Intrinsic tumor resistance to CAR T cells is a dynamic transcriptional state that is exploitable with low-dose radiation.

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement for hematologic malignancies, with some patients achieving long-term remission. However, the majority of treated patients still die of their disease. A consistent predictor of response is tumor quantity, wherein a higher disease burden before CAR T-cell therapy portends a worse prognosis. Focal radiation to bulky sites of the disease can decrease tumor quantity before CAR T-cell therapy, but whether this strategy improves survival is unknown. We find that substantially reducing systemic tumor quantity using high-dose radiation to areas of bulky disease, which is commonly done clinically, is less impactful on overall survival in mice achieved by CAR T cells than targeting all sites of disease with low-dose total tumor irradiation (TTI) before CAR T-cell therapy. This finding highlights another predictor of response, tumor quality, the intrinsic resistance of an individual patient's tumor cells to CAR T-cell killing. Little is known about whether or how an individual tumor's intrinsic resistance may change under different circumstances. We find a transcriptional "death receptor score" that reflects a tumor's intrinsic sensitivity to CAR T cells can be temporarily increased by low-dose TTI, and the timing of this transcriptional change correlates with improved in vivo leukemia control by an otherwise limited number of CAR T cells. This suggests an actionable method for potentially improving outcomes in patients predicted to respond poorly to this promising therapy and highlights that intrinsic tumor attributes may be equally or more important predictors of CAR T-cell response as tumor burden.

18F-FDG PET/CT total lesion glycolysis is associated with circulating tumor cell counts in patients with stage I to IIIA non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), 18F-fluoro-2-deoxy-D-glucose (18F-FDG) uptake determined by PET and presence of circulating tumor cells (CTCs) in the peripheral blood independently predict outcomes. For 18F-FDG PET/CT staging interpretation, standardized uptake values (SUVmax/avg) are routinely used in clinical reporting. The goal was to investigate whether 18F-FDG uptake measured by SUVmax/avg, but also measures of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) (MTV × SUVavg), are associated with CTCs. METHODS: Prospectively, 7.5 mL blood was drawn from NSCLC patients at the time of staging 18F-FDG PET/CT and from healthy control subjects. CTCs were identified by immunofluorescent staining (CK8/18/19pos/EpCAMpos/CD45neg/DAPIpos nucleus). 18F-FDG PET/CTs were analyzed for SUVmax, SUVavg, MTV, and TLG. RESULTS: In 16 NSCLC patients with stage I-IIIA, MTV and TLG, in contrast to SUVmax and SUVavg, were positively associated with CTCs (linear regression analysis). No CTCs were detectable in 20 healthy control subjects. CONCLUSIONS: This pilot study demonstrates that 18F-FDG PET/CT TLG correlates with CTCs in NSCLC patients without distant metastases. TLG might be a more appropriate marker for hematogenous micrometastatic potential than SUVs.

Early development of castrate resistance varies with different dosing regimens of luteinizing hormone releasing hormone agonist in primary hormonal therapy for prostate cancer.

OBJECTIVES: Luteinizing hormone releasing hormone (LHRH) agonist therapy is one of the mainstays of prostate cancer treatment. Three dosing regimens currently exist: calendar-based, intermittent, and a testosterone (T)-based (T-based) regimen. We investigated the differences in development of early castrate resistance rates between these different regimens. METHODS: We evaluated 1617 patients with prostate cancer who received LHRH-agonist monotherapy in the Kaiser Permanente Southern California Cancer Registry between January 2003 and December 2006. Patients who had undergone surgery and/or radiation were excluded. Patients were grouped according to their dosing regimen: calendar-based, intermittent dosing, and T-based. Cox proportional hazard-regression analysis was used to estimate the hazards ratio (HR) for treatment failure. RESULTS: A total of 692 patients who received an LHRH agonist as primary monotherapy for prostate cancer fit our criteria. Calendar-based dosing was used in 325 patients; 252 received T-based dosing and 115 received intermittent dosing. On multivariate analysis controlling for demographic and prostate cancer-related variables, the T-based dosing group showed a significantly lower relative risk of treatment failure (HR = 0.65, P = .02). The intermittent-dosing group trended toward a lower risk treatment failure (HR = 0.80, P = .3). Among the variables analyzed, only a Gleason score >8 (HR = 2.05, P = .01) and a pretreatment prostate-specific antigen >20 (HR = 2.00, P <.01) were associated with a higher risk of treatment failure. CONCLUSIONS: During the time period studied, T-based and intermittent dosing regimen of LHRH agonist had lower rates of early castrate resistance compared with standard calendar dosing, based on measurements for early androgen resistance.

Impact of robotic training on surgical and pathologic outcomes during robot-assisted laparoscopic radical prostatectomy.

