Nick W. Liu

Repeat Partial Nephrectomy on the Solitary Kidney: Surgical, Functional and Oncological Outcomes

PURPOSE We examined outcomes in patients with recurrent or de novo renal lesions treated with repeat partial nephrectomy on a solitary kidney. MATERIALS AND METHODS We reviewed the records of patients who underwent nephron sparing surgery at the National Cancer Institute from 1989 to 2008. Patients were included in analysis if they underwent repeat partial nephrectomy on a solitary kidney. Perioperative, functional and oncological outcomes were assessed. Functional outcomes were evaluated using the Modification of Diet in Renal Disease equation for the estimated glomerular filtration rate. Oncological efficacy was examined by the need for subsequent repeat renal surgery and the development of metastatic disease. RESULTS A total of 25 patients were included in the analysis. A median of 4 tumors were resected. Median estimated blood loss was 2,400 ml and median operative time was 8.5 hours. Perioperative complications occurred in 52% of patients, including 1 death and the loss of 3 renal units. There was a decrease in the estimated glomerular filtration rate at followup visit 1 within 3 months after surgery but at 1-year followup the difference was not significant (p <0.01 and 0.12, respectively). Surgical intervention was recommended in 8 patients (38%) for recurrent or de novo tumors at a median of 36 months. The average metastasis-free survival rate in the cohort was 95% at 57 months (median 50, range 3 to 196). CONCLUSIONS Repeat partial nephrectomy in patients with solitary kidney is a high risk alternative. The complication rate is high and there is a modest decrease in renal function but most patients remain free of dialysis with acceptable oncological outcomes at intermediate followup.

Incidence and Risk Factors of Parastomal Hernia in Patients Undergoing Radical Cystectomy and Ileal Conduit Diversion

PURPOSE We evaluate the incidence and risk factors of parastomal hernia formation in patients undergoing radical cystectomy and ileal conduit urinary diversion. MATERIALS AND METHODS We retrospectively reviewed the Indiana University cystectomy database between 2001 and 2011, and identified 516 patients who underwent radical cystectomy and ileal conduit diversion. Overall 199 patients had a clinical followup of at least 12 months and all underwent postoperative staging computerized tomography to confirm the presence of parastomal hernia. The incidence of parastomal hernia is reported with correlations made to demographic, patient level and perioperative risk factors. RESULTS A parastomal hernia developed in 58 patients (29%) at a median followup of 27 months (range 12 to 125). Of these patients 26 (45%) underwent surgical repair due to abdominal discomfort (58%), acute strangulation or obstruction of the small bowel (15%), partial small bowel obstructions (15%) and elective repair for other intra-abdominal procedures (12%). Prior exploratory laparotomy (adjusted HR 1.98, 95% CI 1.97-3.36, p = 0.011) and severe obesity (adjusted HR 4.26, 95% CI 1.52-11.93, p = 0.006) were predictive of parastomal herniation. The cumulative risk of parastomal hernia formation at 1 and 2 years after cystectomy was 12.2% and 22.5%, respectively. CONCLUSIONS We demonstrated that parastomal hernia will develop in nearly a third of patients after radical cystectomy with ileal conduit diversion. Prior laparotomy and severe obesity are independent risk factors. Preoperative counseling and preventative measures regarding parastomal hernia formation should be emphasized, particularly in these at risk patients.

Impact of Ischemia and Procurement Conditions on Gene Expression in Renal Cell Carcinoma

