T-Cell redirecting bispecific antibodies: a review of a novel class of immuno-oncology for advanced prostate cancer.

Novel T-cell immunotherapies such as bispecific T-cell engagers (BiTEs) are emerging as promising therapeutic strategies for prostate cancer. BiTEs are engineered bispecific antibodies containing two distinct binding domains that allow for concurrent binding to tumor-associated antigens (TAAs) as well as immune effector cells, thus promoting an immune response against cancer cells. Prostate cancer is rich in tumor associated antigens such as, but not limited to, PSMA, PSCA, hK2, and STEAP1 and there is strong biologic rationale for employment of T-cell redirecting BiTEs within the prostate cancer disease space. Early generation BiTE constructs employed in clinical study have demonstrated meaningful antitumor activity, but challenges related to drug delivery, immunogenicity, and treatment-associated adverse effects limited their success. The ongoing development of novel BiTE constructs continues to address these barriers and to yield promising results in terms of efficacy and safety. This review will highlight some of most recent developments of BiTE therapies for patients with advanced prostate cancer and the evolving data surrounding BiTE constructs undergoing clinical evaluation.

Comparison of weight gain after antiretroviral switch to integrase strand transfer inhibitor or tenofovir alafenamide-based therapy.

PURPOSE: Several studies have reported weight gain after switching to integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART). Debate persists if weight gain also occurs when switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF)-based ART. METHODS: We performed a retrospective chart review of virally suppressed HIV-infected patients who were switched from non INSTI- to INSTI-based ART (INSTI switch group) as well as patients switched from TDF- to TAF-based ART (TAF switch group), and compared the mean weight change in these groups to the mean change in weight in patients maintained on NNRTI-based regimens (control group). RESULTS: 329 patients were identified. 256 patients in the INSTI switch group gained a mean 2.4 kg over 17 months compared to 0.5 kg in 54 patients in the control group over the same period (p = 0.008). 161 patients in the TAF switch group gained a mean 2.8 kg over 17 months compared to 0.5 kg in the control group (p = 0.003). There was no statistical difference in weight gain between the INSTI and TAF switch groups. Although the highest mean weight gain of 3.2 kg was seen in those 90 patients switched from both TDF- to TAF-based and non INSTI- to INSTI-based ART (TAF/INSTI switch group), this weight gain was not statistically different compared with the INSTI switch or TAF switch groups. CONCLUSION: Our study suggests that weight gain is associated with both switching HIV regimens from non INSTI- to INSTI-based ART and TDF- to TAF-based ART.

Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET.

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland. Most ACCs are sporadic, but a small percentage of cases are due to hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), and familial adenomatous polyposis (FAP). Multiple endocrine neoplasia type 2A (MEN2A) is an inherited disorder that predisposes to medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. We present here a case of ACC with both LS and MEN2A; the family and medical history were consistent with Lynch. This is, to our knowledge, the first report of a patient with ACC associated with germline mutations in RET and MSH2, and no phenotypical characteristics of MEN2A.

Multimethod Formative Research to Improve the Training and Delivery of Tobacco-cessation Interventions in Behavioral Health Settings.

INTRODUCTION: Despite progress in reducing tobacco use within the general population, high prevalence of tobacco use continues in individuals with mental health and substance use disorders ("clients"). Tobacco use persists as the leading cause of premature mortality in this population. While behavioral health providers have frequent contacts with this population, they lack training in tobacco cessation counseling. METHODS: We conducted multimethod formative data collection consisting of key informant interviews with providers, field observations at clinical sites, and structured group interviews with behavioral health providers, and, separately, clients. Activities were conducted at 4 behavioral health agencies with 9 behavioral health clinic sites in southern Arizona. Recurring phrases and level of repetition were quantified to identify themes. These themes were then used to adapt the method of training delivery and revise the curriculum content for providers at the participating sites. RESULTS: Results indicated that providers had "training fatigue" and low satisfaction with multiple, online trainings. Further, providers noted issues including time constraints, competing clinical priorities, and low access to tobacco-cessation materials. Clients demonstrated high self-awareness around the importance of quitting smoking and professed frustration at being unable to quit, despite multiple attempts. Finally, both providers and clients agreed that a personal, supportive approach to cessation counseling was preferred. CONCLUSIONS: Using results from this formative research to revise delivery and content of existing smoking-cessation training for behavioral health providers may address barriers to assisting clients with smoking cessation. Additional research to determine the efficacy of the adapted training is needed.

