The Rapamycin-Sensitive Complex of Mammalian Target of Rapamycin Is Essential to Maintain Male Fertility.

The mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin and its analogs are being increasingly used in solid-organ transplantation. A commonly reported side effect is male subfertility to infertility, yet the precise mechanisms of mTOR interference with male fertility remain obscure. With the use of a conditional mouse genetic approach we demonstrate that deficiency of mTORC1 in the epithelial derivatives of the Wolffian duct is sufficient to cause male infertility. Analysis of spermatozoa from Raptor fl/fl*KspCre mice revealed an overall decreased motility pattern. Both epididymis and seminal vesicles displayed extensive organ regression with increasing age. Histologic and ultrastructural analyses demonstrated increased amounts of destroyed and absorbed spermatozoa in different segments of the epididymis. Mechanistically, genetic and pharmacologic mTORC1 inhibition was associated with an impaired cellular metabolism and a disturbed protein secretion of epididymal epithelial cells. Collectively, our data highlight the role of mTORC1 to preserve the function of the epididymis, ductus deferens, and the seminal vesicles. We thus reveal unexpected new insights into the frequently observed mTORC1 inhibitor side effect of male infertility in transplant recipients.

Growth characteristics and therapeutic decision markers in von Hippel-Lindau disease patients with renal cell carcinoma.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a multi-systemic hereditary disease associated with several benign and malignant tumor entities, including clear cell renal cell carcinoma (ccRCC). Since ccRCCs grow slowly, nephron sparing surgery is typically performed at a tumor diameter of 3-4 cm before the tumor metastasizes. However, in the case of recurrent disease, repeated surgical intervention can impair renal function. Therefore, it is crucial to optimize the timing for surgical interventions through a better understanding of the growth kinetics of ccRCCs in VHL. We investigated tumor growth kinetics and modern volumetric assessment to guide future therapeutic decisions. RESULTS: The prevalence of ccRCC was 28% in a cohort of 510 VHL patients. Of 144 patients with ccRCC, 41 were followed with serial imaging which identified 102 renal tumors, which exhibited heterogeneous growth kinetics. ccRCCs grew at an average absolute growth rate of 0.287 cm/year, an average relative growth rate [(lnV1-lnV0)/(t1-t0)] of 0.42% and an average volume doubling time of 27.15 months. Women had a faster relative growth rate than men. Age and specific mutations did not influence tumor growth. Because of the tumor heterogeneity, we developed an additional cut-off volume of 40 cm3 for surgical intervention. CONCLUSIONS: Tumor heterogeneity and differences in growth kinetics is suggestive of a state of transient tumor dormancy in ccRCCs of VHL patients. The relative growth rate has not been previously described in other studies. Volumetric assessment as an additional parameter for surgical intervention could be a useful clinical tool and needs further investigation.

SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11).

PURPOSE: This trial compared the sequential therapy with the multikinase inhibitor sorafenib (So) followed by pazopanib (Pa) or vice versa in advanced/metastatic renal cell carcinoma (mRCC) patients. METHODS: This multicenter, randomized phase 3 study assessed the sequential use of So-Pa versus Pa-So in patients with mRCC without prior systemic therapy. Pts were randomized to So 2 × 400 mg/day followed by Pa 1 × 800 mg/day in case of progression or intolerable toxicity or vice versa. Primary endpoint was total PFS (tPFS), defined as time from randomization to progression, or death during second-line therapy. Key secondary endpoints included overall survival (OS), first-line PFS, disease control rate (DCR) and safety. RESULTS: A total of 377 pts were randomized (So-Pa, n = 189; Pa-So, n = 188). Recruitment of a total 544 pts was calculated, but actual accrual rate turned out to be lower than expected. The primary endpoint median tPFS was 8.6 mo (95% CI 7.7-10.2) for So-Pa and 12.9 mo (95% CI 10.8-15.2) for Pa-So with a hazard ratio (HR) of 1.36 (upper limit of one-sided 95% CI 1.68), which exceeded a predefined HR <1.225 as a one-sided 95% confidence interval. Non-inferiority of So-Pa regarding tPFS was not met. Secondary endpoints displayed marked statistical differences in favor of Pa-So in first-line PFS and DCR but not for OS and 2nd-line PFS. Side effect profiles were consistent with known toxicities of the respective multikinase-inhibitor including diarrhea, fatigue, hand-foot skin reaction and hypertension. CONCLUSIONS: Non-inferiority of the primary endpoint tPFS could not be demonstrated for So-Pa. The results for first-line PFS and DCR favored the Pa-So sequence. TRIAL REGISTRATION: NCT01613846, www.clinicaltrials.gov.