Purpose: Previous studies have shown that ischemia alters gene expression in normal and malignant tissues. There are no studies that evaluated effects of ischemia in renal tumors. This study examines the impact of ischemia and tissue procurement conditions on RNA integrity and gene expression in renal cell carcinoma. Experimental Design: Ten renal tumors were resected without renal hilar clamping from 10 patients with renal clear cell carcinoma. Immediately after tumor resection, a piece of tumor was snap frozen. Remaining tumor samples were stored at 4°C, 22°C, and 37°C and frozen at 5, 30, 60, 120, and 240 minutes. Histopathologic evaluation was conducted on all tissue samples, and only those with greater than 80% tumor were selected for further analysis. RNA integrity was confirmed by electropherograms and quantitated using RNA integrity number index. Altered gene expression was assessed by paired, two-sample t test between the zero time point and aliquots from various conditions obtained from the same tumor. Results: One hundred and forty microarrays were conducted. Some RNA degradation was observed 240 minutes after resection at 37°C. The expression of more than 4,000 genes was significantly altered by ischemia times or storage conditions. The greatest gene expression changes were observed with longer ischemia time and warmer tissue procurement conditions. Conclusion: RNA from kidney cancer remains intact for up to 4 hours post surgical resection regardless of storage conditions. Despite excellent RNA preservation, time after resection and procurement conditions significantly influence gene expression profiles. Meticulous attention to preacquisition variables is of paramount importance for accurate tumor profiling. Clin Cancer Res; 19(1); 42–49. ©2012 AACR.

Risk for Clostridium difficile infection after radical cystectomy for bladder cancer: Analysis of a contemporary series

INTRODUCTION This study seeks to evaluate the incidence and associated risk factors of Clostridium difficile infection (CDI) in patients undergoing radical cystectomy (RC) for bladder cancer. METHODS We retrospectively reviewed a single institution׳s bladder cancer database including all patients who underwent RC between 2010 and 2013. CDI was diagnosed by detection of Clostridium difficile toxin B gene using polymerase chain reaction-based stool assay in patients with clinically significant diarrhea within 90 days of the index operation. A multivariable logistic regression model was used to identify demographics and perioperative factors associated with developing CDI. RESULTS Of the 552 patients who underwent RC, postoperative CDI occurred in 49 patients (8.8%) with a median time to diagnosis after RC of 7 days (interquartile range: 5-19). Of the 122 readmissions for postoperative complications, 10% (n = 12) were related to CDI; 2 patients died of sepsis directly related to severe CDI. On multivariate logistic regression, the use of chronic antacid therapy (odds ratio = 1.9, 95% CI: 1.02-3.68, P = 0.04) and antibiotic exposure greater than 7 days (odds ratio = 2.2, 95% CI: 1.11-4.44, P = 0.02) were independently associated with developing CDI. The use of preoperative antibiotics for positive findings on urine culture within 30 days before surgery was not statistically significantly associated with development of CDI (P = 0.06). CONCLUSIONS The development of CDI occurs in 8.8% of patients undergoing RC. Our study demonstrates that use of chronic antacid therapy and long duration of antimicrobial exposure are associated with development of CDI. Efforts focusing on minimizing antibiotic exposure in patients undergoing RC are needed, and perioperative antimicrobial prophylaxis guidelines should be followed.

Risk of Recurrence for Clinical Stage I and II Patients With Teratoma Only at Primary Retroperitoneal Lymph Node Dissection.

OBJECTIVE To evaluate the oncologic outcomes of patients with retroperitoneal teratoma only at primary retroperitoneal lymph node dissection (RPLND) who did not receive adjuvant chemotherapy. MATERIALS AND METHODS Between 1979 and 2010, 23 patients with clinical stage (CS) I and II disease underwent primary RPLND at our institution with teratoma only in the retroperitoneum. No patient received adjuvant chemotherapy and the minimum follow-up was 2 years. RESULTS At the initial diagnosis, 13 patients (56.5%) had CS I disease and 10 patients (43.5%) had CS II disease. Pathologic staging demonstrated IIA in 13 patients (56.5%), IIB in 8 patients (34.8%), and IIC in 2 patients (8.7%). The 5-year disease-free survival (DFS) was 100% with a median follow-up of 5.8 years (range, 2.1-25.4). DFS was not significantly different comparing pathologic stage IIA vs IIB/IIC disease (P = .73). Two patients (14%) developed late relapses. One patient had a pelvic recurrence 11 years after primary RPLND. Final pathology from the pelvic resection demonstrated embryonal carcinoma. He remains disease free after his second surgery. The second patient had a contralateral retroperitoneal recurrence with yolk-sac tumor and teratoma 11 years after primary RPLND. He was treated with chemotherapy followed by postchemotherapy RPLND. CONCLUSION The relapse rate for patients with teratoma only at primary RPLND is low irrespective of PS. Adjuvant chemotherapy is therefore not recommended in the management of these patients.

