Satish Maddineni

Differential Complication Rates Following Radical Cystectomy in the Irradiated and Nonirradiated Pelvis

BACKGROUND Reports suggest that cystectomy following pelvic irradiation is associated with a higher morbidity and mortality than in primary cases. However, such reports are from an era when postcystectomy complication rates were higher than are currently reported. OBJECTIVE This study evaluates perioperative complications and mortality in primary radical and postradiation salvage cystectomy. DESIGN, SETTING, AND PARTICIPANTS Patients treated with cystectomy for bladder cancer or advanced pelvic malignancies involving the bladder were studied. MEASUREMENTS Perioperative complications and mortality were analysed for 426 primary and 420 salvage cystectomies performed at a single institution between 1970 and 2005. RESULTS AND LIMITATIONS The 30- and 60-d mortality in the 2000-2005 cohort were 0% and 1.2%, respectively, in the primary group and 1.4% and 4.3%, respectively, in the salvage cystectomy group. Thirty-day mortality between 1970 and 2005 was not statistically significant in the primary and salvage groups (4.2% and 7.1%, respectively). CONCLUSIONS This large series from a high-volume centre demonstrates no difference in perioperative mortality in primary or postradiation salvage radical cystectomy. Similarly, there was no significant difference in the incidence of most of the surgical or medical complications in either group, although the stomal stenosis rate was higher postradiation.

Differential radiosensitisation by ZD1839 (Iressa), a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines.

The epidermal growth factor receptor (EGFR) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder. Stimulation of the EGFR pathway is blocked by ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor. Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario. The effect of combination treatment with ZD1839 (0.01 μM) and ionising radiation in the established bladder cancer cell lines MGH-U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays. A highly significant radiosensitising effect was seen in both cell lines (P<0.001 for MGH-U1 and S40b cell lines). This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation. Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 (0.01 μM) as a single agent. A modest induction of apoptosis was observed with ZD1839 (0.01 μM) as a single agent, but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation. These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer.

LONG TERM SURVIVAL OUTCOME FOLLOWING RADICAL CYSTECTOMY FOR TCC OF THE BLADDER - COMPARISON BETWEEN PRIMARY AND SALVAGE RADICAL CYSTECTOMY

INTRODUCTION AND OBJECTIVES: To evaluate the long term overall and cancer specific survival for patients undergoing primary and post radiation salvage radical cystectomy stratified according to pathological T staging. METHODS: Outcome for 552 patients who underwent radical cystectomy for transitional cell carcinoma (TCC) of the bladder between 1970 and 2005 was analysed. Of these, 313 patients underwent primary radical cystectomy (PRC) and 239 underwent salvage radical cystectomy (SRC) following radiation failure. The median age was 62.5yr (range 32.2 to 87.2) for the PRC and 65.5yr (range 33.1 to 85) for SRC cohorts. Men accounted for 75% of both the groups. Over the study period of 37 years, 400 patients died, 267 due to cancer specific causes. There were 152 live patients at last follow up in 2007 with a median follow up of 5.05 yr (range 0.5 33.6yr). Statistical analysis was performed to assess overall and cancer specific survival differences between the groups. Analysis was also sub-stratified according to pathological T staging from the cystectomy specimen. RESULTS: There was no statistically significant difference in long term (5yr and 10 yr) overall survival (OAS) (p=0.063) or cancer specific survival (CSS) (p=0.39) between the groups (Fig1). Overall 5 yr survival was 45.5% for the PRC and 42% for the SRC cohorts with a CSS of 51% and 50% respectively. The 10yr OAS for PRC group was 32% and 26% for the SRC group with CSS of 45% for the PRC and 46% for SRC cohorts respectively. Sub-analysis of survival data between the groups following stratification for pathological stage (T2, T3, T4) did not show significant difference between the groups either for overall or cancer specific survival (p=0.23). CONCLUSIONS: Radical cystectomy has been considered as the gold standard treatment for muscle invasive bladder cancer. This study, the first to our knowledge comparing survival rates stratified for T stage between primary and salvage surgical groups, does not confirm this traditionally held view. A bladder preservation strategy involving radiotherapy and salvage cystectomy for radiation failure does not appear to incur a survival disadvantage for patients in the long term.

Aetiology, diagnosis and management of urothelial tumours of the renal pelvis and ureter

TCC of the upper urinary tract (UTTCC) is a relatively uncommon tumour, representing 2–6% of all TCC [1] and 10% of all renal tumours in the USA. It is three times more common in men than women and occurs three to four times more commonly in the renal pelvis than the ureter [2]. Of lower ureteric TCC, 70% occur in the distal third with a further 24% occurring in the midureter. The incidence increases with age and is commonest in the fifth to seventh decades (mean age of occurrence 65–67 years, with a peak incidence in the eighth decade).

