Radiofrequency ablation in the management of primary hepatic and biliary tumors.

In the United States, 80%-90% of primary hepatic tumors are hepatocellular carcinomas and 10%-15% are cholangiocarcinomas (CCA), both with high mortality rate, particularly CCA, which portends a worse prognosis. Traditional management with surgery has good outcomes in appropriately selected patients; however, novel ablative treatment options have emerged, such as radiofrequency ablation (RFA), which can improve the prognosis of both hepatic and biliary tumors. RFA is aimed to generate an area of necrosis within the targeted tissue by applying thermal therapy via an electrode, with a goal to completely eradicate the tumor while preserving surrounding healthy tissue. Role of RFA in management of hepatic and biliary tumors forms the focus of our current mini-review article.

Effect of individualized feedback on learning curves in EGD and colonoscopy: a cluster randomized controlled trial.

BACKGROUND AND AIMS: Gastroenterology fellowships need to ensure that trainees achieve competence in upper endoscopy (EGD) and colonoscopy. Because the impact of structured feedback remains unknown in endoscopy training, this study compared the effect of structured feedback with standard feedback on trainee learning curves for EGD and colonoscopy. METHODS: In this multicenter, cluster, randomized controlled trial, trainees received either individualized quarterly learning curves or feedback standard to their fellowship. Assessment was performed in all trainees using the Assessment of Competency in Endoscopy tool on 5 consecutive procedures after every 25 EGDs and colonoscopies. Individual learning curves were created using cumulative sum (CUSUM) analysis. The primary outcome was the mean CUSUM score in overall technical and overall cognitive skills. RESULTS: In all, 13 programs including 132 trainees participated. The intervention arm (6 programs, 51 trainees) contributed 558 EGD and 600 colonoscopy assessments. The control arm (7 programs, 81 trainees) provided 305 EGD and 468 colonoscopy assessments. For EGD, the intervention arm (-.7 [standard deviation {SD}, 1.3]) had a superior mean CUSUM score in overall cognitive skills compared with the control arm (1.6 [SD, .8], P = .03) but not in overall technical skills (intervention, -.26 [SD, 1.4]; control, 1.76 [SD, .7]; P = .06). For colonoscopy, no differences were found between the 2 arms in overall cognitive skills (intervention, -.7 [SD, 1.3]; control, .7 [SD, 1.3]; P = .95) or overall technical skills (intervention, .1 [SD, 1.5]; control, -.1 [SD, 1.5]; P = .77). CONCLUSIONS: Quarterly feedback in the form of individualized learning curves did not affect learning curves for EGD and colonoscopy in a clinically meaningful manner. (Clinical trial registration number: NCT02891304.).

Control of the interface between heterotypic cell populations reveals the mechanism of intercellular transfer of signaling proteins.

Direct intercellular transfer of cellular components is a recently described general mechanism of cell­cell communication. It is a more non-specific mode of intercellular communication that is not actively controlled by the participating cells. Though membrane bound proteins and small non-protein cytosolic components have been shown to be transferred between cells, the possibility of transfer of cytosolic proteins has not been clearly established, and its mechanism remains unexplained. Using a cell­cell pair of metastatic melanoma and endothelial cells, known to interact at various stages during cancer progression, we show that cytosolic proteins can indeed be transferred between heterotypic cells. Using precise relative cell patterning we provide evidence that this transfer depends on extent of the interface between heterotypic cell populations. This result is further supported by a mathematical model capturing various experimental conditions. We further demonstrate that cytosolic protein transfer can have important functional consequences for the tumor­stroma interactions, e.g., in heterotypic transfer of constitutively activated BRAF, a common melanoma associated mutation, leading to an enhanced activation of the downstream MAPK pathway. Our results suggest that cytosolic protein transfer can have important consequences for regulation of processes involving physical co-location of heterotypic cell types, particularly in invasive cancer growth.

Endoscopic management of peripancreatic fluid collections.

Peripancreatic fluid collections are a well-known complication of pancreatitis and can vary from fluid-filled collections to entirely necrotic collections. Although most of the fluid-filled pseudocysts tend to resolve spontaneously with conservative management, intervention is necessary in symptomatic patients. Open surgery has been the traditional treatment modality of choice though endoscopic, laparoscopic and transcutaneous techniques offer alternative drainage approaches. During the last decade, improvement in endoscopic ultrasound technology has enabled real-time access and drainage of fluid collections that were previously not amenable to blind transmural drainage. This has initiated a trend towards use of this modality for treatment of pseudocysts. In this review, we have summarised the existing evidence for endoscopic drainage of peripancreatic fluid collections from published studies.

