Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity.

Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here, we show that cabozantinib rapidly eradicates invasive, poorly differentiated PTEN/p53-deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anticancer innate immune response, resulting in tumor clearance.Significance: This study is the first to demonstrate that a tyrosine kinase inhibitor can activate neutrophil-mediated antitumor innate immunity, resulting in invasive cancer clearance. Cancer Discov; 7(7); 750-65. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.

Surgical outcomes and complications of reconstructive surgery in the female congenital adrenal hyperplasia patient: What every endocrinologist should know.

Surgical management of classical congenital adrenal hyperplasia (CAH) in 46, XX females has evolved significantly. Virilization of the genitalia of 46, XX females with CAH begins prenatally as a result of excess fetal androgen production. Improved understanding of anatomy and surgical outcomes has driven changes in surgical techniques as well as the timing of surgery. For endocrinologists treating these patients, it is important to understand the outcome of genitoplasty, identify patients who need further treatment and direct these patients to experienced surgeons. We performed a literature search on PubMed of publications addressing CAH and genital reconstruction published in the English language from 1990 to the present. In accordance with our institutional review board, we performed a retrospective analysis of clitoroplasty and/or vaginoplasty procedures performed by a single surgeon at our institution from 1996 to 2015. We found that genital reconstruction in 46, XX CAH patients is associated with few immediate post-operative, infectious, and urinary complications. Vaginal stenosis is a common complication of vaginal reconstruction and requires evaluation by an experienced surgeon. Clitoral pain or decreased sensation can be associated with clitoral recession and clitorectomy. Outcomes in sexual satisfaction and gender identity can also be impacted by surgical technique and success. Long term follow up and patient reported feedback are crucial to our understanding and management of this special group of patients. Improved awareness and understanding of the complications of genital surgery will allow endocrinologists to know what to ask patients and be ready to provide them with a resource with the understanding and experience to help them improve their quality of life.

Trends in Mesh Use for Pelvic Organ Prolapse Repair From the Medicare Database.

OBJECTIVE: To investigate recent trends in mesh use for pelvic organ prolapse (POP)-related reconstruction procedures. MATERIALS AND METHODS: Using the 2001-2011 5% Medicare claims database, we identified POP diagnoses and related procedures. Transvaginal mesh use and sacrocolpopexy were first reported in 2005 and 2004, respectively. RESULTS: A total of 613,160 cases of vaginal and abdominal POP repair procedures were identified. The majority of procedures involved multiple compartments. The rate of mesh use increased dramatically from 2% of repairs in 2005 to 35% by 2008. After the Food and Drug Administration warning in 2008, mesh use plateaued and then decreased in 2011. Mesh was used more commonly in younger (odds ratio [OR] 0.722, P < .001), white (OR 0.712-0.791 for other races, P < .001) women in the South (OR 0.741-0.848 for non-South regions, P < .001). Starting in 2008, the rate of sacrocolpopexy procedures almost doubled yearly until 2011. Sacrocolpopexy was more common in younger patients (49% in women <70 years) and in white women (88%); the majority of sacrocolpopexies were performed in the South (60%) and laparoscopically (83%-98%). CONCLUSION: The treatment of POP has changed over time. The use of mesh increased significantly until 2008, after which it plateaued following the Food and Drug Administration warning regarding mesh-related complications. Concurrently, the number of sacrocolpopexy procedures increased significantly starting in 2008 as the use of laparoscopic and/or robotic technique and concern regarding transvaginal mesh increased.

Is continent cutaneous urinary diversion a suitable alternative to orthotopic bladder substitute and ileal conduit after cystectomy?

