Preoperative Frailty and Malnutrition in Surgical Oncology Patients Predicts Higher Postoperative Adverse Events and Worse Survival: Results of a Blinded, Prospective Trial.

BACKGROUND: Frailty, a multidimensional state leading to reduced physiologic reserve, is associated with worse postoperative outcomes. Despite the availability of various frailty tools, surgeons often make subjective assessments of patients' ability to tolerate surgery. The Risk Analysis Index (RAI) is a validated preoperative frailty assessment tool that has not been studied in cancer patients with plans for curative-intent surgery. METHODS: In this prospective, surgeon-blinded study, patients who had abdominal malignancy with plans for resection underwent preoperative frailty assessment with the RAI and nutrition assessment by measurement of albumin, prealbumin, and C-reactive protein (CRP). Postoperative outcomes and survival were assessed. RESULTS: The study included 220 patients, 158 (72%) of whom were considered frail (RAI ≥21). Frail patients were more likely to be readmitted within 30 and 90 days, (16% vs. 3% [P = 0.006] and 16% vs. 5% [P = 0.025], respectively). Patients with abnormal CRP, prealbumin, and albumin experienced higher rates of unplanned intensive care unit admission (CRP [27% vs. 8%; P < 0.001], albumin [30% vs. 10%; P < 0.001], prealbumin [29% vs. 9%; P < 0.001]) and increased postoperative mortality at 90 and 180 days. Survival was similar for frail and non-frail patients. In the multivariate analysis, frailty remained an independent risk factor for readmission (hazard ratio, 5.58; 95% confidence interval, 1.39-22.15; P = 0.015). In the post hoc analysis using the pre-cancer RAI score, the postoperative outcomes did not differ between the frail and non-frail patients. CONCLUSION: In conjunction with preoperative markers of nutrition, the RAI may be used to identify patients who may benefit from additional preoperative risk stratification and increased postoperative follow-up evaluation.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: Effects of postoperative fluids beyond the first 24 h.

BACKGROUND AND OBJECTIVES: There are no guidelines for intravenous fluid (IVF) administration after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). This study assessed rates of post-CRS/HIPEC morbidity according to perioperative IVF administration. METHODS: All patients undergoing CRS/HIPEC March 2007 to June 2018 were reviewed, recording clinicopathologic, operative, and postoperative variables. Patients were divided by peritoneal cancer index (PCI), comparing IVF volumes and types administered intraoperatively and during the first 72 h postoperatively. Optimal IVF rate cutoffs calculated using area under the receiver operating characteristic curves and Youden's index determined associations with complications. RESULTS: Overall, 185 patients underwent CRS/HIPEC, and 81 (51%) had low PCI (<10) and 77 (49%) had high PCI (≥10). In low-PCI patients, high IVF rates on postoperative days (POD) #0-2 were associated with higher overall complications: POD#0 (46% vs. 89%, p = 0.001), POD#1 (40% vs. 86%, p < 0.05), and POD#2 (42% vs. 72%, p < 0.05). High IVF rates were associated with respiratory distress (7% vs. 26%, p = 0.02) on POD#0, ileus (14% vs. 47%, p = 0.007) and intensive care unit stay (11% vs. 33%, p = 0.022) on POD#1, and ICU stay (8% vs. 33%, p = 0.003) on POD#2. CONCLUSIONS: For low PCI patients undergoing CRS/HIPEC, higher IVF rates were associated with postoperative complications. Post-CRS/HIPEC, IVF rates should be limited to prevent morbidity.

T1 Gastric Cancer Is Associated With a High Incidence of Regional Lymph Node Metastases.