Pelvic lymphadenectomy during robot-assisted radical prostatectomy: Assessing nodal yield, perioperative outcomes, and complications.

OBJECTIVES: To describe our pelvic lymphadenectomy (PLND) technique during robot-assisted radical prostatectomy and to evaluate the nodal yield and perioperative outcomes. PLND is commonly performed with radical prostatectomy for localized prostate cancer. Because of the limitations of the robotic arm pitch in accessing the pelvic sidewall and undersurface of the iliac bifurcation, uro-oncologists have questioned the adequacy of robotic PLND. METHODS: PLND was routinely performed on men with higher risk preoperative prostate cancer parameters (ie, prostrate-specific antigen >10 ng/mL, primary Gleason score > or =4, or clinical Stage T2b or greater). The outcomes of robot-assisted radical prostatectomy with bilateral, standard template PLND (group 1; n = 296 [26%]) were compared with those of a cohort of 859 robot-assisted radical prostatectomy patients (74%) without PLND (group 2). We also compared these data with those from a single-surgeon experience of open, standard-template PLND for retropubic radical prostatectomy. RESULTS: The mean number of lymph nodes removed was 12.5 (interquartile range 7-16). The mean operative time (224 vs 216 minutes; P = .09), estimated blood loss (206 vs 229 mL; P = .14), and hospital stay (1.32 vs 1.24 days; P = .46) were comparable between the 2 groups. The rate of intraoperative complications (1% vs 1.5%; P = .2), overall postoperative complications (9% vs 7%; P = .8), and lymphocele formation (2% vs 0%; P = .9) were not significantly different. The review of our open series and the historically published open standard-template PLND series revealed a mean yield of 15 and a range of 6.7-15 lymph nodes removed, respectively. CONCLUSIONS: Our data support the feasibility and low complication rate of robotic standard-template PLND with lymph node yields comparable to those with open PLND. Considering the low morbidity of PLND in experienced hands, coupled with the potential of preoperative undergrading and understaging and the therapeutic benefit to patients with micrometastatic disease, an increase in overall standard-template PLND use should be considered.

Impact of renal lesion size on perioperative and pathologic outcomes in patients undergoing laparoscopic partial nephrectomy.

BACKGROUND AND PURPOSE: The size of renal lesions managed with laparoscopic partial nephrectomy (LPN) has been increasing, especially as surgical volume and experience matures. The objective of this study was to assess the perioperative and pathologic outcomes of LPN when stratifying for size of renal lesion. PATIENTS AND METHODS: A retrospective review of LPN performed at the University of Chicago by a single surgeon (ALS) between October 2002 to July 2007 was performed. Patients (153) were then stratified into three groups according to radiographic diameter of the lesion: < or = 2 cm (group A), 2 to 4 cm (group B), and > or = 4 cm (group C). Perioperative, operative, and pathologic data were compared using analysis of variance and Pearson test. Moreover, serum creatinine and creatinine clearance (Cockcroft-Gault) were assessed postoperatively. RESULTS: With regard to operative parameters, operative time was significantly longer in renal lesions > 2 cm (P = 0.0012), and the need for collecting system repair was also more prevalent as lesion size increased (P < 0.0001). Warm ischemia time was longest with lesions 2 to 4 cm (35.3 min) compared with masses < or = 2 cm (27.2 min; P < 0.001) or > or = 4 cm (30.3 min; P = 0.028). All other variables were similar among the three groups, including the rates of positive surgical margins, complications, estimated blood loss, conversion, and transfusion. Comparison of pathologic data suggests smaller lesions are more likely to be of lower grade compared with larger lesions. Postoperative renal function did not differ among the groups with a mean follow-up of 19.9 months. CONCLUSIONS: Although LPN for renal masses 2 to 4 cm necessitated longer warm ischemia, short-term postoperative renal function was not affected by lesion size. Differences in warm ischemia time cannot be attributed solely to lesion size but are likely influenced by a combination of tumor size, location, and depth. LPN can be performed safely in selected patients with larger renal lesions.

Laparoscopic port-site metastasis in urologic surgery.