Reorganising specialist cancer surgery for the twenty-first century: a mixed methods evaluation (RESPECT-21)

BackgroundThere are longstanding recommendations to centralise specialist healthcare services, citing the potential to reduce variations in care and improve patient outcomes. Current activity to centralise specialist cancer surgical services in two areas of England provides an opportunity to study the planning, implementation and outcomes of such changes. London Cancer and Manchester Cancer are centralising specialist surgical pathways for prostate, bladder, renal, and oesophago-gastric cancers, so that these services are provided in fewer hospitals. The centralisations in London were implemented between November 2015 and April 2016, while implementation in Manchester is anticipated in 2017.Methods/DesignThis mixed methods evaluation will analyse stakeholder preferences for centralisations; it will use qualitative methods to analyse planning, implementation and sustainability of the centralisations (‘how and why?’); and it will use a controlled before and after design to study the impact of centralisation on clinical processes, clinical outcomes, cost-effectiveness and patient experience (‘what works and at what cost?’). The study will use a framework developed in previous research on major system change in acute stroke services. A discrete choice experiment will examine patient, public and professional preferences for centralisations of this kind. Qualitative methods will include documentary analysis, stakeholder interviews and non-participant observations of meetings. Quantitative methods will include analysis of local and national data on clinical processes, outcomes, costs and National Cancer Patient Experience Survey data. Finally, we will hold a workshop for those involved in centralisations of specialist services in other settings to discuss how these lessons might apply more widely.DiscussionThis multi-site study will address gaps in the evidence on stakeholder preferences for centralisations of specialist cancer surgery and the processes, impact and cost-effectiveness of changes of this kind. With increasing drives to centralise specialist services, lessons from this study will be of value to those who commission, organise and manage cancer services, as well as services for other conditions and in other settings. The study will face challenges in terms of recruitment, the retrospective analysis of some of the changes, the distinction between primary and secondary outcome measures, and obtaining information on the resources spent on the reconfiguration.

Male adnexal tumour of wolffian origin: the first report of metastatic disease.

The first case of a male adnexal tumour of probable wolffian duct origin to develop metastatic disease is reported. The characteristic histological appearance and immunohistochemical profiles of the primary and metastatic male tumours are discussed. The scanty experience relating to metastatic disease makes decisions about the most appropriate treatment challenging.

Mapping Hypoxia in Renal Carcinoma with Oxygen-enhanced MRI: Comparison with Intrinsic Susceptibility MRI and Pathology

Purpose To cross-validate T1-weighted oxygen-enhanced (OE) MRI measurements of tumor hypoxia with intrinsic susceptibility MRI measurements and to demonstrate the feasibility of translation of the technique for patients. Materials and Methods Preclinical studies in nine 786–0-R renal cell carcinoma (RCC) xenografts and prospective clinical studies in eight patients with RCC were performed. Longitudinal relaxation rate changes (∆R1) after 100% oxygen inhalation were quantified, reflecting the paramagnetic effect on tissue protons because of the presence of molecular oxygen. Native transverse relaxation rate (R2*) and oxygen-induced R2* change (∆R2*) were measured, reflecting presence of deoxygenated hemoglobin molecules. Median and voxel-wise values of ∆R1 were compared with values of R2* and ∆R2*. Tumor regions with dynamic contrast agent–enhanced MRI perfusion, refractory to signal change at OE MRI (referred to as perfused Oxy-R), were distinguished from perfused oxygen-enhancing (perfused Oxy-E) and nonperfused regions. R2* and ∆R2* values in each tumor subregion were compared by using one-way analysis of variance. Results Tumor-wise and voxel-wise ∆R1 and ∆R2* comparisons did not show correlative relationships. In xenografts, parcellation analysis revealed that perfused Oxy-R regions had faster native R2* (102.4 sec–1 vs 81.7 sec–1) and greater negative ∆R2* (−22.9 sec–1 vs −5.4 sec–1), compared with perfused Oxy-E and nonperfused subregions (all P < .001), respectively. Similar findings were present in human tumors (P < .001). Further, perfused Oxy-R helped identify tumor hypoxia, measured at pathologic analysis, in both xenografts (P = .002) and human tumors (P = .003). Conclusion Intrinsic susceptibility biomarkers provide cross validation of the OE MRI biomarker perfused Oxy-R. Consistent relationship to pathologic analyses was found in xenografts and human tumors, demonstrating biomarker translation. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Centralising specialist cancer surgery services in England: survey of factors that matter to patients and carers and health professionals