INTRODUCTION: Early stage gastric cancer, particularly T1 disease, is associated with high recurrence-free and overall survival rates following resection with curative intent. However, rare cases of T1 gastric cancer have nodal metastasis and this is associated with poor outcomes. METHODS: Data from gastric cancer patients treated with surgical resection and D2 lymph node (LN) dissection at a single tertiary care institution from 2010 to 2020 were analyzed. Patients with early stage (T1) tumors were assessed in detail to identify variables associated with regional LN metastasis including histologic differentiation, signet ring cells, demographics, smoking history, neoadjuvant therapy, and clinical staging by endoscopic ultrasound (EUS). We used standard statistical techniques including Mann-Whitney U and Chi-squared tests. RESULTS: Of 426 patients undergoing surgery for gastric cancer, 34% (n = 146) were diagnosed with T1 disease on surgical pathology. Among 146 T1 (T1a, T1b) gastric cancers, 24 patients [(17%) T1a (n = 4), T1b (n = 20)] had histologically confirmed regional LN metastases. The age at diagnosis ranged between 19 and 91 y and 54.8% were male. Prior smoking status was not associated with nodal positivity (P = 0.650). Of the 24 patients with positive LN on final pathology, seven patients received neoadjuvant chemotherapy. EUS was performed on 98 (67%) of the 146 T1 patients. Of these patients, 12 (13.2%) had positive LN on final pathology; however, none (0/12) were detected on preoperative EUS. There was no association between node status on EUS and node status on final pathology (P = 0.113). The sensitivity of EUS for N status was 0%, specificity was 84.4%, negative predictive value was 82.2% and positive predictive value was 0%. Signet ring cells were identified in 42% of node negative T1 tumors and 64% of node positive T1 tumors (P = 0.063). For LN positive cases on surgical pathology, 37.5% had poor differentiation, 42% had lymphovascular invasion, and regional nodal metastases were associated with increasing T stage (P = 0.003). CONCLUSIONS: T1 gastric cancer is associated with a substantial risk (17%) of regional LN metastasis, when pathologically staged following surgical resection and D2 lymphadenectomy. Clinically staged N+ disease by EUS was not significantly associated with pathologically staged N+ disease in these patients.

Gallbladder Cancer: A Single-Institution 10-Year Experience-Analysis of Adenocarcinoma Subtypes and Tumors Arising from Intracholecystic Papillary Neoplasms.

BACKGROUND: Gallbladder cancer accounts for 1.2% of global cancer diagnoses. Literature on biliary-type adenocarcinoma (BTA), and specifically carcinoma arising from intracholecystic papillary-tubular neoplasms (ICPNs), is limited. This study describes a retrospective, single-institution experience with gallbladder cancer, focusing on histological subtypes and prognosis. METHODS: A retrospective review was performed of patients who underwent cholecystectomy for a malignant neoplasm of the gallbladder between 2007 and 2017. Demographic, clinicopathologic, and operative variables, as well as survival outcomes, were analyzed. RESULTS: From a total of 145 patients, BTAs were most common (93, 64%). Compared with non-BTAs, BTAs were diagnosed at a lower American Joint Committee on Cancer stage (p = 0.045) and demonstrated longer median recurrence-free survival (38 vs. 16 months, p = 0.014; median follow-up 36 months). Tumors arising from ICPNs (18, 12%) were more commonly associated with BTA (14 cases). Compared with BTAs not associated with ICPNs (29 patients), associated cases demonstrated lower pathologic stage (p = 0.006) and lower rates of liver and perineural invasion (0% vs. 49% and 14% vs. 48%, respectively; p < 0.05). Cumulative 5-year survival probability was higher for patients with gallbladder neoplasm of any subtype associated with ICPNs compared with those that were not associated with ICPNs (54% vs. 41%, p = 0.019; median follow-up 23 months). This difference was also significant when comparing BTAs associated with ICPNs and non-associated cases (63% vs. 52%, p = 0.005). CONCLUSIONS: This study demonstrated unique pathological and prognostic features of BTAs and of carcinomas arising from ICPNs. Histopathological variance may implicate prognosis and may be used to better guide clinical decision making in the treatment of these patients.