OBJECTIVE: To evaluate functional outcomes of continent cutaneous urinary diversion (CCUD) after radical cystectomy (RC) and to compare diversion-related complications and long-term renal function in a contemporary cohort of patients undergoing urinary diversion with CCUD, orthotopic bladder substitute (OBS) and ileal conduit (IC). PATIENTS AND METHODS: In all, 322 patients underwent RC and CCUD, OBS or IC from January 2002 to June 2013. CCUD was performed using either a modified Indiana pouch or an appendiceal stoma. For patients with CCUD, continence status and time intervals between clean intermittent catheterisations at last follow-up were recorded. For all three diversion types, diversion-related complications and renal function outcome, as determined by the estimated glomerular filtration rate (eGFR) at baseline and at different time intervals after surgery, were evaluated. Multivariate regression analysis was used to evaluate the association of diversion type, baseline variables and diversion-related complications with renal function over time. RESULTS: Of all 322 patients, 73 (23%) received a CCUD, 79 (25%) received an OBS, and 170 (53%) received an IC. After a median follow-up of 36 months, the continence rate for patients with a CCUD was 89%. In all, 64 (88%) patients with a CCUD were able to catheterise every 4-8 h and five (7%) were able to catheterise every 8-10 h. After a median follow-up of 35 months, rates of diversion-related complications were similar among patients who underwent a CCUD, an OBS or an IC. Patients who received an IC had poorer renal function preoperatively than those who received a CCUD or an OBS. However, at 1 year after surgery and thereafter, the three groups had comparable renal function. On multivariate analysis, the type of urinary diversion was not associated with decline in renal function. However, patient age at surgery, diabetes mellitus, baseline eGFR, postoperative non-obstructive hydronephrosis and uretero-enteric stricture were associated with decline in renal function. CONCLUSIONS: A CCUD is associated with excellent functional outcomes. The rates of diversion-related complications and renal function outcomes are comparable with those from an OBS and an IC. A CCUD should be considered a valid alternative for patients who undergo cystectomy and require urinary diversion.

Recurrent nephrolithiasis associated with atazanavir use.

A 64-year-old man with HIV on antiretroviral therapy (including atazanavir, a protease inhibitor) presented with left flank pain, nausea and vomiting. A kidney stone was suspected, and a CT scan demonstrated left hydronephrosis but failed to demonstrate nephrolithiasis or extrinsic compression. The patient had a ureteral stent placed which relieved his symptoms. A few months later, he underwent left ureteroscopy and a large ureteral calculus was found. The stone was removed and analysis showed 43% atazanavir and 57% calcium oxalate. Several months later, the patient developed flank pain on the opposite side. A renal ultrasound suggested right-sided nephrolithiasis and he subsequently underwent ureteroscopy with laser lithotripsy of two stones. Stone analysis showed that they were composed of 100% atazanavir. This case highlights the fact that patients treated with protease inhibitors remain at risk for developing nephrolithiasis. Ultrasonography can be a useful diagnostic tool in the setting of these radiolucent calculi.

Combining smoking information and molecular markers improves prognostication in patients with urothelial carcinoma of the bladder.

OBJECTIVES: Tissue-based markers improve the accuracy of prediction models in urothelial carcinoma of the bladder (UCB). Current smoking status and cumulative exposure also affect outcomes. To evaluate whether the combination of molecular markers and smoking features further improved the prognostication of patients who underwent radical cystectomy (RC) for UCB. MATERIALS AND METHODS: A total of 588 patients underwent RC and bilateral lymphadenectomy for UCB from 1995 to 2005. Immunohistochemistry for p53, p21, pRB, p27, Ki-67, and survivin was performed on tissue microarrays from the RC specimen. Smoking features were routinely assessed at diagnosis. Multivariable Cox regression models assessed time to disease recurrence and cancer-specific mortality. RESULTS: Of the 588 patients, 128 were never (22%), 283 former (48%), and 177 current smokers (30%). In total, 227 patients experienced disease recurrence, whereas 190 died of UCB. Smoking status was independently associated with both outcomes (hazard ratio [HR] = 1.48 and 2.62, for former and current vs. never smokers, respectively, P<0.001). All markers were significantly associated with both outcomes (P<0.05) except for survivin. The combination of the 4 cell cycle markers p53, p21, pRB, and p27 increased the discrimination of clinicopathologic model for former and current vs. never smokers with c-indices 0.779 and 0.780, respectively (base model c-indices of 0.741 and 0.740 for former and current vs. never smokers, respectively). The further addition of smoking features and biomarker status improved the discrimination of the model (c-indices of 0.783 and 0.786 for former and current vs. never smokers, respectively). CONCLUSIONS: We confirmed that smoking information and tissue markers status improve prognostication of UCB outcomes after RC; the combination of both reaching the highest level of discrimination.

Cdc45 is a critical effector of myc-dependent DNA replication stress.

c-Myc oncogenic activity is thought to be mediated in part by its ability to generate DNA replication stress and subsequent genomic instability when deregulated. Previous studies have demonstrated a nontranscriptional role for c-Myc in regulating DNA replication. Here, we analyze the mechanisms by which c-Myc deregulation generates DNA replication stress. We find that overexpression of c-Myc alters the spatiotemporal program of replication initiation by increasing the density of early-replicating origins. We further show that c-Myc deregulation results in elevated replication-fork stalling or collapse and subsequent DNA damage. Notably, these phenotypes are independent of RNA transcription. Finally, we demonstrate that overexpression of Cdc45 recapitulates all c-Myc-induced replication and damage phenotypes and that Cdc45 and GINS function downstream of Myc.

