The benefit of liver transplant beyond Milan criteria: An analysis using the National Cancer Database.

BACKGROUND: Published studies examining the efficacy of liver transplantation in patients presenting with hepatocellular cancer beyond the traditional Milan criteria for liver transplantation have primarily been single institution series with limited ability to compare outcomes to alternative methods of management. METHODS: We queried the National Cancer Database to identify patients presenting between 2004 and 2016 with histologically confirmed clinical stage III and IVA hepatocellular cancer. Multivariable regression was used to identify factors associated with liver transplantation. Patients undergoing liver transplantation were 1:1 propensity score-matched for age, demographics, comorbid disease, clinical stage, and histologic resection margin to those undergoing surgical resection. The Kaplan-Meier method was used to compare overall survival profiles for matched cohorts. RESULTS: Seven hundred and ninety-two patients met inclusion criteria-590 (74.5%) underwent surgical resection and 202 (25.5%) liver transplantation. On adjusted analysis, patients undergoing liver transplantation were less likely to have advanced age (>60 years; odds ratio 0.39, 95% confidence interval [0.21-0.71]) and to be of Black race (odds ratio 0.42, 95% confidence interval [0.23-0.73]) or Asian (odds ratio 0.25, 95% confidence interval [0.11-0.53]) ethnicity but were more likely to have advanced (Charlson score >2) comorbidity scores, (odds ratio 2.48, 95% confidence interval [1.58-3.90]) and more likely to have private health insurance (odds ratio 4.17, 95% confidence interval [1.31-18.66]) than those undergoing surgical resection. On Kaplan-Meier analysis of matched cohorts, patients undergoing liver transplantation demonstrated significantly better rates of 5-year overall survival (65.3% vs 26.3%, P < .0001) and longer median overall survival times than those undergoing resection (53.1 ± 2.78 vs 26.9 ± 1.20 months, P < .0001). CONCLUSION: Liver transplantation offers the potential to be an effective treatment modality in select patients presenting with stage III and IVA hepatocellular cancer.

Low and moderate grade retroperitoneal liposarcoma: Is adjuvant radiotherapy associated with improved survival in patients undergoing R1 resection?

BACKGROUND: Few studies evaluate the efficacy of adjuvant radiotherapy (aXRT) in patients with retroperitoneal liposarcoma undergoing resection to histologically positive (R1) margins. METHODS: We queried the National Cancer Database to identify patients undergoing R1 resection for localized, large (>5 cm) low and moderate grade retroperitoneal liposarcoma between 2004 and 2016. Kaplan Meier method was used to compare overall survival (OS) for patients receiving aXRT to a 1:2 propensity-matched cohort of patients undergoing resection alone. RESULTS: A total of 322 (76.5%) patients underwent R1 resection alone, while 99 (23.5%) underwent resection followed by aXRT. The 99 receiving aXRT were successfully 1:2 propensity-score matched to 198 undergoing resection alone. There was no difference in 5-year OS between matched cohorts (69.7% vs 76.2%, p = 0.40). CONCLUSIONS: In patients undergoing R1 resection of moderate- and well-differentiated retroperitoneal liposarcoma, use of aXRT is not associated with an improvement in OS.

Resectable intrahepatic and hilar cholangiocarcinoma: Is margin status associated with survival?

