Comparison of lumen-apposing metal stents versus endoscopic balloon dilation for the management of benign colorectal anastomotic strictures.

BACKGROUND AND AIMS: Limited data exist evaluating lumen-apposing metal stents (LAMSs) with endoscopic balloon dilation (EBD) for the treatment of benign colorectal anastomotic strictures (BCASs). This study compares outcomes of both interventions. METHODS: Patients with left-sided BCAS treated with LAMSs versus EBD were identified retrospectively. The primary outcome was a composite of crossover to another intervention to achieve clinical success or recurrence requiring reintervention. RESULTS: Twenty-nine patients (11 LAMS and 18 EBD) were identified with longer follow-up in the EBD group (734 vs 142 days; P = .003). No significant differences were found in the composite outcome, technical success, clinical success, or components of composite outcome. With LAMS, there was a nonsignificant trend toward fewer procedures (2.4 vs 3.3; P = .06) and adverse events (0% vs 16.7%; P = .26). CONCLUSIONS: LAMS appears to be as effective as EBD for the treatment of BCAS but may require fewer procedures and may be safer than EBD.

Efficacy and safety of long-term indwelling plastic stents after resolution of pancreatic fluid collections with endoscopic transmural drainage: a systematic review and meta-analysis.

BACKGROUND: Pancreatic fluid collections (PFCs) may recur after resolution with endoscopic transmural drainage (ETD) and standard stent removal (SSR). Herein, we compared the efficacy and safety of leaving long-term indwelling plastic stents (LTIS) vs. standard stent removal after PFC resolution with ETD. METHODS: We performed a systematic review of MEDLINE, EMBASE, CINAHL, Scopus, and Cochrane databases from inception to September 2022. Full-text articles comparing long-term (> 6 months) outcomes of LTIS and SSR were eligible, as well as single-arm studies with ≥ 10 patients with LTIS. Two independent reviewers selected studies, extracted data, and assessed the risk of bias using the Newcastle-Ottawa Scale. Measured outcomes included the following: (A) PFC recurrence; (B) interventions for PFC recurrence; (C) technical success; and (D) adverse events (AEs). Meta-analysis was carried out using random-effects models. RESULTS: We included 16 studies, encompassing 1285 patients. Compared to SSR after PFC resolution with ETD, LTIS was associated with significantly lower risk of PFC recurrence (3% vs. 23%; OR 0.22 [95%CI 0.09-0.52]; I2 = 45%) and need for interventions (2% vs. 14%; OR 0.35 [95%CI 0.16-0.78]; I2 = 0%). The superiority of LTIS on reducing PFC recurrence was found with walled-off necrosis, with or without disconnected pancreatic duct, and with placement of ≥ 2 LTIS. When using LTIS, the pooled proportion of AEs was 8% (95%CI 4-11%) and technical success was 93% (95%CI 86-99%). CONCLUSIONS: Our results show that LTIS after PFC resolution with ETD is feasible, safe, and superior to SSR in reducing the risk of PFC recurrence and need for interventions.

Avelumab Plus Axitinib as First-Line Therapy for Advanced Renal Cell Carcinoma: Long-Term Results from the JAVELIN Renal 100 Phase Ib Trial.