BackgroundThe centralisation of specialist cancer surgical services across London Cancer and Greater Manchester Cancer, England, may significantly change how patients experience care. These centres are changing specialist surgical pathways for several cancers including prostate, bladder, kidney, and oesophago-gastric cancers, increasing the specialisation of centres and providing surgery in fewer hospitals. While there are potential benefits related to centralising services, changes of this kind are often controversial. The aim of this study was to identify factors related to the centralisation of specialist surgical services that are important to patients, carers and health care professionals.MethodsThis was a questionnaire-based study involving a convenience sample of patient and public involvement (PPI) and cancer health care professional (HCP) sub-groups in London and Greater Manchester (n = 186). Participants were asked to identify which of a list of factors potentially influenced by the centralisation of specialist cancer surgery were important to them and to rank these in order of importance. We ranked and shortlisted the most important factors.ResultsWe obtained 52 responses (28% response rate). The factors across both groups rated most important were: highly trained staff; likelihood and severity of complications; waiting time for cancer surgery; and access to staff members from various disciplines with specialised skills in cancer. These factors were also ranked as being important separately by the PPI and HCP sub-groups. There was considerable heterogeneity in the relative ordering of factors within sub-groups and overall.ConclusionsThis study examines and ranks factors important to patients and carers, and health care professionals in order to inform the implementation of centralisation of specialist cancer surgical services. The most important factors were similar in the two stakeholder sub-groups. Planners should consider the impact of reorganising services on these factors, and disseminate this information to patients, the public and health care professionals when deciding whether or not and how to centralise specialist cancer surgical services.

Primary Mutational Landscape Linked with Pre-Docetaxel Lactate Dehydrogenase Levels Predicts Docetaxel Response in Metastatic Castrate-Resistant Prostate Cancer

BACKGROUND Docetaxel chemotherapy is a standard of care for metastatic castrate-resistant prostate cancer (mCRPC): 40-50% of patients achieve a biochemical response. However, there is a lack of response predictive biomarkers. OBJECTIVE To assess lactate dehydrogenase (LDH) as a docetaxel response biomarker in mCRPC and to examine the association of LDH with genomic alterations in primary diagnostic biopsies. DESIGN, SETTING, AND PARTICIPANTS Clinical and associated primary tumour-targeted next-generation sequencing data from matched training (n=150) and test (n=120) cohorts of progressive mCRPC patients receiving docetaxel therapy were analysed. Data were correlated with large-scale prostate cancer genomic datasets. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Prostate-specific antigen (PSA) response, radiographic response, biochemical progression-free survival (PFS), overall survival (OS), genomic analysis of primary biopsies, and genomic datasets (Memorial Sloan Kettering Cancer Center [MSKCC] and SU2C/PCF). RESULTS AND LIMITATIONS Serum LDH ≥450U/l is a reliable prognostic biomarker (area under the curve: 0.757 [standard deviation 0.054, 95% confidence interval [CI] 0.650-0.864, p<0.001]) in progressive mCRPC, predicting PFS at 3 mo. Patients with LDH ≥450U/l were poorer PSA responders, with shorter PFS (213 vs 372 d, hazard ratio [HR] 1.876, 95% CI 1.289-2.7300) and OS (362 vs 563 d, HR 1.630, 95% CI 1.127-2.357). High LDH is an independent surrogate marker for survival following docetaxel and predicts a poor radiological response (p=0.043). Of the 14 patients with LDH ≥450U/l available for next-generation sequencing, nine (64.3%) were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2, Fanconi anaemia gene) in their primary biopsy. Cross correlation with MSKCC and SU2C/PCF databases revealed a positive correlation between LDHA, PARP1 (r=0.667, p<0.01), and other DNA repair genes. CONCLUSIONS Genomic abnormalities of LDHA and DNA repair in primary biopsies link to high pretreatment LDH and poor response to docetaxel in mCRPC. PATIENT SUMMARY The presence of mutations of the lactate dehydrogenase and DNA repair pathways are associated with aggressive prostate cancer and poor response to chemotherapy later in the disease.

Discrete-choice experiment to analyse preferences for centralizing specialist cancer surgery services: Preferences for centralizing specialist cancer surgery services

Centralizing specialist cancer surgery services aims to reduce variations in quality of care and improve patient outcomes, but increases travel demands on patients and families. This study aimed to evaluate preferences of patients, health professionals and members of the public for the characteristics associated with centralization.