BACKGROUND: Prior studies evaluating the effect of margin status on clinical outcome in patients undergoing resection for intrahepatic and extrahepatic hilar cholangiocarcinoma include small numbers of patients with histologically positive margins. The value of margin negative resection in these cases remains unclear. METHODS: We queried the National Cancer Database to identify patients undergoing resection for clinical stage I to III intrahepatic and extrahepatic hilar between 2004 and 2015. Patients receiving neoadjuvant therapy and those having <3 lymph nodes examined were excluded. Patients undergoing positive resection were 1:1 propensity matched to those undergoing negative resection. Kaplan-Meier methods were used to compare overall survival for the matched cohorts. RESULTS: In the study, 3,618 patients met the inclusion criteria, and 3,018 (83.4%) underwent negative resection; 600 (16.6%) positive resection. Patients undergoing negative resection had smaller tumors (2.97 ± 0.07 cm vs 3.49 ± 0.15 cm), were less likely to have stage 3 disease (16.7% vs 25.7%) and to receive adjuvant radiation (27.1% vs 45.7%) and chemotherapy (49.4% vs 61.0%) than those undergoing positive resection (all P < .05). On comparison of matched cohorts, patients undergoing negative resection had longer median overall survival (24.5 ± 0.02 vs 19.1 ± 0.02 months) and higher rates of 5-year overall survival (24.5% vs 16.7%) than those undergoing positive resection (P < .01). CONCLUSION: In patients presenting with resectable intrahepatic and extrahepatic hilar, negative resection is associated with improved overall survival. Extended resections performed in an effort to clear surgical margins are warranted in patients fit for such procedures.

Intrahepatic cholangiocarcinoma: Is there a role for liver transplantation?

BACKGROUND: Liver transplantation offers a potential for curative-intent treatment in patients presenting with non-metastatic intrahepatic cholangiocarcinoma that is not amenable to partial hepatectomy. There is little empiric evidence evaluating the efficacy of liver transplantation in patients with intrahepatic cholangiocarcinoma. METHODS: We queried the National Cancer Database to identify patients presenting with histologically confirmed clinical stage I to III intrahepatic cholangiocarcinoma between 2004 and 2016. Propensity scoring was used to develop matched cohorts of patients undergoing treatment with liver transplantation, surgical resection, or chemotherapy alone. Kaplan Meier methods were used to compare rates of overall survival. RESULTS: One thousand four hundred and eleven patients met inclusion criteria. Of these, 66 (4.7%) underwent liver transplantation, 461 (32.7%) underwent surgical resection, and 884 (62.6%) were treated with chemotherapy alone. On adjusted analysis, patients undergoing liver transplantation were more likely to be male (odds ratio 4.35, 95% confidence interval [0.12, 0.42]), have a Charlson Comorbidity Score ≥2 (odds ratio 3.11, 95% confidence interval [1.44, 6.57]), and to receive both neoadjuvant (odds ratio 2.78, 95% confidence interval [1.36,5.75], and adjuvant (odds ratio 1.94, 95% confidence interval [0.97, 3.87]) systemic therapy than those undergoing resection. On Kaplan Meier analysis, patients undergoing liver transplantation demonstrated rates of 5-year overall survival (36.1% vs 34.7%, P = .53) that were statistically identical to those for stage-matched and margin-matched patients undergoing resection but significantly better than those for stage-matched patients treated with systemic therapy alone (36.1% vs 5.3%, P < .0001). CONCLUSION: Patients undergoing liver transplantation for intrahepatic cholangiocarcinoma demonstrate overall survival profiles similar to stage-matched and margin-matched patients undergoing surgical resection. Liver transplantation is an effective treatment modality in select patients presenting with localized intrahepatic cholangiocarcinoma.

Small-sized gastrointestinal stromal tumors: Is there an association between expectant management and overall survival?

BACKGROUND: Small-sized gastrointestinal stromal tumors (GISTs) have limited malignant potential. Few studies evaluate the safety and efficacy of expectant management (EM) for patients presenting with small GIST. METHODS: We queried the National Cancer Database to identify patients ≤65 years presenting with GISTs smaller than 3 cm in size between 2004 and 2015. Patients undergoing EM were 1:3 propensity score matched for relevant covariates to patients undergoing resection. Kaplan-Meier (KM) analysis of matched cohorts was used to evaluate the association between EM and overall survival (OS). RESULTS: 1330 patients met inclusion criteria; 966 (72.6%) had gastric GISTs. 1196 (89.9%) underwent resection; 134 (10.1%) EM. 117 patients undergoing EM were propensity-matched to 356 patients undergoing resection. There was no difference in 5-year OS between patients undergoing EM and those undergoing resection (95.7% vs 92.6%, p = 0.4882). CONCLUSIONS: Survival for small GISTs is similar with expectant management or resection.