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development.

BACKGROUND & AIMS: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.

Adjuvant Chemotherapy Is Not Guided by Pathologic Treatment Effect After Neoadjuvant Chemotherapy in Pancreatic Cancer.

OBJECTIVES: Currently, there is no guidance for optimal adjuvant chemotherapy selection after pancreatectomy with a partial or poor response to neoadjuvant therapy. This study seeks to describe an institution's practice patterns of adjuvant chemotherapy selection after neoadjuvant therapy. METHODS: Patients at a single institution receiving neoadjuvant chemotherapy followed by pancreatectomy for pancreatic cancer were reviewed. Patients enrolled in trials or without follow-up were excluded. Types of chemotherapy, the College of American Pathologists pathologic tumor response, and medical oncology plans were recorded. RESULTS: Forty-one patients met inclusion criteria. Pathologic review of treatment effect demonstrated that 3 patients (7.3%) had complete pathologic response, 3 (7.3%) had near complete pathologic response, 16 (39%) had partial response, and 14 (34.1%) had poor/no response to neoadjuvant chemotherapy. Fourteen of the 30 patients with partial or poor response (46.7%) received an alternate adjuvant regimen. Pathologic response to neoadjuvant chemotherapy specifically guided therapy in 11 (30.5%) patients. CONCLUSIONS: Despite 73.1% of patients with partial or poor response to neoadjuvant chemotherapy, only 46.7% received a different adjuvant regimen. Medical oncologists infrequently considered treatment effect when choosing adjuvant therapy. Pathologic response to neoadjuvant chemotherapy should be considered when selecting adjuvant chemotherapy.

Intratumoral heterogeneity and clonal evolution in liver cancer.

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.

Staging gallbladder cancer with lymphadenectomy: the practical application of new AHPBA and AJCC guidelines.

BACKGROUND: Current guidelines recommend harvesting a total lymph node count (TLNC) ≥6 from portal lymphadenectomy in ≥pT1b gallbladder cancers (GBC) for accurate staging and prognostication. This study aimed to determine nodal yields from portal lymphadenectomy and identify measures to maximize TLNC. METHODS: We retrospectively reviewed all ≥pT1b GBC which underwent resection with curative intent including portal lymphadenectomy at our specialized HPB center from 2007 to 2017. We compared outcomes of TLNC < 6 and TLNC ≥ 6 cohorts and determined factors predictive of TLNC. RESULTS: Of 92 patients, 20% had a TLNC ≥ 6 (IQR 7-11) and 9% had no nodes found on pathology. Malignant lymphadenopathy was twice as common in TLNC ≥ 6 as TLNC < 6 (p = 0.003) most frequently from portal, cystic and pericholedochal stations. On logistic regression analysis, concomitant liver resection was an independent predictor of higher TLNC [4b/5 wedge resection (OR 0.166, CI 0.057-0.486, p = 0.001) extended hepatectomy (OR 0.065, CI 0.012-0.340, p = 0.001)]; biliary resection and en bloc adjacent organ resection were not. CONCLUSION: At our center, prior to current guidelines, a TLNC≥6 was not met in 80% undergoing portal lymphadenectomy for ≥ pT1b GBC. To increase nodal yield, future guidelines should consider including additional lymph node stations and incorporation of frozen section analysis.

A pilot systematic genomic comparison of recurrence risks of hepatitis B virus-associated hepatocellular carcinoma with low- and high-degree liver fibrosis.

