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.

ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer.

BACKGROUND: Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial. MATERIALS AND METHODS: To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term 'HRD test'; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC. RESULTS: A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype. CONCLUSIONS: Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.

Defining the molecular pathology of pancreatic body and tail adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

Pancreatic cancer genomics: where can the science take us?

The incidence of pancreatic ductal adenocarcinoma (PDAC) is steadily increasing and the annual death-to-incidence ratio approaches one. This is a figure that has not changed for several decades. Surgery remains the only chance of cure; however, only less than 20% of patients are amenable to operative resection. Despite successful surgical resection, the majority of the patients still succumb to recurrent metastatic disease. Therefore, there is an urgent need to develop novel therapeutic strategies and to better select patients for current therapies. In this review, we will discuss current management by highlighting the landmark clinical trials that have shaped current care. We will then discuss the challenges of therapeutic development using the current randomized-controlled trial paradigm when confronted with the molecular heterogeneity of PDAC. Finally, we will discuss strategies that may help to shape the management of PDAC in the near future.

Adjuvant chemotherapy in elderly patients with pancreatic cancer.

BACKGROUND: Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer. METHODS: We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative. RESULTS: The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P<0.0001). Older patients (aged ≥70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8%; P<0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27-2.78, P=0.002). CONCLUSION: Patients aged ≥70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer.

The prognostic and predictive value of serum CA19.9 in pancreatic cancer.

BACKGROUND: Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 (CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used. METHODS: We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC. RESULTS: By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P=0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels>90 U/ml did not benefit from adjuvant chemotherapy (P=0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P=0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P=0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%. CONCLUSIONS: Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.

Endoscopic submucosal dissection or transanal endoscopic microsurgery for nonpolypoid rectal high grade dysplasia and submucosa-invading rectal cancer.

BACKGROUND AND STUDY AIMS: Transanal endoscopic microsurgery (TEM) has been shown to be highly effective for early rectal cancer, and endoscopic submucosal dissection (ESD) has been introduced to treat noninvasive colorectal neoplasia. The aim of this study was to compare the outcomes of ESD and TEM for superficial early rectal cancer. PATIENTS AND METHODS: We retrospectively analyzed 63 patients with nonpolypoid rectal high grade dysplasia or submucosa-invading cancer who were treated with ESD or TEM, and compared clinical outcomes and safety between the treatment groups. RESULTS: 30 patients underwent ESD and 33 underwent TEM. For ESD compared with TEM, en bloc resection rates were 96.7% vs. 100% (P = 0.476) and R0 resection rates were 96.7 % vs. 97.0 % (P = 1.000). There were no cases of local recurrence or distant metastasis in either group. Antibiotics were required in 11 patients (36.7%) in the ESD group and 33 (100%) in the TEM group (P < 0.001). There was no difference in net procedure time although ESD was associated with shorter total procedure time and hospital stay than TEM, with mean (standard deviation [SD]) 84.0 (51.2) vs. 116.4 (58.5) min (P = 0.0023), and 3.6 (1.2) vs. 6.6 (3.5) days (P < 0.001), respectively. There were no significant differences in complications between the two groups. CONCLUSIONS: Both ESD and TEM are effective and oncologically safe for treating nonpolypoid rectal high grade dysplasia and submucosa-invading cancers. ESD has the additional advantages of minimal invasiveness and avoidance of anesthesia. Therefore, ESD could be recommended as a treatment option for superficial early rectal cancers.

Criteria for decision making after endoscopic resection of well-differentiated rectal carcinoids with regard to potential lymphatic spread.

BACKGROUND AND STUDY AIM: Rectal carcinoids are low-grade malignancies that are usually treated by endoscopic resection. However, on pathologic examination, resection margins that are positive for carcinoid cells are frequently found. Patient outcomes were reviewed after endoscopic resection of rectal carcinoids and the clinical significance of possible residual disease, as defined by pathologic and endoscopic examination, was evaluated. PATIENTS AND METHODS: The medical records and endoscopic findings of 347 patients presenting with rectal carcinoids to 14 university hospitals in Korea between January 1999 and June 2007 were retrospectively analyzed. RESULTS: A total of 304 patients were treated with endoscopic resection, and 43 patents were treated with surgery. In the endoscopic resection group, the complete resection rate was 88.2% based on endoscopic appearance (CR-E) and 60.2% based on pathologic evaluation (CR-P). The agreement between CR-E and CR-P was low (κ=0.192). No residual tumors were found in 77 of 85 patients (90.6%) who were CR-E but not CR-P and who had endoscopic biopsy taken at 24-month follow-up. The receiver-operating characteristic curve identified an optimal cut-off value of 10.5 mm, at which the sensitivity and the specificity for metastasis were 100% and 89%, respectively. The risk factors for metastasis by multivariate analysis were tumor size, increased mitotic rate, and lymphovascular invasion. CONCLUSIONS: Endoscopic resection is a safe and effective modality for treating well-differentiated rectal carcinoids smaller than 10 mm in diameter. Discrepancies were observed between CR-E and CR-P. The risk factors for metastasis were tumor size, increased mitotic rate, and lymphovascular invasion.