BACKGROUND: Progression-free survival was significantly longer in patients who received avelumab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma (aRCC) in a randomized phase III trial. We report long-term safety and efficacy of avelumab plus axitinib as first-line treatment for patients with aRCC from the JAVELIN Renal 100 phase Ib trial (NCT02493751). MATERIALS AND METHODS: In this open-label, multicenter, phase Ib study, patients with untreated aRCC received avelumab 10 mg/kg every 2 weeks plus axitinib 5 mg twice daily or with axitinib for 7 days followed by avelumab plus axitinib. Safety and efficacy were assessed in all patients receiving at least one dose of avelumab or axitinib. RESULTS: Overall, 55 patients were enrolled and treated. Median follow-up was 55.7 months (95% CI, 54.5-58.7). Treatment-related adverse events of any grade or grade ≥3 occurred in 54 (98.2%) and 34 (61.8%) patients, respectively. The confirmed objective response rate was 60.0% (95% CI, 45.9-73.0), including complete response in 10.9% of patients. Median duration of response was 35.9 months (95% CI, 12.7-52.9); the probability of response was 65.8% (95% CI, 46.7-79.4) at 2 years. Median progression-free survival was 8.3 months (95% CI, 5.3-32.0). Median overall survival was not reached (95% CI, 40.8-not estimable); the 5-year overall survival rate was 57.3% (95% CI, 41.2-70.5). CONCLUSION: Five-year follow-up for combination treatment with avelumab plus axitinib in previously untreated patients with aRCC showed long-term clinical activity with no new safety signals, supporting use of this regimen within its approved indication in clinical practice (Clinicaltrials.gov NCT02493751).

Fidelity of a PDX-CR model for bladder cancer.

Patient-derived xenografts (PDXs) are widely recognised as a more physiologically relevant preclinical model than standard cell lines, but are expensive and low throughput, have low engraftment rate and take a long time to develop. Our newly developed conditional reprogramming (CR) technology addresses many PDX drawbacks, but lacks many in vivo factors. Here we determined whether PDXs and CRCs of the same cancer origin maintain the biological fidelity and complement each for translational research and drug development. Four CRC lines were generated from bladder cancer PDXs. Short tandem repeat (STR) analyses revealed that CRCs and their corresponding parental PDXs shared the same STRs, suggesting common cancer origins. CRCs and their corresponding parental PDXs contained the same genetic alterations. Importantly, CRCs retained the same drug sensitivity with the corresponding downstream signalling activity as their corresponding parental PDXs. This suggests that CRCs and PDXs can complement each other, and that CRCs can be used for in vitro fast, high throughput and low cost screening while PDXs can be used for in vivo validation and study of the in vivo factors during translational research and drug development.

Outcomes and quality of life assessment after per oral endoscopic myotomy (POEM) performed in the endoscopy unit with trainees.

BACKGROUND: Per oral endoscopic myotomy (POEM) has emerged as a promising option for the treatment of achalasia. This study assessed POEM training process, outcomes, and improvement in quality of life after POEM performed by an interventional endoscopist (mentor) with trainees. METHODS: We performed a retrospective review of data for patients who underwent POEM with involvement of trainees. Trainees were trained in performing mucosotomy, submucosal dissection, creating submucosal tunnel, identifying gastroesophageal junction, myotomy, and closure of mucosal incision in a step-by-step fashion. Trainees' performance on each step was evaluated by the mentor based on several key points in each step. The short form 36 (SF36) was obtained before and certain times after the primary POEM procedure was performed. RESULTS: Sixty-two patients, 26 males and 36 females with a mean age of 59 years, who underwent POEM were enrolled. A checklist included all related items for each step was established. All trainees obtained competence within 6 cases for each step. 61/62 (98.3%) patients had a significant improvement in the Eckardt's score post POEM: 9.3 ± 1.5 prior to POEM and 2.6 ± 1.2 after the POEM (P = 0.001) and a decrease in mean lower esophageal sphincter pressure (LES): pre- and post-procedure mean LES pressures were 28.5 ± 11.4 and 12.1 ± 4.5 mmHg, respectively (P = 0.001). The SF-36 questionnaire demonstrated a significant improvement in quality of life and comparable with those without trainees in other studies. CONCLUSION: This preliminary study showed for the first time that training for POEM can be performed in a step-by-step fashion, learning mucosal incision, submucosal dissection, myotomy, and mucosal incision closure from an expert interventional endoscopist without increasing adverse events. The checklist for each step could be used as an important guide in training POEM. The outcomes of POEM in this study were similar to those reported by others without trainees. Further multiple center studies are needed to verify this training process and to establish a formal training protocol.

Risks of Serious Toxicities from Intermittent versus Continuous Androgen Deprivation Therapy for Advanced Prostate Cancer: A Population Based Study.