BACKGROUND: Chronic hepatitis B virus (HBV) infection leads to liver fibrosis, which is a major risk factor in hepatocellular carcinoma (HCC) and an independent risk factor of recurrence after HCC tumor resection. The HBV genome can be inserted into the human genome, and chronic inflammation may trigger somatic mutations. However, how HBV integration and other genomic changes contribute to the risk of tumor recurrence with regards to the different degree of liver fibrosis is not clearly understood. METHODS: We sequenced mRNAs of 21 pairs of tumor and distant non-neoplastic liver tissues of HBV-HCC patients and performed comprehensive genomic analyses of our RNAseq data and public available HBV-HCC sequencing data. RESULTS: We developed a robust pipeline for sensitively identifying HBV integration sites based on sequencing data. Simulations showed that our method outperformed existing methods. Applying it to our data, 374 and 106 HBV host genes were identified in non-neoplastic liver and tumor tissues, respectively. When applying it to other RNA sequencing datasets, consistently more HBV integrations were identified in non-neoplastic liver than in tumor tissues. HBV host genes identified in non-neoplastic liver samples significantly overlapped with known tumor suppressor genes. More significant enrichment of tumor suppressor genes was observed among HBV host genes identified from patients with tumor recurrence, indicating the potential risk of tumor recurrence driven by HBV integration in non-neoplastic liver tissues. We also compared SNPs of each sample with SNPs in a cancer census database and inferred samples' pathogenic SNP loads. Pathogenic SNP loads in non-neoplastic liver tissues were consistently higher than those in normal liver tissues. Additionally, HBV host genes identified in non-neoplastic liver tissues significantly overlapped with pathogenic somatic mutations, suggesting that HBV integration and somatic mutations targeting the same set of genes are important to tumorigenesis. HBV integrations and pathogenic mutations showed distinct patterns between low and high liver fibrosis patients with regards to tumor recurrence. CONCLUSIONS: The results suggest that HBV integrations and pathogenic SNPs in non-neoplastic tissues are important for tumorigenesis and different recurrence risk models are needed for patients with low and high degrees of liver fibrosis.

Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents.

Based on our previous identification of a disubstituted aminothiazole termed HBF-0079 with promising selective toxicity for HCC-derived cell lines versus non-HCC liver lines, a series of tri-substituted aminothiazole derivatives were prepared and evaluated. This work resulted in the discovery of isopropyl 4-(pyrazin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate, 14, which displayed EC50 value of 0.11µM and more than 450times of selectivity, and its methyl carbonate prodrug 24 with improved solubility in organic solvents. Furthermore, 14, was shown to reduce the proliferation of several liver cancer cells derived directly from patients.

Impact of non-neoplastic vs intratumoural hepatitis B viral DNA and replication on hepatocellular carcinoma recurrence.

BACKGROUND: This study aims to determine the impact of intracellular hepatitis B virus (HBV) DNA, covalently closed circular DNA (cccDNA) and viral replicative activity in both tumour and non-neoplastic liver on prognosis and to determine the relationship of viral replicative activity and Ishak fibrosis in predicting outcome following resection. METHODS: A total of 99 prospectively enrolled patients treated with primary liver resection for HBV-HCC are included. Intracellular HBV DNA and cccDNA were quantitated by real-time PCR. The RNA-sequencing (RNA-seq) was performed in a subset of 21 patients who had either minimal liver fibrosis (Ishak stages 0-2) or end-stage fibrosis (Ishak stage 6). RESULTS: Tumour tissue contained a lower cccDNA copy number compared with paired non-neoplastic liver, and larger tumours (>3 cm) had less cccDNA compared with small tumours (⩽3 cm). High viral replicative activity in non-neoplastic liver was associated with higher HCC recurrence rate independent of Ishak fibrosis stage. Genes correlated with viral replicative activity in non-neoplastic liver (620 genes) were distinct from those associated with end-stage fibrosis (1226 genes). Genes associated with viral replicative activity were preferentially distributed in regions on chr3, chr16 and chr19. CONCLUSIONS: Viral replicative activity in non-neoplastic liver is associated with HCC recurrence through mechanisms that are distinct from and independent of Ishak fibrosis stage.

Autologous Tumor Cell Lysate-Loaded Dendritic Cell Vaccine Inhibited Tumor Progression in an Orthotopic Murine Model for Hepatocellular Carcinoma.