Is positive histologic surgical margin associated with overall survival in patients with resectable gallbladder cancer?

BACKGROUND: Achieving microscopically negative (R0) surgical margins in gallbladder cancer often requires a partial hepatectomy with associated risk of morbidity and potential to delay adjuvant therapy. Prior studies on the importance of margin status in resectable gall bladder cancer include small numbers of patients with positive (R1) resection margins and are underpowered. METHODS: We queried the National Cancer Database to identify patients undergoing resection of gallbladder adenocarcinoma between 2004 and 2015. Patients presenting with metastatic disease, those who received neoadjuvant therapy, and those with fewer than 3 lymph nodes assessed were excluded. 1:1 propensity score matching was used to develop cohorts undergoing either R0 or R1 resection, matched for demographic, pathologic, and facility characteristics. Kaplan-Meier analysis was used to assess the association between margin status and overall survival. RESULTS: A total of 1,439 patients met inclusion criteria; 1,285 underwent R0 and 154 underwent R1 resection. On Kaplan-Meier analysis of propensity-matched cohorts, patients undergoing R0 resection had a median overall survival that was 18 months longer than those undergoing R1 resection (34.6 ±â€¯2.0 months vs 16.3 ±â€¯1.7 months, P < .001). CONCLUSION: In patients presenting with resectable gallbladder adenocarcinoma, margin-negative resection is associated with significant improvement in overall survival.

Structural basis for IFN antagonism by human respiratory syncytial virus nonstructural protein 2.

Human respiratory syncytial virus (RSV) nonstructural protein 2 (NS2) inhibits host interferon (IFN) responses stimulated by RSV infection by targeting early steps in the IFN-signaling pathway. But the molecular mechanisms related to how NS2 regulates these processes remain incompletely understood. To address this gap, here we solved the X-ray crystal structure of NS2. This structure revealed a unique fold that is distinct from other known viral IFN antagonists, including RSV NS1. We also show that NS2 directly interacts with an inactive conformation of the RIG-I-like receptors (RLRs) RIG-I and MDA5. NS2 binding prevents RLR ubiquitination, a process critical for prolonged activation of downstream signaling. Structural analysis, including by hydrogen-deuterium exchange coupled to mass spectrometry, revealed that the N terminus of NS2 is essential for binding to the RIG-I caspase activation and recruitment domains. N-terminal mutations significantly diminish RIG-I interactions and result in increased IFNß messenger RNA levels. Collectively, our studies uncover a previously unappreciated regulatory mechanism by which NS2 further modulates host responses and define an approach for targeting host responses.

Nucleotide resolution mapping of influenza A virus nucleoprotein-RNA interactions reveals RNA features required for replication.

Influenza A virus nucleoprotein (NP) association with viral RNA (vRNA) is essential for packaging, but the pattern of NP binding to vRNA is unclear. Here we applied photoactivatable ribonucleoside enhanced cross-linking and immunoprecipitation (PAR-CLIP) to assess the native-state of NP-vRNA interactions in infected human cells. NP binds short fragments of RNA (~12 nucleotides) non-uniformly and without apparent sequence specificity. Moreover, NP binding is reduced at specific locations within the viral genome, including regions previously identified as required for viral genome segment packaging. Synonymous mutations designed to alter the predicted RNA structures in these low-NP-binding regions impact genome packaging and result in virus attenuation, whereas control mutations or mutagenesis of NP-bound regions have no effect. Finally, we demonstrate that the sequence conservation of low-NP-binding regions is required in multiple genome segments for propagation of diverse mammalian and avian IAV in host cells.

Proposed Iraq/Afghanistan War-Lung Injury (IAW-LI) Clinical Practice Recommendations: National Academy of Sciences' Institute of Medicine Burn Pits Workshop.