Endoscopic evaluation of significant gastrointestinal lesions in patients with iron deficiency with and without anaemia: a Korean Association for the Study of Intestinal Disease study.

BACKGROUND: Although endoscopy is recommended for patients with iron deficiency anaemia, there is, currently, no consensus on the role of endoscopy for iron-deficient patients without anaemia. The goal of this study was to determine the prevalence of serious gastrointestinal (GI) lesions, identified by endoscopy in patients with iron deficiency and anaemia compared with patients with iron deficiency without anaemia. METHODS: One thousand five hundred and eighteen patients with a ferritin value of or=300 mg/dL were retrospectively investigated using oesophagogastroduodenoscopy and colonoscopy between January 2005 and September 2006. The lesions identified were classified as clinically important according to standard predetermined criteria. RESULTS: Among the 1518 cases, 749 patients had anaemia and 769 had normal haemoglobin levels. Clinically important lesions were identified in 24.6% of the patients with anaemia and in 22.8% of the patients without anaemia (P > 0.05). The frequency of lower GI tract lesions (13.6 vs 11.4%, P > 0.05) and upper GI tract lesions (11.9 vs 12.5%, P > 0.05) was similar in the comparisons between the two groups. However, the frequency of malignant GI lesions was higher in the patients with anaemia (5.1 vs 0.7%, P < 0.01). In addition, the patients without anaemia were significantly more likely to have early-stage neoplasia (adenoma, early gastric cancer and Dukes' A and B colon cancer) than were the patients with anaemia (98.4 vs 52.5%, P < 0.01). CONCLUSION: The results of this study suggest that patients with iron deficiency should undergo endoscopic evaluation of the GI tract, irrespective of whether they have anaemia. The endoscopic evaluation of the GI tract in patients with iron deficiency without anaemia could provide an opportunity for the detection of early-stage neoplasia at a curable stage.

ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

Primary NK-/T-cell lymphoma of the gastrointestinal tract: clinical characteristics and endoscopic findings.

BACKGROUND AND STUDY AIMS: Primary NK-/T-cell lymphoma of the gastrointestinal tract is a very rare disease with a poor prognosis. The aim of this study was to determine the clinical and endoscopic characteristics of patients with primary gastrointestinal NK-/T-cell lymphoma. PATIENTS AND METHODS: The clinical features of 14 patients with primary gastrointestinal NK-/T-cell lymphoma and the endoscopic findings in 11 of these patients were reviewed. Their median age was 42 years (range 23-78) at the time of diagnosis. RESULTS: The initial presenting symptoms of primary gastrointestinal NK-/T-cell lymphoma were gastrointestinal bleeding (n = 6, 42%), abdominal pain (n = 4, 29%), and epigastric soreness (n = 4, 29%). The disease was at an advanced stage at the time of diagnosis: stage II in 5 patients (36%); stage III in 4 (28%); and stage IV in 5 (36%). Initial treatment was with chemotherapy (n = 8, 57%) or surgical resection (n = 5, 36%). The median survival for all patients was 9 months. On endoscopy in 11 patients, the anatomic location of the primary lesion was found to be: stomach, n = 3 (27%); esophagus, n = 2 (18%); duodenum, n = 1 (9%); and the ileocolonic area, n = 5 (46%). These lesions were ulceroinfiltrative in 4 cases (36%), ulcerative in 3 cases (27%), superficial/erosive in 3 cases (27%), and infiltrative in 1 case (9%). No prominent fungating mass was seen in any patient. CONCLUSIONS: Primary gastrointestinal NK-/T-cell lymphoma was endoscopically characterized by superficial/erosive, ulcerative, or ulceroinfiltrative lesions without fungating mass. The most common presenting symptom was gastrointestinal bleeding. Despite aggressive treatments, the prognosis was very poor.