The immune status of the tumor microenvironment influences tumor progression, and hepatocellular carcinoma (HCC) with an immunosuppressive signature often is associated with a poor prognosis. This study examined the impact of a bone marrow-derived dendritic cell (DC) vaccine loaded with autologous tumor cell lysate on tumor progression and the tumor microenvironment using an orthotopic murine HCC model. An orthotopic murine HCC was established by implantation of Hepa1-6 cells in the liver. The impact of DC vaccine loaded with Hepa1-6 cell lysate on tumor progression, survival, and tumor-infiltrating lymphocytes and cytokines was examined. Treating mice with DC vaccine loaded with Hepa1-6 cell lysate inhibited the progression of murine HCC generated through orthotopic implantation of Hepa1-6 cells and resulted in a 90 % survival rate by day 60 compared with a survival rate lower than 5 % for untreated mice. This anti-tumor response was associated with inhibition of STAT3 phosphorylation within the tumor. The DC vaccine reduced accumulation of Foxp3+CD4+ regulatory T cells within the tumor microenvironment and prevented TGF-ß production from the tumor tissue. Tumor cell lysate-loaded DC vaccine prevented HCC progression in a clinically relevant orthotopic murine HCC model. The effect of DC vaccine on the accumulation of Foxp3+CD4+ regulatory T cells within the tumor microenvironment and on the production of TGF-ß suggests that tumor regression by DC vaccination may be associated with an altered immunosuppressive tumor microenvironment.

Prognostic Role of Immune Cells in Hepatitis B-associated Hepatocellular Carcinoma Following Surgical Resection Depends on Their Localization and Tumor Size.

This study aims to evaluate localized expression of CD4, interleukin (IL)-17, Foxp3, and CD8 in hepatitis B-associated hepatocellular carcinoma (HBV-HCC) and to explore their potential effects on outcome following surgical resection. This prospective study includes 66 HBV-HCC surgical resection patients enrolled from 2008 to 2013. CD4, IL-17, Foxp3, and CD8 mRNA in 4 regions of the resection specimens (center of the tumor, periphery of the tumor, non-neoplastic liver bordering tumor, non-neoplastic liver distant from tumor) was quantitated using real-time polymerase chain reaction. The tumoral regions had lower CD4 and CD8 expression as compared with paired non-neoplastic regions, whereas the expression of IL-17 and Foxp3 did not differ. High Foxp3 in all regions except non-neoplastic liver distant from tumor was associated with poor overall survival, whereas low CD8 expression in distant non-neoplastic liver may be associated with high HCC recurrence rate. Although the expression of almost all molecules did not differ between small (≤3 cm) and large HCC (>3 cm), high IL-17 in periphery of tumor, high CD8 in center of tumor, or low CD8 in distant non-neoplastic liver was associated with high HCC recurrence rate in patients with small HCC, but not in those with large HCC. The effect of immune cells on HCC progression therefore depends on the expression level, localization, and tumor size, and an imbalance toward regulatory T cells is associated with poor outcome.

Serum hepatitis B surface antigen correlates with tissue covalently closed circular DNA in patients with hepatitis B-associated hepatocellular carcinoma.