Association of pretreatment neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line docetaxel.

OBJECTIVE: To determine whether the pretreatment neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammatory response, is associated with overall survival (OS) in men receiving chemotherapy with docetaxel for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Records from 238 consecutive patients who were treated with first-line docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 (and who had adequate information to enable calculation of NLR) were reviewed. Univariable and multivariable Cox regression models were used to predict OS after chemotherapy initiation. RESULTS: In univariable analyses, the NLR as a discrete variable (optimal threshold 3.0) was significantly associated with OS (P = 0.001). In multivariable analyses, a lower NLR (≤3.0) was associated with lower risk of all-cause mortality (P = 0.002). In Kaplan-Meier analysis, the median OS was higher (18.3 vs 14.4 months) in patients that did not have an elevated NLR than in those with an elevated NLR (log-rank; P < 0.001). CONCLUSIONS: Men who were treated with first-line docetaxel for mCRPC who had a low pretreatment NLR (≤3.0) had significantly longer OS. NLR may be a potentially useful clinical marker of systemic inflammatory response in predicting OS in men with mCRPC who receive docetaxel and may be helpful to stratify patients for clinical trials. These findings derived from a retrospective analysis need to be validated in larger populations in prospective studies, and in the context of different therapies.

Update in systemic therapy of urologic malignancies.

Systemic therapy of advanced prostate and renal cancers has gained several recent additions to the therapeutic armamentarium. Treatment of patients with castration-resistant prostate cancer now includes additional immunotherapy (sipuleucel-T), chemotherapy (cabazitaxel), androgen-signaling inhibitors (abiraterone acetate, enzalutamide), and a radiopharmaceutical (alpharadin), based on extension of patient survival. Similarly, therapy for patients with renal cell carcinoma, a chemoresistant malignancy, has undergone dramatic changes based on an understanding of the role of angiogenesis. Multiple vascular endothelial growth factor inhibitors (sorafenib, sunitinib, pazopanib, axitinib, bevacizumab) and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) have been added to the therapeutic arsenal. Additionally, immunotherapy retains an important treatment role, with a continuing application of high-dose interleukin-2 in select patients and the emergence of novel immunotherapeutic agents that may have significant benefit. Other major urologic malignancies, including urothelial, testicular, and penile cancers, have witnessed relatively few or no recent advances in therapy, although testicular germ cell tumors are one of the most curable malignancies. An agent for treatment of advanced urothelial cancer now has commercial approval, the chemotherapeutic agent, vinflunine, as second-line therapy in multiple countries-but not in the United States. Our review summarizes and updates the field of systemic therapy for advanced urologic malignancies, with a focus on castration-resistant prostate cancer and renal cell carcinoma.

Association of the Charlson comorbidity index and hypertension with survival in men with metastatic castration-resistant prostate cancer.

OBJECTIVES: The independent prognostic effect of comorbidities on outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) is unclear. We sought to determine whether the Charlson comorbidity index (CCI) and hypertension (HTN) are associated with overall survival (OS) independent of known clinical prognostic factors in mCRPC. PATIENTS AND METHODS: A retrospective analysis was conducted on 221 patients with mCRPC treated with docetaxel plus prednisone combined with AT-101 (bcl-2 antagonist) or placebo on a prospective randomized phase II trial. The Cox regression analysis was performed to identify whether the CCI or HTN or both (by medical history) independently predicted OS after adjusting for baseline variables known to be associated with OS. The Wilcoxon rank sum test and the Fisher exact test were used to compare data by comorbidity groups (CCI as a continuous variable, CCI = 6 vs. CCI ≥ 7 and HTN vs. no HTN). RESULTS: The CCI was 6 in 116 patients (52.7%), 7 in 70 (31.8%), 8 in 23 (10.5%), 9 in 4 (1.8%), and 10 in 7 patients (3.2%). HTN was present in 107 (48.6%) patients. Patients with CCI of ≥ 7 were older and exhibited worse performance status and anemia than patients with CCI of 6 (P<0.05). The CCI was not independently predictive of OS on univariable and multivariable analyses. HTN alone or in combination with the CCI was borderline significantly associated with OS (P ~ 0.09) on both univariable and multivariable analyses. CONCLUSIONS: The CCI did not predict OS independent of known prognostic factors in mCRPC. Age, performance status, and anemia may adequately capture comorbidities in the context of mCRPC, given their association with higher CCI. Further prospective study of comorbidities in a larger data set may be warranted. The study of HTN in a larger data set may also be warranted given its borderline-independent association with OS.