PURPOSE: Randomized trials have shown that intermittent androgen deprivation therapy for patients with advanced prostate cancer may improve sexual and physical functioning compared to continuous androgen deprivation therapy without compromising survival. To our knowledge it is unknown whether intermittent androgen deprivation therapy alters the risk of serious toxicities associated with continuous androgen deprivation therapy. MATERIALS AND METHODS: We performed a population based cohort study of 9,772 men 66 years old or older who were diagnosed with advanced prostate cancer from 2002 to 2011 and treated with androgen deprivation therapy. Intermittent androgen deprivation therapy was defined as a single 90-day interval between 2 androgen deprivation therapy sessions during which patients visited their physicians or underwent prostate specific antigen testing. Outcomes included acute myocardial infarction, stroke, heart failure, type 2 diabetes and fracture. We used Cox proportional hazard models to estimate the HRs of the comparative risk of serious toxicities between intermittent and continuous androgen deprivation therapy. RESULTS: A total of 2,113 (22%), 769 (9%) and 899 men (9%) had a new cardiovascular event, diabetes or fracture, respectively, within 5 years of starting androgen deprivation therapy. Compared to the continuous androgen deprivation therapy group, the intermittent therapy group was at lower risk for serious cardiovascular events (HR 0.64, 95% CI 0.53-0.77), particularly in reducing the risk of heart failure (HR 0.62, 95% CI 0.49-0.78) and fracture (HR 0.52, 95% CI 0.38-0.70, each p <0.0001). CONCLUSIONS: Intermittent androgen deprivation therapy was associated with a lower risk of heart failure and fracture compared to continuous androgen deprivation therapy. This raises toxicity concerns for continuous relative to intermittent therapy and suggests that intermittent androgen deprivation therapy may represent a safer therapeutic choice in elderly men with advanced prostate cancer.

Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies.

Despite extensive investigation over the past three decades, cancer immunotherapy has produced limited success, with few agents achieving approval by the Food and Drug Administration and even the most effective helping only a minority of patients, primarily with melanoma or renal cancer. In recent years, immune checkpoints that maintain physiologic self-tolerance have been implicated in the down-regulation of anti-tumor immunity. Efforts to restore latent anti-tumor immunity have focused on antibody-based interventions targeting CTL antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T lymphocytes and its principal ligand (PD-L1) on tumor cells. Ipilimumab, an antibody targeting CTLA-4, appears to restore tumor immunity at the priming phase, whereas anti-PD-1/PD-L1 antibodies restore immune function in the tumor microenvironment. Although ipilimumab can produce durable long-term responses in patients with advanced melanoma, it is associated with significant immune-related toxicities. By contrast, antibodies targeting either PD-1 or PD-L1 have produced significant anti-tumor activity with considerably less toxicity. Activity was seen in patients with melanoma and renal cancer, as well as those with non-small-cell lung, bladder and head and neck cancers, tumors not previously felt to be sensitive to immunotherapy. The tolerability of PD-1-pathway blockers and their unique mechanism of action have made them ideal backbones for combination regimen development. Combination approaches involving cytotoxic chemotherapy, anti-angiogenic agents, alternative immune-checkpoint inhibitors, immunostimulatory cytokines and cancer vaccines are currently under clinical investigation. Current efforts focus on registration trials of single agents and combinations in various diseases and disease settings and identifying predictive biomarkers of response.

Emerging monoclonal antibodies for the treatment of renal cell carcinoma (RCC).