Untangling a web: an unusual case of labial necrosis in an adolescent female.

BACKGROUND: Hair tourniquets are commonly described in the pediatric literature. Prompt recognition of a hair tourniquet and treatment with complete removal of the hair by pediatricians, pediatric emergency room physicians, or gynecologists is essential to prevent ischemia and necrosis of affected tissue. CASE: Herein we present the case of a 12-year-old female referred to the pediatric surgery clinic for labial pain and swelling. She was found to have a hair tourniquet of the labia minora caused by pubic hair. The patient was taken to the operating room for examination under anesthesia and removal of the hair. Her post-operative course was unremarkable and she was discharged home the following day. On follow-up visit to the clinic her labial edema had completely resolved and she was pain free. SUMMARY AND CONCLUSIONS: Unlike previous case reports that describe hair tourniquets as originating from hair on the head, our patient had a hair tourniquet caused by pubic hair. In adolescents where personal hygiene of the perineum is difficult, clinicians need to be aware of the possibility of a hair tourniquet forming from pubic hair.

The Fanconi anemia pathway and ICL repair: implications for cancer therapy.

Fanconi anemia (FA) is an inherited disease caused by mutations in at least 13 genes and characterized by genomic instability. In addition to displaying strikingly heterogenous clinical phenotypes, FA patients are exquisitely sensitive to treatments with crosslinking agents that create interstrand crosslinks (ICL). In contrast to bacteria and yeast, in which ICLs are repaired through replication-dependent and -independent mechanisms, it is thought that ICLs are repaired primarily during DNA replication in vertebrates. However, recent data indicate that replication-independent ICL repair also operates in vertebrates. While the precise role of the FA pathway in ICL repair remains elusive, increasing evidence suggests that FA proteins function at different steps in the sensing, recognition and processing of ICLs, as well as in signaling from these very toxic lesions, which can be generated by a wide variety of cancer chemotherapeutic drugs. Here, we discuss some of the recent findings that have shed light on the role of the FA pathway in ICL repair, with special emphasis on the implications of these findings for cancer therapy since disruption of FA genes have been associated with cancer predisposition.

Checkpoint signaling from a single DNA interstrand crosslink.

DNA interstrand crosslinks (ICLs) are the most toxic lesions induced by chemotherapeutic agents such as mitomycin C and cisplatin. By covalently linking both DNA strands, ICLs prevent DNA melting, transcription, and replication. Studies on ICL signaling and repair have been limited, because these drugs generate additional DNA lesions that trigger checkpoint signaling. Here, we monitor sensing, signaling from, and repairing of a single site-specific ICL in cell-free extract derived from Xenopus eggs and in mammalian cells. Notably, we demonstrate that ICLs trigger a checkpoint response independently of origin-initiated DNA replication and uncoupling of DNA polymerase and DNA helicase. The Fanconi anemia pathway acts upstream of RPA-ATR-Chk1 to generate the ICL signal. The system also repairs ICLs in a reaction that involves extensive, error-free DNA synthesis. Repair occurs by both origin-dependent and origin-independent mechanisms. Our data suggest that cell sensitivity to crosslinking agents results from both checkpoint and DNA repair defects.

C620R mutation of the murine ret proto-oncogene: loss of function effect in homozygotes and possible gain of function effect in heterozygotes.

Germline RET mutations are responsible for different inherited disorders: Hirschsprung disease (congenital aganglionic megacolon), caused by loss of function mutations, familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2, caused by gain of function mutations. Intriguingly, some RET mutations, including C620R, are associated with both types of diseases. To investigate the dual role of such RET mutations, a mouse model with a targeted mutation ret(C620R) was generated. ret(C620R/C620R) offspring die during the first postnatal day, and show kidney agenesis and intestinal aganglionosis. Decreased outgrowth of the Ret-positive cells was observed in ret(C620R/C620R) neuronal cell cultures, which is suggestive of an impaired migration, proliferation or survival of the Ret-expressing cells. Electronmicroscopy revealed the absence of membrane-bound Ret in ret(C620R/C620R) cells as compared to ret(+/+) and ret(+/C620R) cells. On the other hand, aged ret(+/C620R) mice develop precancerous lesions in the adrenal gland or in the thyroid. Our results suggest that the ret(C620R) mutation has a loss of function effect in homozygotes and exhibits a dominant gain of function effect with low penetrance causing hyperplasia in heterozygotes.