PURPOSE: Port-site metastasis has been an increasing concern with the spread of laparoscopy in managing urologic malignancies. The purpose of this study was to provide a current review of port-site metastases reported in the urologic oncology literature, as well as etiologic factors and preventative measures. METHODS: A comprehensive Medline search (up to September 2007; subject headings: "neoplasm seeding," "laparoscopy," "urologic neoplasms") of all case reports and series related to laparoscopic urology surgery for malignant disease was performed. The references for each of these case reports and series were also reviewed for any additional reports of port-site metastases. RESULTS: Only 28 cases of port-site metastases involving urologic malignancies have been reported, with laparoscopic procedures involving upper tract transitional cell carcinoma comprising the majority (11/28 or 39%) of these. Recent reports involving renal cell carcinoma, prostatic carcinoma, and bladder cancer have been published as well. SUMMARY: The incidence of port-site metastases is comparable with that seen following open surgery. The etiology is likely multifactorial, but adhering to proper surgical technique is the most effective preventative strategy.

Urinary and sexual quality of life 1 year following robotic assisted laparoscopic radical prostatectomy.

PURPOSE: We evaluated urinary and sexual quality of life 1 year following robotic laparoscopic radical prostatectomy and identified preoperative variables predictive of a severe decrease from baseline. MATERIALS AND METHODS: Using a prospective robotic laparoscopic radical prostatectomy database we identified patients with greater than 1 year of postoperative followup. The UCLA-PCI SF-36v2 questionnaire was used to evaluate urinary and sexual quality of life before and 1 year after surgery. Severe worsening of the postoperative score was defined as a greater than 1 SD decrease. Demographic and preoperative clinical variables were evaluated along with baseline scores on univariate and multivariate analysis. RESULTS: Between February 2003 and September 2007 a total of 1,225 robotic laparoscopic radical prostatectomies were performed at our center and 361 patients (52%) met inclusion criteria. On multivariate analysis baseline urinary function was the only predictor of significant worsening of urinary function (OR 1.04, p = 0.003). Baseline urinary bother was the only predictor of significant worsening of urinary bother (OR 1.05, p <0.0001). A significant decrease in sexual function was predicted by baseline sexual function (OR 1.03, p = 0.0001), baseline sexual bother (OR 1.03, p = 0.005) and nerve sparing technique (OR 0.31, p = 0.05). Predictors of a significant decrease in sexual bother were also baseline sexual function (OR 1.02, p = 0.0001), baseline sexual bother (OR 1.04, p = 0.0007) and nerve sparing technique (OR 0.38, p = 0.02). ORs indicated that higher baseline scores corresponded to a higher risk of postoperative score worsening. CONCLUSIONS: We found that overall better baseline sexual and urinary scores are associated with better postoperative outcomes. However, the risk of a significant decrease in urinary function, urinary bother, sexual function and sexual bother is higher in patients with better baseline scores. Nerve sparing positively affects sexual function and sexual bother.

Long-term functional and oncological outcomes of patients undergoing sural nerve interposition grafting during robot-assisted laparoscopic radical prostatectomy.

PURPOSE: For men with high-volume or high-grade prostate cancer, wide excision of the ipsilateral neurovascular bundle is commonly performed. The concept of nerve reconstruction is intriguing as a feasible approach to preserve sexual function (SF). We sought to evaluate the functional, pathologic, and oncologic outcomes of men who underwent robot-assisted sural-nerve graft (SNG) interposition. PATIENTS AND METHODS: Between February 2003 and May 2007, 1175 consecutive men underwent robot-assisted laparoscopic radical prostatectomy (RLRP). Database analysis identified 27 men who had SNG: 4 bilateral (BL) and 23 unilateral (UL). SF was prospectively evaluated preoperatively and at 1, 3, 6, 12, and 24 months postoperatively using validated questionnaires. Positive surgical margins (PSMs), biochemical recurrence (BCR), and potency were evaluated. RESULTS: Compared with RLRP patients without SNG, patients with SNG were younger (57.2 v 61.8 years, P=0.02), had a higher Gleason score (P=0.02), and had a higher clinical and pathologic stage (P<0.001 for both). Mean surgical time was significantly longer (349 v 195 min, P<0.001) in patients with SNG. With a mean follow-up of 26.1 months, 11 (47.8%) patients with UL-SNG and zero men with BL-SNG regained potency. No significant difference in SF was observed between UL nerve sparing and no SNG (56%) compared with UL nerve sparing with UL-SNG (P=0.44). Rates of return-to-baseline SF (RTB-SF) at 6, 12, and 24 months were 11%, 36% and 45% for UL-SNG, respectively, which were also comparable to UL nerve sparing only (P>0.05). No patient (0%) in the BL-SNG group ever achieved RTB-SF status at any time point. PSMs were observed in 37% (10/27) of all patients. BCR occurred in nine patients (33.3%), seven of whom had PSM (78%); treatment failure occurred within 6 months of surgery, necessitating androgen deprivation therapy. CONCLUSION: Despite optimism regarding SNG, long-term functional outcomes have been disappointing, particularly for BL nerve interposition. UL-SNG functional outcomes do not appear to improve outcomes when compared with men with UL nerve preservation. With the greater risk of PSM and BCR in patients who are considered candidates for SNG, newer treatment modalities are needed to cure their disease while preserving SF.