INTRODUCTION: Advanced renal cell carcinoma (RCC) was considered refractory to most cancer therapies until the 1980s, after which immune modulating agents and targeted agents were developed. Recently the rapid development of therapeutic monoclonal antibodies targeting immune checkpoint pathways has provided significant clinical benefit in patients with many distinct cancer types. Nivolumab, an anti-PD1 monoclonal antibody showed improvement in response rate and overall survival in patients with previously treated RCC and received US FDA approval in late 2015. Current efforts with anti-PD1-based therapy include combinations with ipilimumab and with VEGF pathway blockers in the hopes on building on the activity of single agent therapy. AREAS COVERED: We describe our current understanding of tumor immunology including the basis of the tumor-specific immune response and the adaptive mechanisms used by the tumor for immune escape. We describe the mechanisms of action as well as the therapeutic application of the antibodies, ipilimumab, nivolumab and atezolizumab in patients with RCC. We identify key areas of active research in biomarker development and combination therapies. EXPERT OPINION: Clinical trials and the field of RCC therapeutics are expected to move in the direction of combination therapies using immune checkpoint inhibitors, extending overall survival as a benchmark for new drug approvals, and biomarker validation for improved selection of patients for specific therapies.

Heterotrimeric collagen helix with high specificity of assembly results in a rapid rate of folding.

The most abundant natural collagens form heterotrimeric triple helices. Synthetic mimics of collagen heterotrimers have been found to fold slowly, even compared to the already slow rates of homotrimeric helices. These prolonged folding rates are not understood. Here we compare the stabilities, specificities and folding rates of three heterotrimeric collagen mimics designed through a computationally assisted approach. The crystal structure of one ABC-type heterotrimer verified a well-controlled composition and register and elucidated the geometry of pairwise cation-π and axial and lateral salt bridges in the assembly. This collagen heterotrimer folds much faster (hours versus days) than comparable, well-designed systems. Circular dichroism and NMR data suggest the folding is frustrated by unproductive, competing heterotrimer species and these species must unwind before refolding into the thermodynamically favoured assembly. The heterotrimeric collagen folding rate is inhibited by the introduction of preformed competing triple-helical assemblies, which suggests that slow heterotrimer folding kinetics are dominated by the frustration of the energy landscape caused by competing triple helices.

NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease.

OBJECTIVE: Immune responses are important in dictating non-alcoholic steatohepatitis (NASH) outcome. We previously reported that upregulation of hedgehog (Hh) and osteopontin (OPN) occurs in NASH, that Hh-regulated accumulation of natural killer T (NKT) cells promotes hepatic stellate cell (HSC) activation, and that cirrhotic livers harbour large numbers of NKT cells. DESIGN: The hypothesis that activated NKT cells drive fibrogenesis during NASH was evaluated by assessing if NKT depletion protects against NASH fibrosis; identifying the NKT-associated fibrogenic factors; and correlating plasma levels of the NKT cell-associated factor OPN with fibrosis severity in mice and humans. RESULTS: When fed methionine-choline-deficient (MCD) diets for 8 weeks, wild type (WT) mice exhibited Hh pathway activation, enhanced OPN expression, and NASH-fibrosis. Ja18-/- and CD1d-/- mice which lack NKT cells had significantly attenuated Hh and OPN expression and dramatically less fibrosis. Liver mononuclear cells (LMNCs) from MCD diet fed WT mice contained activated NKT cells, generated Hh and OPN, and stimulated HSCs to become myofibroblasts; neutralising these factors abrogated the fibrogenic actions of WT LMNCs. LMNCs from NKT-cell-deficient mice were deficient in fibrogenic factors, failing to activate collagen gene expression in HSCs. Human NASH livers with advanced fibrosis contained more OPN and Hh protein than those with early fibrosis. Plasma levels of OPN mirrored hepatic OPN expression and correlated with fibrosis severity. CONCLUSION: Hepatic NKT cells drive production of OPN and Hh ligands that promote fibrogenesis during NASH. Associated increases in plasma levels of OPN may provide a biomarker of NASH fibrosis.

Efficacy of peripheral androgen blockade in prostate cancer patients with biochemical failure after definitive local therapy: results of Cancer and Leukemia Group B (CALGB) 9782.