Quantitation of hepatitis B surface antigen (HBsAg) in hepatitis B-associated hepatocellular carcinoma (HBV-HCC) remains to be clearly defined. This study aims to determine the association of HBsAg quantity with intrahepatic HBV viral load and activity in both tumor and non-neoplastic liver of HBV-HCC patients. Data were obtained from 89 prospectively enrolled patients treated with primary liver resection for HBV-HCC at a single Western institution (2008-2013). Circulating HBsAg was quantitated using ELISA. HBV DNA, covalently closed circular (cccDNA) and precore-pregenomic RNA (preC-pgRNA) in both tumor and non-neoplastic liver were quantitated by real-time PCR from fresh liver resection specimens. Circulating HBsAg was detectable in all 89 patients. HBsAg negatively correlated with age, and positively correlated with pre-operative serum AFP and ALT levels. HBsAg correlated with HBV cccDNA copy number in tumor or non-neoplastic liver tissue. It also correlated with preC-pgRNA copy number in non-neoplastic liver tissue. HBsAg did not correlate with serum HBV DNA, total intrahepatic HBV DNA, viral replicative activity or transcriptional activity. In HBV-HCC patients, HBsAg levels correlated with cccDNA copy number in tumor or non-neoplastic liver tissue, suggesting that a greater pool of cccDNA is associated with a higher rate of HBsAg production.

The Severity of Liver Fibrosis Influences the Prognostic Value of Inflammation-Based Scores in Hepatitis B-Associated Hepatocellular Carcinoma.

BACKGROUND: This study was designed to evaluate the prognostic value of three systemic inflammation markers, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and prognostic nutritional index (PNI), for hepatocellular carcinoma (HCC) associated with hepatitis B (HBV). METHODS: This analysis included 234 HBV-HCC patients who underwent primary surgical resection at the Mount Sinai Medical Center between 1988 and 2013. Serum albumin and circulating neutrophil, lymphocyte, and platelet counts immediately before surgery were obtained to calculate NLR, PLR, and PNI. RESULTS: Patients with larger tumor size (>3 cm) had higher NLR, higher PLR, and lower PNI. Stratified analysis showed that the impact of three markers on outcome depends on the severity of liver fibrosis. High NLR, high PLR, or low PNI was associated with poor outcome only in patients without end-stage fibrosis (Ishak stage 0-5) and not in those with cirrhosis (Ishak stage 6). Multivariate analysis in Ishak stage 0-5 patients showed that only high NLR was associated with poor outcome independent of tumor size. Of the three markers, only NLR correlated with PD-L1 expression in center of tumor, but not in nonneoplastic liver. CONCLUSIONS: The prognostic value of these three markers following surgery was only significant for HBV-HCC patients without end-stage fibrosis, and among the three markers, only NLR remained a significant prognostic indicator independent of tumor size. The correlation of NLR with intratumoral PD-L1 expression raises a hypothesis for shared pathways leading to PD-L1-mediated local tolerance within tumor and systemic inflammatory responses represented by elevated NLR in HBV-HCC.

An Unusual Course of Metastatic Gastroesophageal Cancer.

We are reporting on a case of a 41-year-old woman who presented with metastatic gastroesophageal junction cancer and who achieved prolonged survival with a multimodal treatment approach. After initially experiencing robust response to chemotherapy, she was treated for distant recurrence with palliative radiation to the gastrohepatic and supraclavicular lymph nodes and subsequently, given her unusual near-complete response, with reirradiation to the abdomen with curative intent for residual disease. The case presented is unique due to the patient's atypical treatment course, including technically difficult reirradiation to the abdomen, and the resulting prolonged survival despite metastatic presentation.

Assessing prognostic significance of preoperative alpha-fetoprotein in hepatitis B-associated hepatocellular carcinoma: normal is not the new normal.