Prognostic risk stratification derived from individual patient level data for men with advanced penile squamous cell carcinoma receiving first-line systemic therapy.

BACKGROUND: Prognostic factors in men with penile squamous cell carcinoma (PSCC) receiving systemic therapy are unknown. A prognostic classification system in this disease may facilitate interpretation of outcomes and guide rational drug development. We performed a retrospective analysis to identify prognostic factors in men with PSCC receiving first-line systemic therapy for advanced disease. PATIENTS AND METHODS: Individual patient level data were obtained from 13 institutions to study prognostic factors in the context of first-line systemic therapy for advanced PSCC. Cox proportional hazards regression analysis was conducted to examine the prognostic effect of these candidate factors on progression-free survival (PFS) and overall survival (OS): age, stage, hemoglobin, neutrophil count, lymphocyte count, albumin, site of metastasis (visceral or nonvisceral), smoking, circumcision, regimen, ECOG performance status (PS), lymphovascular invasion, precancerous lesion, and surgery following chemotherapy. The effect of different treatments was then evaluated adjusting for factors in the prognostic model. RESULTS: The study included 140 eligible men. Mean age across all men was 57.0 years. Among them, 8.6%, 21.4%, and 70.0% of patients had stage 2, 3, and 4 diseases, respectively; 40.7% had ECOG PS ≥ 1, 47.4% had visceral metastases, and 73.6% received cisplatin-based chemotherapy. The multivariate model of poor prognostic factors included visceral metastases (P<0.001) and ECOG PS ≥ 1 (P<0.001) for both PFS and OS. A risk stratification model constructed with 0, 1, and both poor prognostic factors was internally validated and demonstrated moderate discriminatory ability (c-statistic of 0.657 and 0.677 for OS and PFS, respectively). The median OS for the entire population was 9 months. Median OS was not reached, 8, and 7 months for those with 0, 1, and both risk factors, respectively. Cisplatin-based regimens were associated with better OS (P = 0.017) but not PFS (P = 0.37) compared with noncisplatin-based regimens after adjusting for the 2 prognostic factors. CONCLUSIONS: In men with advanced PSCC receiving first-line systemic therapy, visceral metastases and ECOG PS ≥ 1 were poor prognostic factors. A prognostic model including these factors exhibited moderate discriminatory ability for outcomes and warrants external validation. Patients receiving cisplatin-based regimens exhibited better outcomes compared with noncisplatin-based regimens after adjusting for prognostic factors.

Clinical Evaluation of Abiraterone in the Treatment of Metastatic Prostate Cancer.

Treatment of castration-resistant prostate cancer remains an area of unmet medical need. Evidence suggests that this entity continues to be driven by androgens and androgen receptor (AR) signaling. Abiraterone acetate, a pregnenolone derivative, is an oral selective and irreversible inhibitor of the key steroidogenic enzyme CYP17. It possesses dual 17-α hydroxylase and C17,20-lyase blocking activity, the result of which is decreased gonadal and extra-gonadal androgen synthesis. Abiraterone was first approved by the US Food and Drug Administration (FDA) in 2011 following the demonstration of superior survival compared with placebo in the post-docetaxel population. Since that time, more evidence has been generated from preclinical studies and clinical trials which have considerably enhanced our understanding of this complex disease. In this paper, we review the development of abiraterone acetate, its pharmacological characteristics, and its effects on the androgen-AR signaling axis, along with the combined experience from clinical trials. We also discuss some of the ongoing trials using this agent, as well as potential mechanisms of abiraterone resistance, novel bio-marker development, and future directions using AR-directed therapies.

Determinants of outcomes after resection of renal cell carcinoma with venous involvement.