BACKGROUND: The treatment for prostate cancer patients with biochemical failure after local therapy remains controversial. Peripheral androgen blockade using a combination of a 5-alpha reductase inhibitor and an antiandrogen may allow control of the prostate-specific antigen (PSA). Because testosterone levels are not suppressed, this approach may be associated with less morbidity than conventional gonadal androgen suppression. METHODS: All patients had undergone previous definitive local therapy and had evidence of a rising PSA >1ng/mL, with no evidence of recurrent disease. Patients received both finasteride, 5 mg orally per day, and flutamide, 250 mg orally 3× a day. Patients were followed for a PSA response and quality of life assessment. RESULTS: Ninety-nine of 101 accrued patients were eligible. A ≥80% PSA decline was seen in 96 (96%) patients. The median time to PSA progression was 85 months. With a median follow-up of 10 years, the median survival time had not been reached, and the 5-year overall survival rate was 87%. Toxicity was mild, with 18 patients stopping for toxicity; 15 had diarrhea, 4 had gynecomastia, and 3 had transaminase elevation. Baseline Functional Assessment of Cancer Therapy Prostate Module and Treatment Outcome Index scores decreased by 5 points each at 6 months after enrollment. CONCLUSIONS: The use of the finasteride/flutamide combination is feasible, and results in PSA declines of ≥80% in 96% of patients with serologic progression after definitive local therapy. There were no unexpected toxicities, and the change in quality of life was mild. Further evaluation of this or a similar regimen in a controlled clinical trial is warranted.

Long-term Outcome of Per-oral Endoscopic Myotomy Performed in the Endoscopy Unit With Trainees.

INTRODUCTION: Per-oral endoscopic myotomy (POEM) has been widely adopted for the treatment of achalasia as it provides a precise, tailored myotomy in a minimally invasive endoscopic procedure. Several short-term studies and a few long-term studies have confirmed that POEM is a safe and effective treatment for achalasia. However, the long-term outcome of POEM performed by trainees is unknown. MATERIALS AND METHODS: We conducted a retrospective study of all patients who underwent POEM for achalasia at our tertiary care center during December 2012 and January 2019. All procedures performed with trainees were included. The primary outcome was the clinical response to POEM, defined as an Eckardt score of <3 after POEM. Trainees were trained in performing mucosotomy and submucosal dissection, creating a submucosal tunnel, identifying gastroesophageal junction, and performing myotomy and closure of mucosal incision in a step-by-step fashion. Trainees' performance was evaluated by the mentor based on several key points in each step. RESULTS: A total of 153 consecutive patients with a median age of 57±18 years were analyzed in this study. Of the total patients, 69 (45%) were male. The median length of follow-up after POEM was 32 months (range: 7 to 77 mo). A clinically significant response to POEM was achieved in 95% of patients at year 1, 84% at year 2, 80% at year 3, 79% at year 4, 78% at year 5, and 78% at year 6 and above. All trainees obtained competence within 6 cases for each step and could perform the procedure alone after 20 supervised cases. CONCLUSIONS: Overall, 78% of patients maintained positive clinical response at 6 years following POEM procedure. The recurrence rate of symptoms following POEM was 22% at a 6-year follow-up. This long-term outcome of POEM performed with trainees was comparable to those without trainees in other studies. To our knowledge, this is the longest follow-up and the largest number of patients after the POEM procedure performed with trainees.

STAG2 as a prognostic biomarker in low-grade non-muscle invasive bladder cancer.