Effects of written information material on help-seeking behavior in patients with erectile dysfunction: a longitudinal study.

INTRODUCTION: Neither men with erectile dysfunction (ED) nor their physicians are willing to discuss sexual problem sufficiently. Written information material could facilitate a dialogue and encourage men to seek treatment. AIM: The central task of this article was to determine the effectiveness and acceptance of patient information material for sexual dysfunction. METHODS: Through an information campaign, men received informational material. Eight thousand men also received a first survey, which asked about the intention to seek treatment and to discuss the sexual problem with a physician or partner. A second follow-up questionnaire, 3-6 months after the first one, asked for the implementation of these intentions. Descriptive and regression-based analyses were applied. MAIN OUTCOME MEASURES: Help-seeking behavior, subjective assessment of change in disease severity and partnership quality, satisfaction. RESULTS: Four hundred forty-three men participated in both surveys. Nearly 90% of them became active after reading the information material. More than half talked with their partner (57.8%) and a physician (65%), and one-third sought treatment (31.8%). Especially discussing the problem with the partner and receiving treatment improved erectile functioning and led to an increase in the quality of partnership (P

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML. Sorafenib-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD+ AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8+ T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

Erratum: Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

This corrects the article DOI: 10.1038/nm.4484.

Adjuvant intravesical treatment with a standardized mistletoe extract to prevent recurrence of superficial urinary bladder cancer.

BACKGROUND: Adjuvant intravesical Bacillus Calmette-Guerin (BCG) treatment after resection of non invasive superficial bladder cancer has been shown to significantly decrease tumor recurrence. However, the serious local and systemic side-effects of this treatment have promoted the use of other immunoactive substances, which, to date, have all failed to show efficacy equal to BCG therapy. PATIENTS AND METHODS: In the present phase I/II clinical trial, an aqueous mistletoe extract, standardized to mistletoe lectin, was applied intravesically to 30 patients with superficial urothelial bladder carcinomas of stages pTa and pT1, grades 1 to 2. After transurethral resection, each patient received 6 instillations at weekly intervals of 50 ml of the extract with mistletoe lectin concentrations between 10 ng/ml and 5000 ng/ml. This was retained in the bladder for 2 hours. Three patients per group received a dose, which was then doubled in the next group. The clinical follow-up consisted of examinations by cystoscopy, cytology and random biopsies. RESULTS: Within the observation time of 12 months, 9 patients had tumor recurrence, while 21 patients remained tumor-free. This recurrence rate was comparable to that of local historical controls with superficial bladder cancer of the same stages and grades that had been treated with adjuvant BCG. The tolerability of the intravesically-administered mistletoe extract was very good. None of the study patients had local or systemic side-effects according to the WHO classification 1-4. CONCLUSION: From these results, it is concluded that the standardized mistletoe extract could be a potential adjuvant therapy for superficial bladder cancer. Further studies may show the optimal intravesical treatment regimen.

Adjuvant intravesical treatment of superficial bladder cancer with a standardized mistletoe extract.

PURPOSE: Adjuvant intravesical immunotherapy with bacillus Calmette-Guerin (BCG) for noninvasive superficial bladder cancer has been shown to decrease tumor recurrence significantly. However, serious local and systemic side effects of this treatment have promoted the use of other immunoactive substances, which to date have failed to show efficacy equal to that of BCG immunotherapy. MATERIALS AND METHODS: In the current phase I/II clinical trial an aqueous mistletoe extract standardized to mistletoe lectin was administered intravesically to 30 patients with superficial urothelial bladder carcinoma. About 4 weeks after transurethral resection each patient received 6 instillations at weekly intervals of 50 ml extract with mistletoe lectin concentrations between 10 and 5,000 ng/ml, which was retained in the bladder for 2 hours. Three patients per group received a dose, which was then doubled in the next group. Clinical followup consisted of examinations with cystoscopy, cytology and random biopsies. To detect cytokines and tumor necrosis factor-p75 receptor venous blood and urine samples were taken before instillation, and 2, 6 and 24 hours thereafter. RESULTS: The tolerability of intravesically administered mistletoe extract was good at all applied concentrations. None of the patients had local or systemic side effects according to WHO classification 1-4. Within the 12-month observation time study patients with pTa G2 and pT1 G2 tumors showed a recurrence rate of 33%, comparable to that in a local historical control group of patients with equal stage and grade who were treated with adjuvant BCG. Comparison of urine cytokine levels before instillation, and 2, 6 and 24 hours thereafter brought about no significant alterations in all measured cytokines. CONCLUSIONS: From these results it is concluded that standardized mistletoe extract could be a potential alternative adjuvant therapy for superficial bladder cancer. Nevertheless, the optimal intravesical treatment regimen has yet to be defined.