BACKGROUND: Hepatitis B (HBV)-associated hepatocellular carcinoma (HCC) is often associated with alpha-fetoprotein (AFP) production. Although serum AFP has been demonstrated to be a prognostic factor for patient survival, optimal cutoff levels remain unclear. METHODS: Patients with HBV-associated HCC treated by primary liver resection were prospectively followed at a single institution between 1995 and 2008. AFP level was categorized into quintiles for Kaplan­Meier analysis and multivariable Cox proportional hazards regression models. RESULTS: Best 5-year survival after surgery was observed for patients with AFP in the first quintile (1.4-4.1 ng/mL), with progressively worse outcomes for patients in each increasing quintile. AFP was associated with overall survival (HR = 1.61; 95 % CI 1.30-1.98), disease-free survival (HR = 1.26; 95 % CI 1.10-1.44), and 2-year recurrence (HR = 1.30; 95 % CI 1.07-1.57) in multivariate analysis. Noncirrhotic patients (Ishak 1-5) with AFP in quintile 1 had 94 % 5-year survival, compared with 0 % survival for patients with AFP in quintile 5 (2,332.7-327,560.0 ng/mL) and Ishak stage 6 cirrhosis. CONCLUSIONS: Preoperative serum AFP is an independent predictor of prognosis among HBV-HCC patients following surgical resection. Categorizing AFP into quintiles creates the opportunity to observe differences in outcomes even at low serum levels within the normal range. Additionally, combining AFP quintiles and fibrosis staging provides a predictive model of prognosis for HCC. Thus, even small differences in AFP within the normal range may impact prognosis and disease progression for HBV-HCC.

Peritoneal carcinomatosis in patients with gastric cancer, and the role for surgical resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The aims of this study were to create a model of peritoneal carcinomatosis in patients with gastric cancer and to evaluates outcomes in patients with gastric cancer treated using surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A single-institution cohort of patients with gastric cancer was analyzed according to the development of gastric cancer with peritoneal carcinomatosis (GCPC). Variables were evaluated using regression analysis. Kaplan-Meier analysis was used to evaluate outcomes after surgical resection, cytoreductive surgery, and HIPEC. RESULTS: Age ≤60 years and local tumor stage (T3/T4) were significantly associated with GCPC (odds ratio, 3.95 and 3.94, respectively). Thirty-six-month survival was 57% for patients without peritoneal disease and 39% for patients with GCPC. There was no significant trend of improved survival after surgical management or HIPEC. CONCLUSIONS: Age ≤60 years and T3/T4 tumor stage are risk factors for GCPC. Intermediate-term survival of patients with GCPC treated with surgical resection or cytoreductive surgery and HIPEC was not improved, though future research should address the possible benefits of aggressive approaches to the treatment of GCRC.

Impact of intrahepatic hepatitis B DNA and covalently closed circular DNA on survival after hepatectomy in HBV-associated hepatocellular carcinoma patients.

BACKGROUND: Chronic hepatitis B virus (HBV) infection induces persistent but ineffective immune activation that contributes to necroinflammation, fibrosis, and risk of hepatocellular carcinoma (HCC). This study aims to determine the relationship of intrahepatic total HBV (ih HBV) DNA and covalently closed circular DNA (cccDNA) with necroinflammation and fibrosis, and their impact on prognosis after resection in HBV HCC patients. METHODS: Data are from 111 patients treated with primary liver resection for HBV HCC at Mount Sinai, New York (1991-2008). ih HBV DNA and cccDNA were quantitated by real-time PCR. Necroinflammation was graded according to histologic activity index (HAI), and liver fibrosis was staged by the modified Ishak method. RESULTS: A total of 106 (95%) and 89 patients (80%) had detectable ih HBV DNA and cccDNA, respectively, while 43% had detectable serum HBV DNA. cccDNA made up a small proportion of ih HBV DNA (median cccDNA/ih HBV DNA ratio = 0.022). Higher levels of ih HBV DNA were associated with higher HAI and serum alanine aminotransferase (ALT), while a lower ratio of cccDNA/ih HBV DNA was associated with higher HAI, ALT, and Ishak fibrosis stage. ih HBV and cccDNA were not associated with survival, but the lowest quintile of cccDNA/ih HBV DNA ratio (<0.0024) was independently associated with poor overall survival. CONCLUSIONS: A lower cccDNA/ih HBV DNA ratio was associated with greater necroinflammation and liver fibrosis, and was independently associated with poor overall survival. Thus, intracellular virus loads and relative proportions of virus DNA reflect histologic damage in the liver and influence the clinical outcome of HBV HCC patients.