PURPOSE: To determine the outcomes and to identify prognostic variables determining mortality and recurrence after surgery for renal cell cancer (RCC) with venous involvement. METHODS: Retrospective evaluation of the medical records of 132 patients with RCC and tumor thrombi treated at Johns Hopkins Hospital (1997-2008) was done. Kaplan-Meier analysis was used to determine survivals. Uni- and multivariate Cox proportional analysis was done to identify predictors for recurrence, all-cause mortality (ACM) and cancer-specific mortality (CSM). RESULTS: Mean follow-up was 30.3 (0.03-159.5) months. Sixty-four (48.5%) patients had renal vein thrombus (Group 1), 55 (41.7%) had subdiaphragmatic inferior vena cava (IVC) tumor thrombus (Group 2), while 13 (9.8%) had involvement of IVC above diaphragm or atrial extension (Group 3). IVC thrombus was more common from the right-sided tumors. Patients with higher thrombus levels had more blood loss and complicated and longer hospital stay. Thrombus level was not found to be a predictor of recurrence, ACM and CSM. One- and three-year recurrence-free survivals for non-metastatic patients were 69 and 53%. Tumor size (p=0.015), grade (p=0.007) and venous wall invasion (p=0.027) were predictors for recurrence. Five-year overall survival was 48, 35 and 13% for 3 groups, respectively. Presence of distant metastasis (p=0.032), size (p=0.002), histology (p=0.020) and grade (p=0.013) were predictors of ACM. Five-year cancer-specific survival was 65, 43 and 36 for 3 groups, respectively. Tumor size (p=0.001) and distant metastasis at presentation (p=0.025) were the predictors of CSM. CONCLUSIONS: Tumor thrombus level does not predict recurrence or mortality in RCC with venous involvement. Survival is determined by inherent aggressiveness of the cancer manifested by tumor size, grade and distant metastasis at presentation.

The effect of clinical trial participation versus non-participation on overall survival in men receiving first-line docetaxel-containing chemotherapy for metastatic castration-resistant prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? Previous studies have reported better outcomes in cancer patients that enrolled in clinical trials, suggesting that trial participation in itself might be beneficial. We investigated the potential positive effect of clinical trial participation on survival outcomes of patients with metastatic castration-resistant prostate cancer who were treated with first-line docetaxel-containing chemotherapy. After accounting for potential baseline inequalities, participation in a clinical trial itself was associated with significantly longer overall survival in these patients. OBJECTIVE: • To study differences in baseline characteristics and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line docetaxel-containing chemotherapy on prospective clinical studies (trial participants) versus those receiving this therapy outside of a clinical study (non-participants). PATIENTS AND METHODS: • Records from 247 consecutive chemotherapy-naive patients who were treated with docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 were reviewed. • All patients received docetaxel either as clinical trial participants (n= 142; 11 separate studies) or as non-participants (n= 105). • Univariable and multivariable Cox regression models predicted overall survival after chemotherapy initiation. RESULTS: • There was no significant difference between trial participation and non-participation with respect to patient age, type of primary treatment, tumour grade or clinical stage. • Multivariable analyses showed a significantly lower risk of all-cause mortality (hazard ratio 0.567; P= 0.027) among trial participants vs non-participants. CONCLUSIONS: • Patients that were treated with docetaxel for mCRPC showed a significantly longer overall survival when enrolled in a clinical trial. • Improved survival in trial participants may reflect the better medical oversight typically seen in patients enrolled in trials, more regimented follow-up schedules, or a positive effect on caregivers' attitudes because of greater contact with medical services. • With the retrospective nature of this analysis and the small study population, prospective studies are needed to validate the present findings and to further investigate the relationship between clinical trial participation and outcomes.

Single-center comparative oncologic outcomes of surgical and percutaneous cryoablation for treatment of renal tumors.

PURPOSE: To compare outcomes between patients undergoing surgical and percutaneous cryoablation for treatment of renal masses and identify prognostic variables that determine survival. PATIENTS AND METHODS: We retrospectively evaluated the medical records of 194 patients who underwent cryoablation for renal tumors between 1997 and 2008 at a single large center. Patient demographics, tumor characteristics, perioperative data, and follow-up details were recorded. Univariate and multivariate Cox proportional hazards analysis was performed to identify predictors of overall (OS), cancer-specific (CSS), and recurrence-free survival (RFS). RESULTS: Cryoablation was performed percutaneously (PCA) in 141 patients for 154 tumors, while 53 patients were treated surgically (SCA) using an open or laparoscopic approach for 54 tumors. Mean follow-up was 44.5 months in SCA and 36.1 months in PCA. PCA had a shorter duration of hospital stay (0.7 days vs 3.2 days, P<0.0001). The rate of residual (P=0.38) and recurrent disease (P=0.18) was not significantly different between the two groups. Five-year OS, CSS, and RFS were 78.81%, 100%, and 85.23% for SCA, and 77.71%, 98%, and 95.56% for PCA, respectively; the type of approach was not predictive of OS, CSS, and RFS. CONCLUSIONS: SCA and PCA both provide adequate oncologic control for renal masses. Duration of hospital stay was lower in patients undergoing PCA.

Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases.

Patients with castration-resistant prostate cancer (CRPC) frequently have metastases to the bone, which may cause pain and lead to a deterioration in quality-of-life. Bone-seeking radiopharmaceuticals are agents which, when administered systemically, localize to the site of bone metastases and deliver focal radiation there. In this review, we will summarize the current literature on bone-targeting radiopharmaceuticals for CRPC, focusing on strontium-89, samarium-153, rhenium-186 and radium-223. We will discuss their indications, clinical efficacy, and toxicities and highlight some of the challenges in optimizing treatment with these agents. Historically, clinical trials with these drugs have failed to demonstrate survival improvements, restricting their use for palliative purposes only. Radium-223 is the first agent in this class to show an overall survival advantage in CRPC patients with bone metastases. This landmark finding will likely have a considerable impact on the treatment paradigm of bone-metastatic CRPC, and will pave the way for further developments in the future.

Surgical resection of malignant melanoma metastatic to the pancreas: case series and review of literature.

BACKGROUND: Malignant melanoma only rarely metastasizes to the pancreas. As such, there is limited medical literature on the clinical course and outcomes for patients who have undergone surgical management of these tumors. The aim of our study was to review our experience with the surgical resection of melanoma metastatic to the pancreas. METHODS: The records of five patients (four females, one male) with surgically resected melanoma metastatic to the pancreas were retrospectively reviewed. Tumor characteristics, patient presentation, operative details, and follow-up data were evaluated. RESULTS: The primary site of melanoma was known in three cases and unknown in two cases. Four patients were symptomatic at presentation, including abdominal pain (n = 3), jaundice (n = 2), abdominal distension (n = 1), bleeding metastases (n = 1), and fatigue (n = 1). In one patient, the metastasis was an incidental discovery. Surgical resection was accomplished by pylorus-preserving pancreaticoduodenectomy in four patients and distal pancreatectomy in one patient. Single-site resection was done in two patients while the other three underwent synchronous multiple-site resections. Complications developed post-operatively in three patients. Two patients had progression of disease in the form of new metastatic lesions and received subsequent chemotherapy. The median survival was 11.4 months (range, 3-26 months). CONCLUSIONS: Aggressive surgical management of pancreatic metastases provides palliative relief of symptoms and may be considered in appropriately selected candidates.

Renal function and oncologic outcomes after cryoablation or partial nephrectomy for tumors in solitary kidneys.

PURPOSE: Preservation of renal function is of paramount importance in patients with tumors in solitary kidneys. We compared the renal function and oncologic outcomes of patients treated by partial nephrectomy with those of patients treated by cryoablation for solitary kidney tumors. MATERIALS AND METHODS: All patients with solitary kidneys who were treated for renal tumors at our institution between 1997 and 2007 were included in the screen. We retrospectively identified 23 patients who underwent cryoablation and 15 patients who underwent partial nephrectomy. RESULTS: The two groups were similar with regard to age, gender, and tumor laterality. Patients in the partial nephrectomy group had a larger tumor size (3.4 cm vs. 2.5 cm, p=0.01), higher mean estimated blood loss (316 cc vs. 87 cc, p<0.001), longer duration of hospital stay (5.8 vs. 1.8 days, p<0.001), and a higher rate of perioperative complications (53.3% vs. 8.7% patients, p=0.03). Percentage changes in the glomerular filtration rate postoperatively and on follow-up were found to be similar in the two groups. Both the cryoablation and the partial nephrectomy groups with mean follow-ups of 31.2 months and 30.8 months, respectively, had evidence of local or distant recurrence in 3 patients each (13% and 20% respectively, p=0.7). Both groups had a similar mean overall survival (88.9 and 86.9 months in the cryoablation and partial nephrectomy groups, respectively, p=0.8). CONCLUSIONS: For tumors in solitary kidneys, renal functional and clinical outcomes for cryoablation were not significantly different from those for partial nephrectomy. However, cryoablation has the distinct advantage of a lower morbidity rate and can be preferentially offered to selected cases.

Large renal metastasis from rare pulmonary neoplasm.

A 50-year-old man, with a history of right lower lobectomy for pulmonary adenocystic carcinoma, presented with chronic flank pain due to a large mass in the right kidney. He also had bilateral pulmonary nodules and cardiac masses, indicating metastatic disease. Simultaneous metastatic involvement of the kidney and the heart from a rare pulmonary tumor made this case unique in the prevailing medical data.