OBJECTIVES: To prospectively compare outcomes during robotic prostatectomy between surgeons with formal training in either robotic prostatectomy (RALP) or laparoscopic prostatectomy (LRP). METHODS: A total of 286 robotic prostatectomies were performed by 12 urologists between August 2008 and March 2009 as part of a new robotic surgery program at one of the largest health maintenance organizations in the United States. Four surgeons had formal training in RALP and 8 had formal training in LRP. We prospectively compared surgical and pathologic outcomes between these 2 groups of surgeons. RESULTS: The 4 RALP surgeons performed 121 RALPs and the 8 LRP surgeons performed 165 RALPs. Patient demographics were similar between groups. The robot-naive group had significantly more clinical stage T1c than the robot-trained group (87.9% vs 74.4%, P = .003). Prostatectomy parameters were similar between the 2 groups of surgeons in terms of prostate size, Gleason score, pathologic stage, and estimated blood loss. The robot-trained surgeons had significantly lower overall positive margin rates (24% vs 34.6%, P = .05) and lower margin rates in T3 tumors (38.5% vs 61.8%, P = .07), which were approximately statistically significant. There was no difference in margin rates in T2 tumors. The robot-trained surgeons had significantly lower apical margin rates (8.3% vs 21.2%, P = .003) and lateral margin rates (1.7% vs 7.3%, P = .05). The robot-trained surgeons had 10%-15% shorter procedure times. There was no difference in complication rates. CONCLUSIONS: Formal RALP training may be beneficial for surgical and pathologic outcomes of RALP compared with formal LRP training during the initial implementation of a new robotics program.

Rapid implementation of a robot-assisted prostatectomy program in a large health maintenance organization setting.

PURPOSE: We present the rapid implementation of a robot-assisted surgery program by one of the largest health maintenance organizations (HMOs) in the United States. MATERIALS AND METHODS: A core group of 10 urologists were offered access to a new da Vinci S surgical system. A core group of five ancillary staff was assembled and trained at an Intuitive Surgical-designated training site. An experienced robotic surgeon acted as a proctor. Data regarding patient demographics, preoperative parameters, operative times, pathologic outcomes, and EPIC-26 quality-of-life questionnaires were collected prospectively and reviewed. All procedures were recorded on digital video disc as part of a quality assurance protocol. The core group reviewed complications monthly and received feedback on surgical techniques and pathologic outcomes. RESULTS: A total of 100 robot-assisted laparoscopic radical prostatectomies were performed from August to October 2008. The patient demographics, preoperative parameters, operative times, and pathologic outcomes of these first 100 procedures are outlined. CONCLUSIONS: We demonstrate the rapid implementation of an efficient multisurgeon HMO-based robot-assisted prostatectomy program with promising initial outcomes.

Differences in left and right laparoscopic adrenalectomy.

BACKGROUND AND OBJECTIVES: The classic belief is that right-sided laparoscopic adrenalectomy is technically more difficult to perform than left-sided. The purpose of this study was to determine whether objective outcomes are different for the right- versus left- sided operation. METHODS: A retrospective review of 163 laparoscopic adrenalectomies was performed to compare outcomes. Variables extracted included age, demographics, body mass index (BMI), laterality, indication, operative time, estimated blood loss (EBL), gland size, complications, open conversion rates, and length of stay. RESULTS: Of the adrenalectomies performed, 109 were on the left and 54 on the right. Age, BMI, and indication were similar for each group. The mean EBL on the left side was 113 mL (range, 2 to 3000) and 84 mL (range, 10 to 700) for the right (P=0.85). The mean operative time on the left side was 187 minutes (range, 62 to 475) and on the right was 156 minutes (range, 50 to 365) (P=0.02). There was no difference in complication or conversion rate. CONCLUSIONS: There was no difference in complication or conversion rates between each side, and we observed a trend toward lower blood loss for the right side. Although we report generally similar outcomes, the mean operative time for a right-sided laparoscopic adrenalectomy was significantly less (31 minutes) than the left side.

The poppy seed test for colovesical fistula: big bang, little bucks!

PURPOSE: Diagnosis of a colovesical fistula is often challenging, and usually involves numerous invasive and expensive tests and procedures. The poppy seed test stands out as an exception to this rule. We evaluated the accuracy and cost-effectiveness of various established diagnostic tests used to evaluate a suspected colovesical fistula. MATERIALS AND METHODS: We identified 20 prospectively entered patients with surgically confirmed colovesical fistulas between 2000 and 2006. Each patient was evaluated preoperatively with a (51)chromium nuclear study, computerized tomography of the abdomen and pelvis with oral and intravenous contrast medium, and the poppy seed test. Costs were calculated using institutional charges, 2006 Medicare limiting approved charges and the market price, respectively. The z test was used to compare the proportion of patients who tested positive for a fistula with each of these modalities. RESULTS: The chromium study was positive in 16 of 20 patients (80%) at a cost of $490.83 per study. Computerized tomography was positive in 14 of 20 patients (70%) at a cost of $652.92 per study. The poppy seed test was positive in 20 of 20 patients (100%) at a cost of $5.37 per study. The difference in the proportion of patients who tested positive for a fistula on computerized tomography and the poppy seed test was statistically significant (p = 0.03). There was no difference between the chromium group and the computerized tomography or poppy seed group (p = 0.72 and 0.12, respectively). CONCLUSIONS: The poppy seed test is an accurate, convenient and inexpensive diagnostic test. It is an ideal initial consideration for evaluating a suspected colovesical fistula.