Can we predict spontaneous capsule passage after retention? A nationwide study to evaluate the incidence and clinical outcomes of capsule retention.

BACKGROUND AND STUDY AIMS: Although capsule endoscopy has become a central diagnostic tool for small-bowel evaluation, retention of a capsule remains a major concern. This study attempted to investigate the incidence and clinical outcomes of capsule retention, and to determine the factors predictive of spontaneous capsule passage after retention. PATIENTS AND METHODS: Through a nationwide multicenter survey, we retrospectively reviewed the records of 1291 patients who had a capsule endoscopy between February 2002 and July 2006 in Korea. Clinical and procedural characteristics and postprocedural outcomes were analyzed for the cases with capsule retention. RESULTS: Capsule retention occurred in 2.5 % of total cases (32/1291). The major diseases accompanying capsule retention were Crohn's disease, malignant tumors, and tuberculous enterocolitis, in decreasing order. In 11 of the 32 patients (34.4 %), early surgical or endoscopic interventions were instituted for diagnosis or treatment of diseases before retention symptoms developed. The remaining 21 (65.6 %) patients initially received medical treatments. Of these, 10 (31.3 %) ultimately underwent surgical intervention due to the development of symptoms of intestinal obstruction or medical treatment failure. The other 11 (34.4 %) eventually passed the capsule. The presence of a larger lumen diameter (greater than two-thirds of the capsule diameter) at the stricture site was associated with spontaneous passage. CONCLUSIONS: Our large-scale study suggests that retention occurs infrequently during capsule endoscopy. Moreover, a retained capsule might indicate the best intervention for the offending pathology, or it may spontaneously pass in the long run, particularly in patients with less small bowel stricture.

Nonsurgical treatment of abdominal or pelvic abscess in consecutive patients with Crohn's disease.

BACKGROUND: There is little agreement about the efficacy of nonsurgical treatment for abscess associated with Crohn's disease. Furthermore, there is no study on characteristics of abscess or patient that nonsurgical treatment could be worth trying as initial treatment. AIMS: To evaluate the outcome of nonsurgical treatment in Crohn's disease-related abscess and identify factor leading to failure of nonsurgical treatment of this complication. PATIENTS: Twenty-four patients, who consecutively admitted for Crohn's disease-related abscess to our institution during a 7-year period, underwent nonsurgical treatment as initial therapy. METHODS: Outcome data such as recurrence and intractability, and clinical features were retrospectively analysed. Univariate analysis with patient-related factors and abscess-related factors was performed for risk factor identification. RESULTS: Median follow-up period was 47.5 months. Of the eligible patients, 19 patients were treated medically and 5 patients underwent percutaneous catheter drainage with medical treatment. Overall success rate of nonsurgical treatment in our centre was 66.7%. The cumulative recurrence rate at 7 months was 12.5%. All recurrences occurred within 7 months from complete resolution on follow-up imaging. Univariate analysis showed that the significant factors which lead to failure of nonsurgical treatment were presence of associated fistula and concurrent steroid use (P=0.019 and P=0.019, respectively). CONCLUSION: Nonsurgical treatment can be considered as initial treatment modality for the Crohn's disease-related abscess without concurrent steroid therapy or relevant fistula.

Influence of bulky side chains of amino acids on the solution conformation of peptide fragment (81-92) derivatives of CD4, TYICEVEDQKEE, as studied by NMR spectroscopy and molecular modeling.

Solution conformation of CD4 fragment 81-92 TYICEVEDQKEE and two of its benzylated analogues was determined by two-dimensional 1H NMR spectroscopy, distance geometry and simulated annealing techniques. The structures of both benzylated derivatives are similar but are distinct from that of wild-type dodecapeptide. It is concluded from structural analysis that bulky side chain(s) of amino acid(s) at an appropriate position can have a marked effect on the conformation and thus the functions of a peptide.

A helix initiation motif, XLLRA, is stabilized by hydrogen bond, hydrophobic and van der Waals interactions.