High rates of respiratory symptoms (14%) and new-onset asthma in previously healthy soldiers (6.6%) have been reported among military personnel post-deployment to Iraq and Afghanistan. The term Iraq/Afghanistan War-Lung Injury (IAW-LI) is used to describe the constellation of respiratory diseases related to hazards of war, such as exposure to burning trash in burn pits, improvised explosive devices, and sandstorms. Burnpits360.org is a nonprofit civilian website which voluntarily tracks medical symptoms among soldiers post-deployment to the Middle East. Subsequent to initiation of the Burnpits360.org website, the Department of Veterans Affairs started the Airborne Hazards and Open Burn Pit registry. This paper: (a) analyzes the latest 38 patients in the Burnpits360.org registry, validated by DD214 Forms; (b) compares strengths and weaknesses of both registries as outlined at the National Academy of Sciences Institute of Medicine Burn Pits Workshop;

L-arginine availability regulates inducible nitric oxide synthase-dependent host defense against Helicobacter pylori.

Helicobacter pylori infection of the stomach causes an active immune response that includes stimulation of inducible nitric oxide (NO) synthase (iNOS) expression. Although NO can kill H. pylori, the bacterium persists indefinitely, suggesting that NO production is inadequate. We determined if the NO derived from iNOS in macrophages was dependent on the availability of its substrate, L-arginine (L-Arg). Production of NO by H. pylori-stimulated RAW 264.7 cells was dependent on the L-Arg concentration in the culture medium, and the 50% effective dose for L-Arg was 220 microM, which is above reported plasma L-Arg levels. While iNOS mRNA induction was L-Arg independent, iNOS protein increased in an L-Arg-dependent manner that did not involve changes in iNOS protein degradation. L-lysine, an inhibitor of L-Arg uptake, attenuated H. pylori-stimulated iNOS protein expression, translation, NO levels, and killing of H. pylori. While L-Arg starvation suppressed global protein translation, at concentrations of L-Arg at which iNOS protein was only minimally expressed in response to H. pylori, global translation was fully restored and eukaryotic translation initiation factor alpha was dephosphorylated. H. pylori lacking the gene rocF, which codes for a bacterial arginase, induced higher levels of NO production by increasing iNOS protein levels. When murine gastric macrophages were activated with H. pylori, supraphysiologic levels of L-Arg were required to permit iNOS protein expression and NO production. These findings indicate that L-Arg is rate limiting for iNOS translation and suggest that the levels of L-Arg that occur in vivo do not permit sufficient NO generation by the host to kill H. pylori.

Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation.

Helicobacter pylori infection of the stomach elicits a vigorous but ineffective host immune and inflammatory response, resulting in persistence of the bacterium for the life of the host. We have reported that in macrophages, H. pylori up-regulates inducible NO synthase (iNOS) and antimicrobial NO production, but in parallel there is induction of arginase II, generating ornithine, and of ornithine decarboxylase (ODC), generating polyamines. Spermine, in particular, has been shown to restrain immune response in activated macrophages by inhibiting proinflammatory gene expression. We hypothesized that spermine could prevent the antimicrobial effects of NO by inhibiting iNOS in macrophages activated by H. pylori. Spermine did not affect the up-regulation of iNOS mRNA levels but in a concentration-dependent manner significantly attenuated iNOS protein levels and NO production. Reduction in iNOS protein was due to inhibition of iNOS translation and not due to iNOS degradation. ODC knockdown with small interfering (si) RNA resulted in increased H. pylori-stimulated iNOS protein expression and NO production without altering iNOS mRNA levels. When macrophages were cocultured with H. pylori, killing of bacteria was enhanced by transfection of ODC siRNA and prevented by addition of spermine. These results identify a mechanism of immune dysregulation induced by H. pylori in which stimulated spermine synthesis by the arginase-ODC pathway inhibits iNOS translation and NO production, leading to persistence of the bacterium and risk for peptic ulcer disease and gastric cancer.