No abstract

The management of hepatocellular carcinoma (HCC) remains challenging due to late presentation and the presence of accompanying liver dysfunction. As such, most patients are not eligible for curative resection and liver transplant. Management in this scenario depends on a number of factors including hepatic function, tumor burden, patency of hepatic vasculature and patients' functional status. Based on these, patients can be offered catheter based intra-arterial therapy for intermediate stage disease and in more advanced disease, sorafenib. Given recent data, regorafenib is now an option following failure of sorafenib.Catheter directed intra-arterial therapy takes advantage of tumor hypervascularity and the unique dual blood supply of the liver, as hepatic tumors receive arterial perfusion via the hepatic artery while the rest of the liver is supplied by the portal vein. This allows selective embolization and delivery of chemotherapeutic agents to the tumor. Compared to best supportive care, intra-arterial therapy offers a survival benefit in intermediate stage HCC and is the recommended approach for treatment. None of the catheter based approaches; including bland embolization, conventional trans-arterial chemoembolization (cTACE), drug eluting bead trans-arterial chemoembolization (DEB-TACE) or trans-arterial radioembolization (TARE) offers a clear advantage over the other, although DEB-TACE may be characterized by less systemic toxicity. All of these approaches are contraindicated in patients with portal vein thrombosis (PVT). On the other hand, intraarterial, radio embolization, with Yttrium-90 (Y90) can be offered to patients with PVT. The place of this modality in management of HCC is still being investigated. The role of sorafenib in advanced HCC is not in doubt, as until recently, it was the only systemic therapy approved for the management in this setting. This is despite multiple trials evaluating other agents. The addition of sorafenib to catheter-based therapy in intermediate stage disease has also failed to show any benefit. The modest survival benefit with sorafenib and the failure of other targeted agents suggest that it is important to look beyond inhibition of angiogenesis in advanced HCC. Identification of key drivers and mediators of HCC remains paramount for successful drug development. In line with this, it is refreshing that the excitement that has followed developments in cancer immunotherapy is finding its way to HCC with early trials of anti-PD1 monoclonal antibodies showing sufficient activity that phase III trials are now ongoing for Pembrolizumab and Nivolumab in advanced HCC. Future drug development efforts will focus on defining the feasibility of combining different treatment approaches targeting multiple important modulators of HCC.

No abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan-Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 ( = 7), BRCA2 ( = 5), PALB2 ( = 3), MSH2 ( = 1), and FANCF ( = 1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), 0.29-1.14; log-rank = 0.08]. Multivariate logistic (OR, 1.47; 95% CI, 1.04-2.06; = 0.04) and Cox regression (HR, 0.37; 95% CI, 0.15-0.94; = 0.04) showed presence of DDR gene mutations was associated with improved OS. In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.

Pemetrexed is an active agent in this heavily pretreated population of patients with recurrent thymic malignancies, especially thymoma.

Background Only a few patients with pancreatic ductal adenocarcinoma (PDAC) recurring after curative resection and peri-operative (neoadjuvant and adjuvant) therapy are included in clinical trials of metastatic PDAC. As such, there is a paucity of data to guide treatment after relapse, and patients are treated similarly to those with de novo metastatic PDAC (mPDAC). We evaluated the patterns of chemotherapy use and over-all survival (OS) in patients with recurrent PDAC (rPDAC) following curative therapy. Methods In this retrospective study, the Indiana University pancreatic cancer database was used to identify patients with PDAC who underwent curative resection and subsequently developed recurrence. Demographics, tumor and treatment characteristics were collected. Patients were broadly divided into those who received chemotherapy for rPDAC and those who did not. Patients in the former category were further subdivided into those who received single agent therapy, any standard combination therapy (5-fluorouracil/irinotecan/oxaliplatin combination or gemcitabine/nab-paclitaxel) and those who received non-standard combinations. Survival analysis was performed by the Kaplan-Meier method. Log rank tests were used to determine differences in survival between treated rPDAC patients and those not treated. Cox regression analysis was employed to evaluate factors associated with OS. Results We identified 435 patients with resected PDAC treated between 2008 and 2014. Two hundred and twenty-three patients (51.2%) were diagnosed with rPDAC. Of these, 140 patients (63%) received chemotherapy whereas 71 patients (32%) did not receive chemotherapy. The 74 patients (53%) who received any standard, approved multiagent combination regimen had a median OS of 14 months compared to 8 months for the 47 patents (34%) who received other non-standard combinations and the 19 (13%) who received single agent therapy ( P = 0.029). Multivariate cox regression analysis showed that margin negative resection, peri-operative therapy, radiotherapy and the use of any chemotherapy for rPDAC were associated with improved OS. Conclusion Our findings support the use of standard approved multi-agent therapy in rPDAC. Patients derive significant benefit from these standard combination therapies with median OS that is comparable to what is observed with treatment for de novo mPDAC. Electronic supplementary material The online version of this article (10.1186/s12885-019-5630-4) contains supplementary material, which is available to authorized users.

No abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive disease with poor survival rates and limited treatment options. Upregulation of αvβ6 integrins within the alveolar epithelial cells is a characteristic feature of IPF and correlates with poor patient survival. The pro-fibrotic cytokine TGFβ1 can upregulate αvβ6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous TGFβ1 increases expression of the integrin β6 subunit gene (ITGB6) and αvβ6 integrin cell surface expression in a time- and concentration-dependent manner. TGFβ1-induced ITGB6 expression occurs via transcriptional activation of the ITGB6 gene, but does not result from effects on ITGB6 mRNA stability. Basal expression of ITGB6 in, and αvβ6 integrins on, lung epithelial cells occurs via homeostatic αvβ6-mediated TGFβ1 activation in the absence of exogenous stimulation, and can be amplified by TGFβ1 activation. Fundamentally, we show for the first time that TGFβ1-induced ITGB6 expression occurs via canonical Smad signalling since dominant negative constructs directed against Smad3 and 4 inhibit ITGB6 transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the ITGB6 promoter abolishes TGFβ1-induced ITGB6 transcriptional activity. Using chromatin immunoprecipitation we demonstrate that TGFβ1 stimulation of lung epithelial cells results in direct binding of Smad3, and Smad4, to the ITGB6 gene promoter within this region. Finally, using an adenoviral TGFβ1 over-expression model of pulmonary fibrosis we demonstrate that Smad3 is crucial for TGFβ1-induced αvβ6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of αvβ6 integrin activated TGFβ1-induced ITGB6 gene expression regulates epithelial basal αvβ6 integrin expression, and demonstrates that this occurs via Smad-dependent transcriptional regulation at a single Smad binding site in the promoter of the β6 subunit gene. Active TGFβ1 amplifies this pathway both in vitro and in vivo, which may promote fibrosis.