.

In a prospective study, the authors compared 22 delusional and 36 non-delusional depressive patients with respect to demographic and clinical variables, personality, and response to treatment. Delusional depressives had a higher total score than non-delusional depressives on Hamilton's Rating Scale for Depression, as well as a higher score for depressed mood and psychomotor retardation. The type of treatment failed to differentiate the two groups as to outcome at discharge. However, six of the seven delusional depressives who did not respond to tricyclic antidepressants had a full recovery with ECT. The results indicate that delusional depression represents a more severe type of major depression.

Extravesical foreign body presenting as a bladder tumor.

Although foreign bodies left in the abdominal cavity may remain asymptomatic for long periods, they may also cause serious complications. We present a case of gauze forgotten in the lower abdomen which remained asymptomatic for almost 1 year. When a granuloma had formed, it infiltrated the bladder wall giving the clinical and imaging appearance of an invasive bladder tumor.

Neoadjuvant cisplatin and interferon-alpha 2B in the treatment and organ preservation of penile carcinoma.

We investigated the antitumor activity and toxicity of cisplatin and interferon-alpha 2B as the primary treatment of penile carcinoma. A total of 13 consecutive patients with nonmetastatic, histologically confirmed invasive squamous cell carcinoma of the penis underwent treatment consisting of 20 mg./m.2 cisplatin intravenously and 5 x 10(6) mu./m.2 interferon-alpha 2B subcutaneously daily for 5 consecutive days. An equivalent dose of interferon was then administered subcutaneously every 2 days for 3 weeks and the regimen was repeated at 28-day intervals. Of 12 evaluable patients 9 responded: 4 achieved a pathologically confirmed complete remission of 38+, 21+, 10 and 7 months in duration (2 with relapse were treated with local therapy and remain with no evidence of disease), and 5 achieved a partial response, underwent surgical removal of residual disease and remained disease-free for 14+ to 24+ months. The most significant toxicities were anemia in 5 patients and reversible renal impairment in 3 but no patient had neutropenic fever or required platelet transfusion. We conclude that primary treatment with cisplatin and interferon-alpha 2B induced responses in 75% of 12 patients with penile carcinoma and allowed for a less radical operation than originally scheduled. A larger number of patients and longer followup will be required to confirm these encouraging preliminary results.

Evidence of less severe aortic valve destruction after treatment of experimental staphylococcal endocarditis with vancomycin and dexamethasone.

The beneficial effects of therapy combining an antibiotic and dexamethasone have been reported in human studies on meningitis and in experimental studies on septic arthritis, nephritis, and endophthalmitis. Since most patients with staphylococcal endocarditis need a combination of medical and surgical treatment, the purpose of this study was to determine whether the addition of dexamethasone to vancomycin has any beneficial effect regarding the degree of valve tissue damage or the course of experimental aortic valve endocarditis caused by a methicillin-resistant strain of Staphylococcus aureus. Rabbits with catheter-induced aortic valve vegetations were randomly assigned to a control group and to groups receiving dexamethasone (0.5 mg/kg of body weight, intravenously [i.v.], twice a day [b.i.d]), vancomycin (30 mg/kg, i.v., b.i.d), or dexamethasone plus vancomycin, for a total of 10 doses (two doses per day for 5 days). The severity of valve tissue damage was significantly less in groups receiving vancomycin plus dexamethasone compared with that of the group receiving vancomycin alone (P < 0.001). The severity of tissue damage was inversely correlated with the mean polymorphonuclear leukocyte number in valve tissue. No statistically significant differences were observed between the vancomycin-treated group and the vancomycin-plus-dexamethasone-treated group in survival, blood culture sterilization rate, or reduction of the microbial burden (in CFU per gram) in valvular tissue. In conclusion, treatment with a combination of vancomycin and dexamethasone for 5 days reduces the severity of valve tissue damage in experimental staphylococcal aortic valve endocarditis. These findings could have significant implications in the treatment of staphylococcal endocarditis and deserve further confirmation in clinical trials.