OBJECTIVE: Improvements to bladder cancer risk stratification guidelines are needed to better tailor post-operative surveillance and adjuvant therapy to individual patients. We previously identified STAG2 as a commonly mutated tumor suppressor gene in bladder cancer and an independent predictor of progression in NMIBC. Here we test the value of combining STAG2 immunostaining with other risk stratification biomarkers in NMIBC, and as an individual biomarker in MIBC. MATERIALS AND METHODS: STAG2 immunohistochemistry was performed on a progressor-enriched cohort of tumors from 297 patients with NMIBC, and on tumors from 406 patients with MIBC from Aarhus University Hospital in Denmark. Survival analysis was performed using Kaplan-Meier survival analysis, the log rank test, and Cox proportional hazards models. RESULTS: STAG2-negative low-grade NMIBC tumors were 2.5 times less likely to progress to muscle invasion than STAG2-positive low-grade NMIBC tumors (Log-rank test, P = 0.008). In a composite group of patients with AUA intermediate and high-risk NMIBC tumors, STAG2-negative tumors were less likely to progress (Log-rank test, P = 0.02). In contrast to NMIBC, we show that STAG2 is not useful as a prognostic biomarker in MIBC. CONCLUSIONS: STAG2 immunostaining can be used to subdivide low-grade NMIBC tumors into two groups with substantially different risks of disease progression. Furthermore, STAG2 immunostaining may be useful to enhance NMIBC risk stratification guidelines, though larger cohorts are needed to solidify this conclusion in individual risk groups. STAG2 is not useful as a biomarker in MIBC. Further study of the use of STAG2 immunostaining as a biomarker for predicting the clinical behavior in NMIBC is warranted.

Nitrous oxide-induced toxic leukoencephalopathy.

Toxic leukoencephalopathy (TL) is characterised by an insult to the myelin of the cerebral white manner which can be attributed to a number of offending agents, including drugs of abuse. We report a case of a fit and well young man presenting to hospital with an altered mental state. It was subsequently determined that the patient inhaled a significant volume of nitrous oxide recreationally. Nitrous oxide is easily accessible and the second most consumed drug among young adolescents (16-24 years old). Following extensive investigations and brain imaging, the patient was subsequently diagnosed with TL. After a prolonged hospital admission, he went on to make a complete neurological recovery.

Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer.

PURPOSE: Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. "Switch maintenance" therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS: Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS: Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION: Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

Oxygen desaturation during sleep in hepatopulmonary syndrome.

UNLABELLED: Sleep alters respiratory mechanics and gas exchange, which can adversely affect arterial oxygenation. Whether sleep affects oxygenation in hepatopulmonary syndrome is unknown. The aim of this study was to assess oxygen desaturation during sleep in hepatopulmonary syndrome. Twenty adults with cirrhosis including 10 controls and 10 patients with hepatopulmonary syndrome underwent home pulse-oximetry during sleep. Subjects at high risk for obstructive sleep apnea were excluded through the Berlin questionnaire. Subjects who spent more than 10% of total sleep time with arterial oxygen saturation < 90% were classified as sleep-time oxygen desaturators. Sleep-time desaturation was correlated with clinical variables. The results showed that 7 of 10 hepatopulmonary syndrome subjects and none of the 10 controls had sleep-time oxygen desaturation. The median percentage of total sleep time with arterial oxygen saturation < 90% was significantly higher in hepatopulmonary syndrome subjects than in controls (medians 25% versus 0%, P = 0.005). Hepatopulmonary syndrome subjects had significantly lower wake-time arterial oxygen saturation level (median, 97% versus 95%; P = 0.003) and mean sleep-time arterial oxygen saturation level (median, 96% versus 91%; P = 0.0008) than did the controls. Sleep-time desaturation directly correlated with alveolar-arterial oxygen gradient (P = 0.0007) and inversely correlated with wake-time arterial oxygen tension (P = 0.0007) and oxygen saturation (P < 0.0001). CONCLUSION: Oxygen desaturation occurred during sleep in 70% of hepatopulmonary syndrome subjects, the degree of which correlated with the severity of hepatopulmonary syndrome. Marked hypoxemia during sleep may occur in hepatopulmonary syndrome patients who, according to wake-time oxygen values, have only mild to moderate hypoxemia.

A Curious Case of Coil-Angitis.

A 43-year-old man with a history of pedestrian-truck collision 18 months prior presented with right-sided abdominal pain and chills. His trauma consisted of orthopedic injuries and a grade 4 liver laceration. Surgical liver repair was complicated by a biloma requiring common bile duct stenting. Postendoscopy hemobilia led to extensive coiling of a hepatic artery pseudoaneurysm. Remaining hospitalization was relatively uneventful, and he was lost to follow-up. Repeat presentation was marked by leukocytosis and obstructive transaminitis. Computed tomography raised concern for a dilated 14-mm common bile duct with migrated coil mass near the pancreatic head. The patient underwent urgent endoscopic retrograde cholangiopancreatography with cholangioscopy and successful removal of a coil mass measuring approximately 4 × 3 cm without injury to the common bile duct or vascular structures. His pain was relieved, and he was discharged with a common bile duct stent and outpatient follow-up.