IMPACT OF ISCHEMIA AND TISSUE PROCUREMENT CONDITIONS ON GENE EXPRESSION IN RENAL CELL CARCINOMA

Methods: Solid renal tumors from patients with von Hippel Lindau who underwent partial nephrectomy at the National Cancer Institute were included if they were resected without clamping of the renal hilum and had greater than 80% homogeneity on immediate gross examination. The procurement of the tumor was performed in the operating room. Immediately upon surgical resection, a piece of tumor was snap frozen to represent the zero time point. Remaining tissue samples were then stored in PBS at 4C, 22C and 37C and frozen at 5, 30, 60, 120, and 240 mins after surgical resection. All tissue samples were stored in liquid nitrogen until RNA extraction. Histopathologic evaluation was performed by a single pathologist on Hematoxylin & Eosin stained frozen sections obtained from each time point. Only tissue samples with at least 80% tumor on H & E were selected and used for RNA extraction, analysis, and gene expression microarrays. RNA integrity was confirmed by the presence of prominent 18S and 28S ribosomal peaks. Gene expression microarrays were performed using the Affymetrix platform. Class comparison paired t-test was performed between the zero time point and tissue samples from all other conditions obtained from the same tumor.

Progression from tubulovillous adenoma to high-grade adenocarcinoma in Indiana pouch urinary diversion

Urologists are aware of the increased risk of adenocarcinoma in urinary diversions that mix urine and feces, such as ureterosigmoidostomy.1 There are also several published case reports of this occurring in isolated bowel segments that are used for urinary reconstructions after cystectomy for several diseases, both benign and malignant. Here, we update a previous case report of an adenoma in an Indiana pouch urinary diversion, with further progression to a high-grade adenocarcinoma over 4 years.2

Comparative Genomic Profiling of Refractory/Metastatic Penile and non-Penile Cutaneous Squamous Cell Carcinoma: Implications for Selection of Systemic Therapy

