Reshaping preoperative treatment of pancreatic cancer in the era of precision medicine.

This review summarises the recent evidence on preoperative therapeutic strategies in pancreatic cancer and discusses the rationale for an imminent need for a personalised therapeutic approach in non-metastatic disease. The molecular diversity of pancreatic cancer and its influence on prognosis and treatment response, combined with the failure of 'all-comer' treatments to significantly impact on patient outcomes, requires a paradigm shift towards a genomic-driven approach. This is particularly important in the preoperative, potentially curable setting, where a personalised treatment allocation has the substantial potential to reduce pancreatic cancer mortality.

Increasing the human chorionic gonadotrophin cut-off to ≤1000 IU/l for starting actinomycin D in post-molar gestational trophoblastic neoplasia developing resistance to methotrexate spares more women multi-agent chemotherapy.

BACKGROUND: A human chorionic gonadotropin (hCG) cut-off of ≤300 IU/l for starting actinomycin D (ActD) in post-molar gestational trophoblastic neoplasia (GTN) patients developing methotrexate resistance (MTX-R) reduced the number of women needing toxic multi-agent chemotherapy (etoposide, MTX and ActD alternating weekly with cyclophosphamide and vincristine; EMA/CO) without affecting survival. Here we assess whether an increased hCG cut-off of ≤1000 IU/l spares more women EMA/CO. PATIENTS AND METHODS: All post-molar GTN patients treated with first-line methotrexate and folinic acid (MTX/FA) were identified in a national cohort between 2009 and 2016. Data collected included age, FIGO score, the hCG levels at MTX-R, and treatment outcomes. RESULTS: In total, 609 GTN patients commenced treatment with MTX/FA achieving a complete response in 57% (348/609). Resistance developed in 25.1% (153/609) at an hCG ≤ 1000 IU/l and switching to ActD achieved remission in 92.8% without any major toxicity with the remaining 7.2% remitting on EMA/CO. Comparative analysis of patients switching at an hCG <100 versus 100-300 versus 300-1000 IU/l revealed a significant fall in the cure rate with second-line ActD from 97% (93/96) to 87% (34/39) to 78% (14/18), respectively, P = 0.009. However, by increasing the hCG cut-off from ≤300 to ≤1000 IU/l, 14 patients were spared EMA/CO chemotherapy. Moreover, in the present series, all post-molar GTN remain in remission. CONCLUSION: This study demonstrates that increasing the hCG cut-off from ≤300 to ≤1000 IU/l for choosing patients for ActD following MTX-R spares more women with GTN from the greater toxicity of EMA/CO without compromising 100% survival outcomes.

New genetic associations detected in a host response study to hepatitis B vaccine.

The immune response to hepatitis B vaccination differs greatly among individuals, with 5-10% of healthy people failing to produce protective levels of antibodies. Several factors have been implicated in determining this response, chiefly individual genetic variation and age. Aiming to identify genes involved in the response to hepatitis B vaccination, a two-stage investigation of 6091 single-nucleotide polymorphisms (SNPs) in 914 immune genes was performed in an Indonesian cohort of 981 individuals showing normal levels of anti-HBs versus 665 individuals displaying undetectable levels of anti-HBs 18 months after initial dose of the vaccine. Of 275 SNPs identified in the first stage (476 normal/372 nonresponders) with P<0.05, significant associations were replicated for 25 polymorphisms in 15 genes (503 normal/295 nonresponders). We validated previous findings (HLA-DRA, rs5000563, P-value combined=5.57 x 10(-10); OR (95%CI)=0.61 (0.52-0.71)). In addition, we detected a new association outside of the human leukocyte antigen loci region that passed correction for multiple testing. This SNP is in the 3' downstream region of FOXP1, a transcription factor involved in B-cell development (P-value combined=9.2 x 10(-6); OR (95%CI)=1.38 (1.2-1.6)).These findings might help to understand the biological reasons behind vaccine failure and other aspects of variation in the immune responses of healthy individuals.

The role of laparoscopy and laparoscopic ultrasound in the preoperative staging of pancreatico-biliary cancers--A meta-analysis.

BACKGROUND: Staging laparoscopy (SL) may prevent non-therapeutic laparotomy in patients with otherwise resectable pancreatico-biliary cancers, but evidence is inconclusive. This meta-analysis aims to ascertain the true benefit of SL. METHODS: All studies undertaking SL as a diagnostic sieve were included and data homogenised. Standard meta-analytical tools with emphasis on sensitivity testing and meta-regression to detect the cause for heterogeneity between studies were used. RESULTS: 29 studies satisfied the criteria. 3305 patients underwent SL of which 12 were incomplete. Morbidity (n = 15) and mortality (n = 1) was low. True yield of SL for pancreatic/perpancreatic cancers (PPC) was 25% (95% CI 24-27) with a Diagnostic Odds Ratio (DOR) of 104 (95% CI 48-227). Resection rate improved from 61% to 80%. For proximal biliary cancers (PBC), SL increased the curative resection rate from 27% to 50%, with true yield of 47% (95% CI 42-52) and a DOR 61 (95% CI 19-189). Sub-group analysis for detection of liver and peritoneal lesions demonstrated a sensitivity of 88% (95% CI 83-92) and 92% (95% CI 84-96) for PPC; 83% (95% CI 69-92) and 93% (95% CI 81-99) for PBC, respectively. There was no between-study heterogeneity for peritoneal lesions. However for detection of local invasion, sensitivity was low: 58% (95% CI 51-65) for PPC and only 34% (95% CI 22-47) for PBC. Meta-regression did not reveal any cause for the observed heterogeneity between studies. CONCLUSION: SL offers significant benefit to patients with resectable pancreatico-biliary cancers in avoiding non-therapeutic laparotomy and should be adopted in routine clinical practice in a judicious algorithm.