Tumor volume changes on 1.5 tesla endorectal MRI during neoadjuvant androgen suppression therapy for higher-risk prostate cancer and recurrence in men treated using radiation therapy results of the phase II CALGB 9682 study.

PURPOSE: We prospectively determined whether the change in tumor volume (TV) during 2 months of neoadjuvant androgen suppression therapy (nAST) measured using conventional 1.5 Tesla endorectal magnetic resonance imaging (eMRI) was associated with the risk of recurrence after radiation (RT) and 6 months of AST. PATIENTS AND METHODS: Between 1997 and 2001, 180 men with clinical stage T1c-T3cN0M0 adenocarcinoma of the prostate were registered. Fifteen were found to be ineligible and the institutional MR radiologist could not assess the TV in 32, leaving 133 for analysis. Multivariable Cox regression analysis was used to assess whether a significant association existed between eMRI-defined TV progression during nAST and time to recurrence adjusting for prostate-specific antigen (PSA) level, Gleason score (8 to 10 or 7 vs. 6 or less) and stage (T3 vs. T1-2). RESULTS: After a median follow up of 6.7 years and adjusting for known prognostic factors, there was a significant increase in the risk of PSA failure (HR, 2.3 [95% CI, 1.1-4.5; p = 0.025) in men with eMRI-defined TV progression during nAST. Specifically, adjusted estimates of PSA failure were significantly higher (p = 0.032) in men with, compared with men without, eMRI-defined TV progression reaching 38% vs. 19%, respectively, by 5 years. CONCLUSION: Eradicating intraprostatic hormone refractory prostate cancer (HRPC) by maximizing local control and randomized trials assessing whether survival is improved when agents active against HRPC are combined with maximal local therapy are needed in men who progress based on eMRI during nAST.

Pilot study of pentoxifylline in hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) results when chronic liver disease or portal hypertension causes intrapulmonary microvascular dilatation with hypoxemia. In experimental HPS, tumor necrosis factor alpha (TNF-alpha) overproduction contributes to vasodilatation, which is improved by pentoxifylline, a TNF-alpha inhibitor. The effectiveness of pentoxifylline in humans is unknown. The aim of this open-label, single-arm clinical trial was to assess the efficacy and tolerability of pentoxifylline in patients with cirrhosis and advanced HPS undergoing liver transplantation evaluation. Nine adults with cirrhosis and moderate to severe HPS were enrolled. All patients had an initial 2-week titration to a target dose of pentoxifylline of 400 mg by mouth every 8 hours, which was continued for 6 weeks. Baseline and follow-up arterial blood gases and TNF-alpha levels were evaluated. Adverse effects and tolerability were assessed. The 9 patients had a mean age of 55 +/- 10 years, and 67% were female. The most common causes of cirrhosis were hepatitis C virus and alcohol (55%). The mean Model for End-Stage Liver Disease score was 11 (range, 6-19), and patients had advanced hypoxemia [mean partial pressure of arterial oxygen (PaO(2)) = 54 +/- 12 mm Hg, mean alveolar-arterial oxygen gradient (A-a PaO(2)) = 57 +/- 15 mm Hg]. Of the 9 patients enrolled, follow-up blood gases were done in 7. There was no significant change in PaO(2) (P = 0.3) or A-a PaO(2) (P = 0.3) with treatment. Pentoxifylline was poorly tolerated. Nausea (100%) and vomiting (56%) were the predominant side effects, and only a single patient was able to complete full-dose therapy. Treatment with pentoxifylline did not improve arterial oxygenation in advanced HPS, and tolerance was limited by gastrointestinal toxicity.