Antibody-dependent cell cytotoxicity to breast cancer targets despite inhibitory KIR signaling.

BACKGROUND: Natural killer (NK) cells express killer immunoglobulin-like (KIR) inhibitory receptors, which recognize certain HLA class I molecules (KIR ligands), and stimulatory receptors such as FcgammaRIII. The purpose of this study was to test the possible influence of inhibitory KIR signaling on antibody-dependent cell cytotoxicity (ADCC) mediated by allogeneic NK cells against breast cancer targets. MATERIALS AND METHODS: The cytotoxic activity of volunteer donor NK cells against the cell lines SKBR-3, T47D and MCF-7, which have high, low and no HER2 gene amplification, respectively, were studied. Both cell lines and donors were assigned to the C1 or C2 superfamily, defined by the structure of the HLA-Cw molecule. RESULTS: It was found that ADCC mediated by allogeneic NK cells occurred despite combinations of NK cells and breast cancer targets predicted to trigger inhibitory KIR signaling. CONCLUSION: We suggest that adoptive immunotherapy with allogeneic NK cells and trastuzumab may be an effective combination against breast cancer targets.

Expanding indications for neuromodulation.

Neuromodulation in one form or another has been studied for decades for various disease states. Although its mechanism of action remains un-explained, numerous clinical success stories suggest it is a therapy with efficacy and durability. Controlled studies have led to the approval of sacral neuromodulation for urinary urgency and frequency, urinary retention, and urinary urge incontinence. The future holds hopeful possibilities for the application of neuromodulation, namely in the areas of interstitial cystitis, in-tractable pain syndromes, fecal incontinence and constipation, spinal cord injury, and erectile dysfunction. Neuromodulators have also been used in nonurologic conditions, including chronic headaches and intractable chest pain. In adults and children, in the neurologically intact and neurologically impaired, neuromodulation has been shown to improve the quality of life of those suffering chronic disease states. Neuromodulation is changing the future of urology. Treatment of voiding dysfunction and likely other disorders, such as pelvic pain, sexual dysfunction, and bowel disorders, will no longer rely only on medications that are "OK" or destructive-reconstructive procedures that suffer from significant complications. Rather, by modulating the nerves, the urologists will treat these disorders in a minimally invasive fashion and neuromodulation will become the first-line therapy before any major surgery is undertaken.

Prolonged activated partial thromboplastin time in pregnancy: a brief report.

BACKGROUND: Limited data are available regarding causes of prolonged activated partial thromboplastin time (aPTT) in otherwise normal pregnancies. We retrospectively evaluated clinical data of pregnant women in whom an elevated aPTT was noted on routine prenatal testing. Our intent was to identify various causes of prolonged aPTT and to evaluate whether the pregnancies were adversely affected. METHODS: A retrospective review of medical records of 36 pregnant patients with a prolonged aPTT as the sole abnormal coagulation test seen in the outpatient department of a tertiary care hospital over a period of 4 years. RESULTS: Patients' median age was 26 (range, 19-41) years and median duration of gestation period was 19 (range, 8-38) weeks. Fifteen patients were primigravida. Of 36 patients, repeated aPTT values were normal in 24 (67%) patients, whereas 12 (33%) patients had persistently elevated aPTT values. Factor XI deficiency was found in 5 patients, lupus anticoagulant in 3 patients, elevated anticardiolipin antibody in 2 patients, and low von Willebrand Factor level in 1 patient. Overall, 23 patients delivered. No patients experienced excessive bleeding or thromboembolism. CONCLUSION: Factor XI deficiency and antiphospholipid antibody were 2 major abnormalities identified in patients with prolonged aPTT. These coagulopathies were not associated with excessive bleeding or thromboembolism. Repeat normal aPTT in approximately 2 thirds of patients suggests that proper sample collection and processing are important for coagulation assays to avoid erroneous clotting times.