Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer.

BACKGROUND: Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT. METHODS: Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens. RESULTS: In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so. CONCLUSIONS: These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.

Cancer Induces a Stress Ileopathy Depending on ß-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis.

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of ß-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies. SIGNIFICANCE: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a ß-adrenergic receptor-dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.-related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873.

High postoperative neutrophil-to-lymphocyte ratio as a poor prognostic marker in patients with upper tract urothelial carcinoma.

Previously, the preoperative neutrophil-to-lymphocyte ratio (NLR) has been demonstrated to be a beneficial prognostic marker in patients with upper tract urothelial carcinoma (UTUC). However, to the best of our knowledge, the postoperative NLR has rarely been investigated. Therefore, the present study evaluated the prognostic significance of postoperative NLR in patients with UTUC. Data of patients with UTUC who underwent surgical treatment at Kurume University hospital (Kurume, Japan) between 2004 and 2015 were retrospectively reviewed. Clinicopathological characteristics were analyzed, including pre- and postoperative NLRs. Overall survival (OS) and cancer-specific survival (CSS) rates were estimated using the Kaplan-Meier method and compared with a log-rank test. Multivariate proportional Cox regression models were applied for both endpoints to identify the independent prognostic significance of NLR. The median age of the 134 enrolled patients was 70 years. The postoperative NLR was elevated in 35 patients (26.1%). A high postoperative NLR of ≥2.5 was significantly associated with a high postoperative C-reactive protein level of ≥0.3 mg/dl, an advanced pathological T stage and positive lymphovascular invasion in surgical specimens (P<0.001, P=0.019 and P=0.024, respectively). The 5-year OS rates in patients with high and low postoperative NLR were 33.7 and 70.2%, respectively (P<0.001), and the 5-year CSS rates in patients with a high and low postoperative NLR were 33.7 and 80.7%, respectively (P<0.001). Multivariate analysis revealed that a high postoperative NLR was an independent prognostic marker for OS (hazard ratio, 4.66; 95% confidence interval, 2.11-10.00; P<0.001) and CSS (hazard ratio, 10.90; 95% confidence interval, 4.32-28.40; P<0.001), and the preoperative NLR was not identified as a prognostic marker. In conclusion, a high postoperative NLR is associated with a poor prognosis in patients with UTUC. Therefore, postoperative NLR may be a potential prognostic marker in patients with UTUC undergoing nephroureterectomy.

Personalized peptide vaccination as second-line treatment for metastatic upper tract urothelial carcinoma.

This study investigated the applicability of personalized peptide vaccination (PPV) for patients with metastatic upper tract urothelial cancer (mUTUC) after failure of platinum-based chemotherapy. In this single arm, open-label, phase II clinical trial, patients with mUTUC received PPV at a single institution. Personalized peptide vaccination treatment used a maximum of four peptides chosen from 27 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for six s.c. injections weekly as one cycle. The safety of PPV, as well as its influence on host immunity and effect on overall survival were assessed. Forty-eight patients were enrolled in this study. Personalized peptide vaccinations were well tolerated without severe adverse events. Median survival time was 7.3 months (95% confidence interval [CI], 5.3-13.1) with 13.0 months for patients receiving combined salvage chemotherapy (95% CI, 5.7-17.5) and 4.5 months for patients receiving PPV alone (95% CI, 1.7-10.1) (P = 0.080). Patients with positive CTL responses showed a significantly longer survival than patients with negative CTL responses (hazard ratio, 0.37; 95% CI, 0.16-0.85; P = 0.019). Multivariate Cox regression analysis showed that lower numbers of Bellmunt risk factors and lower levels of B-cell activating factor were significantly associated with favorable overall survival for patients under PPV treatment. This study indicated that PPV for patients with mUTUC after failure of platinum-based chemotherapy induced substantial peptide-specific CTL responses without severe adverse events and has the potential to prolong survival when combined with salvage chemotherapy. UMIN Clinical Trials Registry ID: 000001854.

A Laparoscopic Management Combined with a Flexible Ureteroscope for Ureteral Polyps of More Than 3 cm Length.

Ureteral polyps are benign tumors of the ureter, which are relatively rare. The etiology has proposed various hypotheses, involving chronic inflammation and congenital disease. Most of them are commonly diagnosed in the upper ureter including the ureteropelvic junction. Some studies have reported polypectomy using a holmium laser, but several studies presented laparoscopic ureteroureterostomy for patients in whom the mentioned procedure is difficult. We underwent laparoscopic ureteroureterostomy with a combination of flexible ureteroscope for ureteral polyps of more than 3 cm length. We used ureteroscopy with a laparoscopic approach to minimize the length of ureter resection. Using the light guide of ureteroscopy is useful to decide the exact and minimal excision range for ureteroureterostomy.

Comprehensive Health-Related Quality of Life is Influenced by Nocturia and Sleep Disturbance: Investigation Based on the SF-8.

We investigated the influence of nocturia and sleep disturbance on health-related quality of life(HRQOL) using the Medical Outcomes Study 8-item Short Form Health Survey (SF-8) in patients with nocturia. We also assessed the effect of therapeutic intervention by means of an anticholinergic agent on the results of the SF-8. One hundred and eighty-four patients who voided at least once per night were surveyed using the SF-8, Overactive Bladder Symptom Score (OABSS), Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS). These parameters were also evaluated before and after 12 weeks of imidafenacin treatment in 51 patients with OAB accompanied by nocturia. The SF-8 physical component summary score (PCS) showed a significant decrease as nighttime voiding frequency increased. The mental health component summary score was 47.1 and 47.6 (which were lower than the standard value of 50) in the group with a nighttime frequency of once and ≥3/night, respectively. The SF-8 PCS and 6 subscales were negatively associated with nighttime voiding frequency, while the PSQI global score was positively associated with it. Imidafenacin significantly improved the OABSS, PSQI, and ESS, as well as the SF-8 score. This is the first study using the SF-8 to show that nocturia and sleep disturbance have a major influence on comprehensive HRQOL and that the SF-8 can be used to monitor HRQOL in OAB patients receiving treatment for nocturia.

Clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification.

Combined hepatocellular-cholangiocarcinoma comprises <1% of all liver carcinomas. The histogenesis of combined hepatocellular-cholangiocarcinoma has remained unclear for many years. However, recent advances in hepatic progenitor cell (HPC) investigations have provided new insights. The concept that combined hepatocellular-cholangiocarcinoma originates from HPCs is adopted in the chapter "combined hepatocellular-cholangiocarcinoma" of the latest World Health Organization (WHO) classification. In this study, we conducted clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification. Fifty-four cases were included in this study. Pathologic diagnosis was made according to the WHO classification. When a tumor contained plural histologic patterns, predominant histologic pattern (≥50%) was defined. Minor histologic patterns were also appended. Immunohistochemical staining with biliary markers (CK7, CK19, and EMA), hepatocyte paraffin (HepPar)-1, HPC markers (CD56, c-kit, CD133, and EpCAM), and vimentin was performed. Forty-five and 50 patients were analyzed for progression-free survival and overall survival, respectively. Ten, 1, 32, and 11 cases were diagnosed as: combined hepatocellular-cholangiocarcinoma, classical type; combined hepatocellular-cholangiocarcinoma, stem cell features, typical subtype; combined hepatocellular-cholangiocarcinoma, stem cell features, intermediate cell subtype; and combined hepatocellular-cholangiocarcinoma, stem cell features, cholangiolocellular type, respectively. Combined hepatocellular-cholangiocarcinomas usually have high expression of biliary markers. CD56, c-kit, and EpCAM were expressed to various degrees in all combined hepatocellular-cholangiocarcinomas apart from the hepatocellular carcinoma component of combined hepatocellular-cholangiocarcinoma, classical type. The expression of CD133 and vimentin was observed only in combined hepatocellular-cholangiocarcinoma, stem cell features of intermediate cell subtype and cholangiolocellular subtype. The expression of CD133, EpCAM, and vimentin was significantly high in combined hepatocellular-cholangiocarcinoma, subtypes with stem cell features, especially cholangiolocellular subtype. Minor histologic patterns were significantly frequent in combined hepatocellular-cholangiocarcinoma, subtypes with stem cell features, compared with combined hepatocellular-cholangiocarcinoma, classical type. There was no significant difference in clinical outcome between each subtype. Combined hepatocellular-cholangiocarcinoma has wide histologic diversity and shows immunophenotypic expression of not only biliary markers but also HPC markers to various degrees, suggesting that the histogenesis of combined hepatocellular-cholangiocarcinoma could be strongly associated with HPCs. Our results pathologically validate the latest WHO classification of combined hepatocellular-cholangiocarcinoma. However, the complex mixture of histologic subtypes has presented a challenge to the classification of combined hepatocellular-cholangiocarcinoma. Further study should be conducted using a large cohort to support this classification.

Successful treatment of T4 renal cell carcinoma after a neoadjuvant targeted therapy using sunitinib: report of a case.

Since the introduction of targeted therapy, treatment of metastatic renal cell carcinoma (RCC) has undergone dramatic changes. Responses to targeted therapy within the primary tumor and metastatic lesions are novel findings not seen with immunotherapeutic-based strategies. We report here a case of T4 RCC in which cytoreductive nephrectomy became possible after a neoadjuvant targeted therapy using sunitinib. Our experience with the present case suggests that targeted therapy in the neoadjuvant setting may have a variety of potential applications. Further investigations should be encouraged.

[Spontaneous rupture of renal cancer: a case report].

A 53-year-old man presented to our hospital as an emergency admission with sudden right flank pain. No examinations using contrast media could be performed due to allergies. Abdominal plain computed tomography and ultrasonography revealed right peri-renal hematoma, but causes were unknown. Magnetic resonance imaging (MRI) contrasted with gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) revealed right spontaneous rupture of renal cancer and radical nephrectomy was performed. The surgical specimen displayed renal subcapsular hematoma, and histopathology revealed renal clear cell carcinoma, grade 3, INF gamma, pT1a, pV0. The patient was well and without local recurrence or distant metastasis at 14 months postoperatively. Spontaneous rupture of renal cancer is uncommon, and our case is the 68th reported in Japan. MRI is useful for diagnosis and surgical intervention is recommended. Analysis by the Kaplan-Meier method showed good prognosis in spite of spindle cell carcinoma and advanced disease (stage IV).

Effect of functional magnetic particles on radiofrequency capacitive heating: an in vivo study.

Specific heating of magnetic particles in radiofrequency (RF) capacitive hyperthermia and its hyperthermic effect were investigated in an in vivo study. Magnetite cationic liposomes (MCLs) were injected into a rat tumor on the femur and 8 MHz-RF capacitive heating was applied to the rat under "mild heating" conditions. Although the input power of RF capacitive heating was low under the same power conditions, the MCLs-injected tumor was heated over 43 degrees C, whereas it was only heated to 41 degrees C in the case of the rats not injected with MCLs. A necrotic area in the tumor was observed in the heated rats. From the results of histological observation of the removed tissue, the necrotic area in the MCLs-injected tumor was wider than that in MCLs-free tumor. Complete tumor suppression was observed in 71% (5 / 7) of MCLs-injected rats, and the hyperthermic effect was greatly improved by the MCLs.