Scrotal reconstruction using rapid intraoperative tissue expansion: a preliminary report.

PURPOSE: Extensive scrotal skin loss can pose a difficult management problem. In most cases delayed scrotal approximation is feasible due to the redundancy of scrotal skin. However, large defects usually require reconstruction using flaps or grafts. We present a novel technique of scrotal closure using rapid intraoperative tissue expansion to manage select extensive partial scrotal defects. MATERIALS AND METHODS: Between January 1996 and April 2006, 3 patients underwent delayed closure using rapid intraoperative tissue expansion for approximately 75% scrotal skin loss. Intraoperatively the residual lateral scrotal and medial thigh skin, and subcutaneous tissues were dissected, creating bilateral cavities for the placement of round 300 cc tissue expanders. Gradual inflation for a total of 20 minutes allowed adequate tissue expansion of the 2 thigh flaps, enabling tension-free scrotal closure. RESULTS: Each patient was followed for 12 months. The resulting reconstruction provided a tension-free, cosmetically appealing scrotum with complete testicular coverage. There were no perioperative or postoperative complications. CONCLUSIONS: Although rapid intraoperative tissue expansion has been successfully used for the closure of facial and extremity defects, to our knowledge it has not been described for genital skin loss. Our experience suggests that this relatively simple method is a viable addition to the reconstructive armamentarium in a select group of patients with extensive scrotal skin defects that are not amenable to scrotal approximation alone.

Impact of positive surgical margins in patients undergoing partial nephrectomy for renal cortical tumours.

OBJECTIVE: To evaluate the clinical outcome of patients undergoing partial nephrectomy (PN) for renal cortical tumours who had a positive surgical margin (SM), as recent studies have shown that a minimal SM is required to achieve equivalent disease-free survival (DFS). PATIENTS AND METHODS: Between 1989 and 2005, 777 PNs were performed at the authors' institution. Clinical and pathology data were obtained from our prospective surgical database after obtaining institutional review board approval. Variables were analysed in a logistic regression model to determine predictors of positive SMs. The clinical outcome was reported for local recurrence and distant metastasis and analysed using the log-rank test. RESULTS: Of the 777 PNs, the SM status was documented in 770; the SMs were positive in 57 of 770 (7%). Positive SMs occurred in 33 of 423 (8%) patients with tumours of high malignant potential, and in 24 of 347 (7%) patients with tumours of low malignant potential. On multivariate analysis, an imperative indication for a PN was a significant predictor for a positive SM (P = 0.003). With a median follow-up for survivors of 22 months, there was a local recurrence in two of 57 (4%) patients with a positive SM and four of 713 (0.5%) with a negative SM. No patients with a tumour of low malignant potential had a recurrence, despite having a positive SM. CONCLUSIONS: Although local recurrence after PN for renal cortical tumours is rare, our data suggest that patients with a tumour of high malignant potential and a positive SM might have a higher incidence of local recurrence.

Cavernous hemangioma of tunica albuginea testis manifesting as testicular pain.

Cavernous hemangioma of the tunica albuginea of the testis is very rare; only 2 cases have been reported in published studies. Both cases presented as testicular masses. We report what we believe to be the third case of cavernous hemangioma of the tunica albuginea that manifested as pain without any mass.

Radical prostatectomy in patients infected with human immunodeficiency virus.

OBJECTIVE: To present the complications and early outcomes in a small series of men infected with human immunodeficiency virus (HIV) and treated with radical prostatectomy (RP) for prostate cancer, and to review reports on surgery in HIV-positive patients. PATIENTS AND METHODS: During 2002-2005, seven men infected with HIV underwent RP at our institution. For the five patients whose HIV status was known before surgery, we retrospectively examined preoperative variables, including HIV-specific data (clinical category, CD4+ lymphocyte count, viral load, duration of HIV diagnosis, and opportunistic infections), and the complications and early outcomes after RP. RESULTS: Before RP all the patients were in the Center for Disease Control clinical category A (asymptomatic HIV infection). The CD4+ counts before RP ranged from 269-870 cells/microL and viral loads ranged from <50-18 700 copies/mL. Three patients were on highly active anti-retroviral therapy (HAART) at the time of surgery. After RP, two patients had incisional wound infections, including one requiring re-hospitalization for intravenous antibiotics. During the follow-up (median 26 months) none of the patients progressed to acquired immunodeficiency syndrome or developed biochemical recurrence of prostate cancer. One healthcare worker was exposed to contaminated urine and placed on prophylactic therapy, but has not sero-converted. CONCLUSIONS: The risk of peri-operative complications in HIV-positive patients can be minimized by carefully selecting the patient and procedure, and by measuring routine and HIV-specific preoperative variables. The two infectious complications in this series were in patients with less favourable preoperative factors, i.e. the lowest CD4+ count and the highest viral load. Further experience is needed to determine whether the risk of surgical infections is higher in this cohort. However, our results are consistent with reports from other surgical specialities that surgery in asymptomatic HIV-positive patients is safe and effective.