Peritoneal regression grading score (PRGS) in peritoneal metastasis: how many biopsies should be examined?

Objectives: The four-tied peritoneal regression grading score (PRGS) is increasingly used to evaluate the response of peritoneal metastases (PM) to chemotherapy. The minimal number of peritoneal biopsies needed for PRGS determination remains unclear. Methods: A prospective cohort of 89 PM patients treated with 210 pressurized intraperitoneal aerosol chemotherapy (PIPAC) cycles was investigated. Four biopsies from every abdominal quadrant were recommended. Histological tumor response was defined as a stable or decreasing mean PRGS between therapy cycles, progression increasing. We compared the diagnostic uncertainty induced by missing biopsies to the histological response. Results: A total of 49 patients had at least two PIPAC and were eligible for therapy response assessment. Mean PRGS decreased from 2.04 (CI 5-95% 1.85-2.27) to 1.79 (CI 5-95% 1.59-2.01), p=0.14, as a proof of therapy effectiveness. 35 (71.4%) patients had a stable or decreasing PRGS (therapy response), 14 (28.6%) a PRGS increase (disease progression). Histology showed agreement between four biopsies in 42/210 laparoscopies (20%), between ≥3 biopsies in 103 (49%), and between ≥2 biopsies in 169 laparoscopies (81%). Mean loss of information with one missing biopsy was 0.11 (95% CI=0.13) PRGS points, with two missing biopsies 0.18 (95% CI 0.21). In 9/49 patients (18.3%), the loss of information with one less biopsy exceeded the change in PRGS under therapy. Conclusions: A minimum of three biopsies is needed to diagnose PM progression with an accuracy superior to 80%. Missing biopsies often result in a false diagnosis of tumor progression.

Feasibility, Safety, and Efficacy of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Peritoneal Metastasis: A Registry Study.

INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel drug delivery system with superior pharmacological properties for treating peritoneal metastasis (PM). Safety and efficacy results of PIPAC with cisplatin/doxorubicin or oxaliplatin from a registry cohort are presented. METHODS: IRB-approved registry study. Retrospective analysis. No predefined inclusion criteria, individual therapeutic recommendation by the interdisciplinary tumor board. Safety assessment with CTCAE 4.0. Histological assessment of tumor response by an independent pathologist using the 4-tied peritoneal regression grading system (PRGS). Mean PRGS and ascites volume were assessed at each PIPAC. RESULTS: A total of 142 PIPAC procedures were scheduled in 71 consecutive patients with PM from gastric (n = 26), colorectal (n = 17), hepatobiliary/pancreatic (n = 9), ovarian (n = 6), appendiceal (n = 5) origin, pseudomyxoma peritonei (n = 4), and other tumors (n = 3). Mean age was 58 ± 13 years. Patients were heavily pretreated. Mean PCI was 19 ± 13. Laparoscopic nonaccess rate was 11/142 procedures (7.7%). Mean number of PIPAC/patient was 2. All patients were eligible for safety analysis. There was no procedure-related mortality. There were 2.8% intraoperative and 4.9% postoperative complications. 39 patients underwent more than one PIPAC and were eligible for efficacy analysis, and PRGS could be assessed in 36 of them. In 24 patients (67%), PRGS improved or remained unchanged at PIPAC#2, reflecting tumor regression or stable disease. Ascites was present in 24 patients and diminished significantly under therapy. Median survival was 11.8 months (95% CI: 7.45-16.2 months) from PIPAC#1. CONCLUSION: PIPAC is feasible, safe, and well-tolerated and can induce histological regression in a significant proportion of pretreated PM patients. This trial is registered with NCT03210298.

Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study.

PURPOSE: Patients with carcinoma in situ (CIS) of the bladder refractory to bacillus Calmette-Guérin (BCG) treatment are usually treated with cystectomy. Therefore, new treatment options with preservation of the urinary bladder are needed. The objective of the study was to investigate the feasibility, safety and efficacy of a novel targeted alpha-emitter immunotherapy for CIS after BCG treatment failure. METHODS: A pilot study was conducted in 12 patients (age range 64-86 years, ten men, two women) with biopsy-proven CIS of the bladder refractory to BCG treatment. The patients were treated intravesically with a single instillation (one patient was treated twice) of the alpha-emitter 213Bi coupled to an anti-EGFR antibody (366-821 MBq). The primary aims of the study were to determine the feasibility of treatment with the 213Bi-immunoconjugate and evaluation of adverse effects. Therapeutic efficacy was monitored by histological mapping of the urinary bladder 8 weeks after treatment and at different time points thereafter. RESULTS: The study proved that intravesical instillation of the 213Bi-immunoconjugate targeting EGFR is feasible. No adverse effects were observed and all blood and urine parameters determined remained in their normal ranges. Therapeutic efficacy was considered satisfactory, in that three of the 12 patients showed no signs of CIS 44, 30 and 3 months after treatment. CONCLUSION: Intravesical instillation of 213Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy. Repeated instillation and/or instillation of higher activities of the 213Bi-immunoconjugate might lead to better therapeutic outcomes. A phase I clinical trial is planned.

Diagnosis, Treatment, and Outcome of Arterioureteral Fistula: The Urologist's Perspective.