Purpose: Metastatic penile squamous cell carcinoma is an aggressive malignancy with limited treatment options. We compared the potential therapy impacting genomic alterations between metastatic penile squamous cell carcinoma and nonpenile metastatic cutaneous squamous cell carcinoma. Materials and Methods: DNA was extracted from 40 &mgr; of formalin fixed, paraffin embedded samples from 78 cases of metastatic penile squamous cell carcinoma and 338 of metastatic cutaneous squamous cell carcinoma. Comprehensive genomic profiling was performed using a hybrid capture, adaptor ligation based, next generation sequencing assay to a mean coverage depth of greater than 500×. The tumor mutational burden was determined on 1.1 Mbp of sequenced DNA and microsatellite instability was determined on 114 loci. Results: Potential targeted therapy opportunities in metastatic penile squamous cell carcinoma cases included alterations in the MTOR pathway (NF1 genomic alterations in 7% and PTEN genomic alterations in 4%) and in the DNA repair pathway (BRCA2 and ATM genomic alterations in 7% each) and tyrosine kinase (EGFR genomic alterations in 6%, and FGFR3 and ERBB2 genomic alterations in 4% each). The tumor mutational burden was significantly higher in predominantly ultraviolet light exposed metastatic squamous cell carcinoma than in metastatic penile squamous cell carcinoma, making metastatic squamous cell carcinoma potentially more responsive to immunotherapies than metastatic penile squamous cell carcinoma. Microsatellite high status was extremely rare for metastatic penile and metastatic cutaneous squamous cell carcinoma. CD274 (PD-L1) amplification was also rare in both tumor types. Conclusions: Metastatic penile squamous cell carcinoma is a unique subtype of squamous cell carcinoma with distinctive genomic features which contrast with those identified in metastatic cutaneous squamous cell carcinoma of nonpenile ultraviolet light exposed skin. Although not rich in predictors of the response to immunotherapy (the tumor mutational burden and microsatellite instability are low), more than a quarter of metastatic penile squamous cell carcinoma cases may potentially benefit from existing and available therapies targeting MTOR, DNA repair and tyrosine kinase pathways.PURPOSE Metastatic penile squamous cell carcinoma is an aggressive malignancy with limited treatment options. We compared the potential therapy impacting genomic alterations between metastatic penile squamous cell carcinoma and nonpenile metastatic cutaneous squamous cell carcinoma. MATERIALS AND METHODS DNA was extracted from 40 μ of formalin fixed, paraffin embedded samples from 78 cases of metastatic penile squamous cell carcinoma and 338 of metastatic cutaneous squamous cell carcinoma. Comprehensive genomic profiling was performed using a hybrid capture, adaptor ligation based, next generation sequencing assay to a mean coverage depth of greater than 500×. The tumor mutational burden was determined on 1.1 Mbp of sequenced DNA and microsatellite instability was determined on 114 loci. RESULTS Potential targeted therapy opportunities in metastatic penile squamous cell carcinoma cases included alterations in the MTOR pathway (NF1 genomic alterations in 7% and PTEN genomic alterations in 4%) and in the DNA repair pathway (BRCA2 and ATM genomic alterations in 7% each) and tyrosine kinase (EGFR genomic alterations in 6%, and FGFR3 and ERBB2 genomic alterations in 4% each). The tumor mutational burden was significantly higher in predominantly ultraviolet light exposed metastatic squamous cell carcinoma than in metastatic penile squamous cell carcinoma, making metastatic squamous cell carcinoma potentially more responsive to immunotherapies than metastatic penile squamous cell carcinoma. Microsatellite high status was extremely rare for metastatic penile and metastatic cutaneous squamous cell carcinoma. CD274 (PD-L1) amplification was also rare in both tumor types. CONCLUSIONS Metastatic penile squamous cell carcinoma is a unique subtype of squamous cell carcinoma with distinctive genomic features which contrast with those identified in metastatic cutaneous squamous cell carcinoma of nonpenile ultraviolet light exposed skin. Although not rich in predictors of the response to immunotherapy (the tumor mutational burden and microsatellite instability are low), more than a quarter of metastatic penile squamous cell carcinoma cases may potentially benefit from existing and available therapies targeting MTOR, DNA repair and tyrosine kinase pathways.

PD59-10 THE NATURAL HISTORY OF LARGE RENAL MASSES ON ACTIVE SURVEILLANCE & EXPECTANT MANAGEMENT

validate a criterion for AS eligibility based on tumour clinical size and age on a cohort of patients treated with surgery. METHODS: 1922 patients diagnosed with a cT1cN0cM0 renal mass elected for surgical treatment and collected into a prospective database were assessed. Under the assumption that older patients with smaller tumours are optimal candidates for AS relative to younger patients with larger tumours, we relied on the ratio [R] between tumour clinical size and age in order to differentiate patients suitable for AS (R<5) from patients unsuitable for AS (R 5). X2 test was used to compare the rate of malignant histology, stage pT3-pT4 and grade G3G4 at final pathology in patients suitable vs. unsuitable for AS. Smoothed Poisson’s incidence plots were used to examine the rate of cancer specific [CSM] and other cause mortality [OCM] in patients suitable vs. unsuitable for AS. RESULTS: According to the proposed definition, the rate of patients suitable for AS was 34%. Patient suitable for AS had a lower rate of malignant histology (78 vs. 87%; p<0.001), pT3-pT4 (4 vs. 10% p1⁄40.001) and grade G3-G4 (7 vs. 17% p<0.001) relative to patients unsuitable for AS. In patients suitable for AS, the 10-year rates of CSM and OCM were 1.7 and 19%, respectively (Fig. 1A). In patients unsuitable for AS, the 10-year rates of CSM and OCM were 6.7 and 11% (Fig. 1B), respectively. CONCLUSIONS: When validated in a cohort of surgically treated patients, the ratio between tumour clinical size and age is a useful parameter to differentiate patients with adverse pathologic outcomes from patients with more favourable pathologic outcomes. These differences translate into critically different relative rates of CSM and OCM. These findings suggest that the proposed strategy criterion deserve further examination as a potential criterion for AS.