Five partially overlapping synthetic peptides containing the N-terminal portion of the leucine zipper (LZ)-like domain of human immunodeficiency virus envelope glycoprotein gp41 were used to deduce the helix initiation site. Circular dichroism (CD) data suggested a strong helix-inducing motif, LLRA. The coupling constant and nuclear Overhauser effect (NOE) results obtained from nuclear magnetic resonance experiments in 20% trifluoroethanol aqueous solution at 280 K for the four decapeptides under study suggested that the motif XLLRA, where X is a group or an amino acid residue capable of forming hydrogen bond to arginine, constitutes a helix nucleation core. A similar conclusion was reached for a pentadecapeptide in water, suggesting that the result was not dependent on both chain length and the helix promoting medium. Detailed analysis of NOE and CD data from the four decapeptides indicated that the acetyl group and asparagine had a strong tendency to be helix N-capping, in confirmation of previous studies. Molecular modeling using restraints derived from NOE data showed that van der Waals, hydrophobic interactions and hydrogen bonds contribute synergetically to the stability of the core structure. The concept of nucleation core consisting of a few amino acids may be generally applied in proton design and folding studies.

Cardiotoxin III from the Taiwan cobra (Naja naja atra). Determination of structure in solution and comparison with short neurotoxins.

The structure in solution of cardiotoxin III, a membrane toxin purified from the venom of the Taiwan cobra, Naja naja atra, is reported. Sequence-specific assignment of 1H-NMR lines was completed and the NMR data show the presence of a triple and a double-stranded antiparallel beta-sheet. Many NOE cross peaks identified in NOESY spectra were applied as distance constraints based on a hybrid distance geometry/dynamical simulated annealing technique; 20 structures were found within a single family. The average value of atomic RMS differences between the 20 structures and their geometric mean is 0.087 nm for the backbone atoms and 0.152 nm for all heavy atoms; they are 0.055 nm and 0.12 nm, respectively for the segments of secondary structure. In these selected structures the backbone of the polypeptide chain folds such that five strands emerge from a globular head. Three major loops link these strands to form a double and a triple-stranded antiparallel beta-sheet. Comparison of the structures of the toxin in solution with the X-ray crystal structure of its homologous protein, cardiotoxin V4II from Naja mossambica mossambica, showed good agreement between the structures except at segments of the turns. As the functions of short neurotoxins and cardiotoxins are distinct, despite their similar secondary structural patterns and tertiary folding, a comparative analysis has been carried out between cardiotoxin III and short neurotoxins of known structures. We discuss their structural features in order to clarify relationships between their structure and function.

Proline inhibits aggregation during protein refolding.

The in vitro refolding of hen egg-white lysozyme is studied in the presence of various osmolytes. Proline is found to prevent aggregation during protein refolding. However, other osmolytes used in this study fail to exhibit a similar property. Experimental evidence suggests that proline inhibits protein aggregation by binding to folding intermediate(s) and trapping the folding intermediate(s) into enzymatically inactive, "aggregation-insensitive" state(s). However, elimination of proline from the refolded protein mixture results in significant recovery of the bacteriolytic activity. At higher concentrations (>1.5 M), proline is shown to form loose, higher-order molecular aggregate(s). The supramolecular assembly of proline is found to possess an amphipathic character. Formation of higher-order aggregates is believed to be crucial for proline to function as a protein folding aid. In addition to its role in osmoregulation under water stress conditions, the results of this study hint at the possibility of proline behaving as a protein folding chaperone.

Sequence dependent conformation and local geometry of the conserved branch site sequence element d(TpApCpTpApApC), essential for yeast mRNA splicing, deduced from high resolution 1H-NMR.

The conserved sequence element and branch site splice signal d(TpApCpTpApApC) has been synthesized by a solid phase procedure. All the non-exchangeable protons have been assigned using a combination of one-dimensional and two-dimensional 1H-NMR analytical procedures. On the basis of the low NOE intensities in the 1D-NOE and NOESY experiments, the heptamer exists in solution as a random coil. The deoxyribose rings towards the 5' terminus exist predominantly in the S form (2'-endo-3'-exo) while residues on or adjacent to the 2' branch site in the eventual lariat structure [A(6) of TACTAAC] show more N-character (3'endo-2'-exo). In addition unique propeller twisting at contiguous AT base pairs in the consensus 5'-splice site occurs in the region in which there is partial complementarity with the branch splice signal TACTAAC. These subtle structural features, if carried over to the corresponding RNA, may have significance either as a recognition signals or for stereochemical reasons in the formation of the lariat intermediate in the maturation process of mRNA.