INTRODUCTION: Arterioureteral fistula (AUF) is a rare but potentially life-threatening disease that primarily arises as a long-term complication in oncological patients who have permanent ureteral stenting. The incidence is rising. The objective of this study was to outline the risk factors for management and outcome of AUF in a large individual case series. PATIENTS AND METHODS: Twenty-six AUF cases in 24 patients from six German tertiary referral centers occurring between 2008 and 2016 were identified retrospectively and entered into a dedicated database by using patient notes and out-patient visits. RESULTS: Of 24 patients, 23 had a history of abdominopelvic surgery for oncological disease, 21/24 had undergone radiotherapy, and 23/24 had long-term ureteral stenting. All cases presented with visible hematuria, 11/26 at the time of a stent exchange. Blood transfusions were required in 92.3%, and intravenous inotropes were needed in 46.2%. Of 26 patients, 11 had flank pain. CT angiogram was positive in 35.7%. Angiography and endovascular fistula repair was performed in 88.5%, and the rest received open surgical repair. Mortality was 7.7%. Endovascular treatment was technically successful in 91.3%, and open surgery was successful in 3/4 cases. Recurrent AUF developed in 3/24 patients. Stent-related complications occurred in 15%. Vascular complications were common. Long-term survival was limited due to progression of the underlying malignant disease. CONCLUSION: AUF results in major hemorrhage and warrants time-efficient diagnosis and treatment. Awareness is key. When AUF is considered, interventional angiography should promptly be performed. Fistula detection can be improved by guidewire manipulation. Pre-interventional CT angiogram may be omitted due to low sensitivity. Endovascular repair with stenting and/or coiling is effective and safe.

Human papilloma virus is not detectable in samples of urothelial bladder cancer in a central European population: a prospective translational study.

BACKGROUND: Previous investigations on the association of human papillomavirus (HPV) and human bladder cancer have led to conflicting results. The aim of this study was to determine if low and high risk HPV play a role in the etiology of superficial low grade and invasive high grade urothelial carcinoma of the bladder. METHODS: We prospectively collected tumor samples of urothelial carcinoma of the bladder from 109 patients treated with transurethral resection or cystectomy, with bladder tissue from transurethral resection of the prostate serving as control. Unfixed, frozen tumor samples were analyzed for the presence of 14 high risk HPV types using real time PCR. Additionally, all specimens were tested for 35 low risk HPV types with a conventional PCR using degenerate primers located in the L1 region. Six frozen samples of cervical carcinoma served as positive controls. RESULTS: We included 109 cases of bladder cancer with 41 superficial (pTa low grade) tumors, 56 invasive (pT1-T4) high grade tumors and 12 others (pTa high grade + pTis). We have not detected HPV-DNA in any sample (95 % Confidence Interval [CI] 0-3.3 %), superficial tumors (95 % CI 0-6.4 %) or in invasive tumors (95 % CI 0-8.6 %) with correct positive controls. CONCLUSIONS: Using a broad, sensitive assay with prospectively collected specimens of a Central European population we could not detect HPV-DNA in any of the cases. Our results suggest that it is unlikely that HPV infections play a major role in the development of urothelial bladder cancer.

Optimizing selective renal clamping in nephron-sparing surgery using the Nussbaum clamp.

OBJECTIVES: Selective clamping techniques are an attractive surgical option in nephron-sparing surgery. We describe the use of the Nussbaum clamp for this procedure and point out the advantages of this clamping technique. TECHNICAL CONSIDERATIONS: The perirenal fat overlying the tumor is removed from the kidney. It is unnecessary to expose the renal artery and vein. The Nussbaum clamp is placed around the tumor 1 to 2 cm proximal to the line of resection. Afterward, the tumor is excised and a hemostasis achieved. Twelve patients underwent nephron-sparing surgery that used the Nussbaum clamp between January 2006 and November 2006. The indications for nephron-sparing surgery were complicated renal cysts or a suspected renal carcinoma in 3 and 9 patients, respectively. The location of the tumor was in the upper pole, lower pole, middle portion, and in a horseshoe-shaped kidney in 4, 6, 1, and 1 patient, respectively. The median time of selective clamping and intraoperative blood loss was 19 minutes (range 12 to 31 minutes) and 300 mL (range: 100 to 500 mL), respectively. CONCLUSIONS: The Nussbaum clamp is a commercially available, easy-to-use and effective instrument for selective clamping in nephron-sparing surgery.

Linkage of aggressive prostate cancer to chromosome 7q31-33 in German prostate cancer families.

It has been suggested that chromosome 7q32 contains genes that influence the progression of prostate cancer from latent to invasive disease. In an attempt to confirm this linkage to prostate cancer aggressiveness, 100 German prostate cancer families were genotyped using a panel of eight polymorphic markers on chromosome 7q. We used a multipoint allele sharing method based upon a likelihood ratio test implemented in GENEHUNTERPLUS v1.2 in order to calculate the nonparametric Z(lr) and the associated LOD scores. We applied the aggressiveness of prostate cancer given by the pathological tumour grade of each individual, and the mean age of onset of a family as covariates, and constructed two weighted models. The first (weight(0-1) model) puts weights on families with at least two cases of GIII prostate cancer. The second (weight(0-2) model) also adds weights to families with early and late onset cancer respectively. The unweighted analysis gave no evidence of linkage to chromosome 7q. The Z(lr) scores increased when including the covariates, to 2.60 (P=0.005) using the weight(0-1) and to 3.02 (P=0.001) using the weight(0-2) model for late onset prostate cancer. The associated LOD scores were respectively 1.47 (P=0.009) and 1.98 (P=0.002). The markers that gave most evidence for linkage were exactly in the range of the published prostate cancer aggressiveness region. Our results support a widespread relevance of this locus and suggest that aggressive and late onset prostate cancer is linked to chromosme 7q31-33 in the German population.