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Impaired perfusion is a hallmark of solid tumors that promotes progression, immunosuppression and treatment-resistance, and is partly caused by vascular compression from excessive extravascular stresses (Chauhan et al., 2013; Stylianopoulos et al., 2012). The extravascular stress exerted by fluid is referred to as interstitial fluid pressure (IFP) and that by solid components as solid stress (SS). IFP is near-zero in most tissues, but rises in tumors as impaired lymphatics fail to drain fluid leaking from blood vessels and IFP equilibrates with microvascular pressure (MVP) (Boucher and Jain, 1992). Due to equilibration, IFP in tumors can only transiently exceed MVP and thus cannot compress tumor vessels (Figure S1A). SS is generated as cells push and pull on their surroundings during proliferation and migration, and is transmitted by extracellular matrix (Stylianopoulos et al., 2012). SS is greatly and chronically elevated in tumors due to high cell and matrix densities, and can compress blood vessels (Figure S1A). Since the causes and consequences of elevated IFP and SS are different, strategies for alleviating these mechanical stresses are likely to be distinct. In their article, Provenzano et al. elegantly showed that hyaluronan (HA) can mechanically compress blood vessels in pancreatic ductal adenocarcinoma (PDA) (Provenzano et al., 2012). However, their proposed mechanism—that HA leads to very high IFP that collapses vessels—is not consistent with the physiology of fluid homeostasis and calls for careful assessment of IFP in PDAs. They suggest that mean IFP can reach 99 mmHg (range 75–130 mmHg), presumably higher than MVP, in the Pdx1-Cre/KrasLSL-G12D/+/p53LSL-R172H/+ (KPC) PDA model based on measurements using a piezoelectric-probe. To evaluate this, we measured IFP in KPC tumors (Figure S1B) with the wick-in-needle technique—which has been validated against the gold-standard micropipette technique (Boucher and Jain, 1992). We further measured IFP in additional PDA models, Ptf1-Cre/KrasLSL-G12D/+/p53L/+ (KPdC) and Ptf1-Cre/ROSA26-LSL-rtTA-IRES-GFP/KrasTetO-LSL-G12D/+/p53L/+ (iKPdC), which highly express HA (Figure S1E). The mean IFP was 8.1 mmHg (range 4.7–10.9 mmHg) in KPC, 3.4 mmHg (range 1.6–5.6 mmHg) in KPdC, and 6.7 mmHg (range 6.1–8.0 mmHg) in iKPdC—over an order of magnitude lower than the IFP levels reported by Provenzano et al. We also measured IFP with wick-in-needle in the tumors of four treatment-naive PDA patients (Figure S1B), and the mean IFP was 11.8 mmHg (range 6.1–16.6 mmHg). As these IFPs are in the range of typical MVPs, our established concept holds: SS compresses PDA vessels while IFP cannot. Provenzano et al. also propose that PDA IFP is not driven by equilibration with MVP because PDA vessels are non-leaky, i.e. non-permeable to macromolecules. As evidence, they state that PDA IFP measured with the piezeoelectric-probe remains elevated upon cardiac cessation, indicating that blood pressure is not driving IFP. With wick-in-needle, we found that cardiac cessation reduced IFP to zero in all three PDA models, confirming that blood pressure drives elevated IFP (Boucher and Jain, 1992). Furthermore, their hypothesis that PDA vessels are non-permeable to macromolecules is contradicted by their own data—PEGPH20, a macromolecule, clearly permeates across PDA vessels since it acts on interstitial HA. Moreover, the efficacy in PDA patients of nanoparticle-albumin-bound-paclitaxel, an FDA-approved macromolecule, also indicates that PDA vessels are somewhat leaky. We conclude that PDA IFP is indeed driven by blood pressure, and that fluid exchange between the intravascular and interstitial space in PDA facilitates equilibration of IFP and MVP as in other tumors. The discrepancy between our IFP measurements and those of Provenzano et al. may stem from their use of the piezoelectric-probe technique (Ozerdem and Hargens, 2005), which we believe suffers from artifacts coming from SS. As strong evidence for our hypothesis, Provenzano et al. measured an IFP of 10.4 mmHg (range 8–13 mmHg) in normal mouse pancreata, although normal murine tissues typically have slightly negative IFPs. Ozerdem and Hargens tested this technique against wick-in-needle in a single tumor model in two mice, but they did not carefully test for such artifacts—for example by comparing to wick-in-needle in tissues of varying matrix or cell density. We therefore compared the piezoelectric-probe technique to wick-in-needle in multiple normal murine tissues. We found that the piezoelectric-probe produces significantly higher measurements when compared with wick-in-needle (Figure S1C, D). For example, we measured pancreas IFP as -0.7 mmHg (range -0.9 – -0.5 mmHg) with wick-in-needle, whereas our pancreas measurements with the piezoelectric-probe were 9.8 mmHg (range 8.5–11.3 mmHg). This discrepancy likely occurs because the sensor in the piezoelectric-probe, unlike that in wick-in-needle, directly contacts cells and matrix allowing solid tissue components to contribute to the reading. We conclude that the piezoelectric-probe method developed by Ozerdem and Hargens—and used by Provenzano et al.—measures pressures that are higher than the actual IFP due to artifacts from solid tissue components. As demonstrated here, HA-rich desmoplasia in PDA does not produce unusually high IFP, IFP cannot compress PDA vessels, and the technique Provenzano et al. used to measure IFP actually measures a combination of IFP and SS. Meanwhile, we found that HA increases SS through storage and transmission mechanisms (Stylianopoulos et al., 2012). Thus PEGPH20 likely reduces SS, thereby decompressing vessels. Since IFP cannot compress blood vessels, we propose that the mechanism of vessel decompression by PEGPH20 is solely a reduction in SS. Importantly, therapies that alleviate SS decompress vessels and improve PDA treatment (Chauhan et al., 2013). Thus we concur that PEGPH20 has immense promise for PDA, and we hope that this Correspondence clarifies its mechanism.

IntroductionIntrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.Case presentationWe present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.ConclusionThese findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.

Objective: The aim of this study was to establish clinically relevant outcome benchmark values using criteria for pancreatoduodenectomy (PD) with portomesenteric venous resection (PVR) from a low-risk cohort managed in high-volume centers. Summary Background Data: PD with PVR is regarded as the standard of care in patients with cancer involvement of the portomesenteric venous axis. There are, however, no benchmark outcome indicators for this population which hampers comparisons of patients undergoing PD with and without PVR resection. Methods: This multicenter study analyzed patients undergoing PD with any type of PVR in 23 high-volume centers from 2009 to 2018. Nineteen outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of the centers (NCT04053998). Results: Out of 1462 patients with PD and PVR, 840 (58%) formed the benchmark cohort, with a mean age was 64 (SD11) years, 413 (49%) were females. Benchmark cutoffs, among others, were calculated as follows: Clinically relevant pancreatic fistula rate (International Study Group of Pancreatic Surgery): ≤14%; in-hospital mortality rate: ≤4%; major complication rate Grade≥3 and the CCI up to 6 months postoperatively: ≤36% and ≤26, respectively; portal vein thrombosis rate: ≤14% and 5-year survival for patients with pancreatic ductal adenocarcinoma: ≥9%. Conclusion: These novel benchmark cutoffs targeting surgical performance, morbidity, mortality, and oncological parameters show relatively inferior results in patients undergoing vascular resection because of involvement of the portomesenteric venous axis. These benchmark values however can be used to conclusively assess the results of different centers or surgeons operating on this high-risk group.

The social impact bond (SIB), at the present in Italy, is a financial instrument issued by a bank to support social initiatives in which the subscriber will receive a limited financial return on investment. As part of that performance, the social return for the community is considered as an integration of the financial performance that will replace a part of the interest rate. The first experience in Italy is represented by a bank that has issued 45 Social Bond for 472 million euros. The research analyses, on the basis of the character-ristics of the third sector in Italy, with particular reference to the financial weakness of the sector, the possible impact on the financial management process in the social enterprises by the use of SIB. Moreover, we would demonstrate that, with a well-conducted cost-benefit analysis, it is possible to construct a hypothesis of SIB in which the repayment is based on market rate. In particular, is proposed the development of a SIB with the objective of formulating hypotheses of response to the innovative following questions: Given certain cost drivers, what social outcomes would generate savings for the state budget able to fully repay the fixed costs of the SIB, to give a percentage of the benefit to the government and to ensure the repayment to investors? How to identify the timing of cash flows in order to structure a potential internal rate of return objective satisfactory for investors? Due to the lack of already developed case studies, with the technics of the business plan, we analyse the impact of SIB on social and financial performance, both from the point of view of the Public Administration and of the social enterprise, in a project of social housing introducing a remuneration rate at market level. The development of the project shows that, with the integration of the private and public perspective, it is possible to improve the social and financial performance offering an adequate interest rate and, moreover, without limit the hypothesis of SIB underwriting to the philanthropic institution.

Background Intraductal papillary mucinous neoplasms (IPMN) have been reported to be associated with concurrent, distinct pancreatic ductal adenocarcinoma (con-PDAC) in about 8% (range, 4–10%) of resected branch duct (BD) lesions. In addition, other pancreatic and ampullary tumors are occasionally diagnosed with IPMN in patients undergoing pancreatic surgery. The objective of this study is to describe the prevalence, clinicopathologic characteristics and prognosis of IPMN with concurrent pancreatic and ampullary neoplasms, especially con-PDAC. Methods The combined databases of pancreatic resections from the Massachusetts General Hospital and the Negrar Hospital, Italy, were analyzed for patients who had been diagnosed with IPMN and concurrent pancreatic or ampullary neoplasms. Results 2762 patients underwent pancreatic surgery from January 2000 to December 2012. Sixteen percent (n = 441) had pathologically confirmed IPMN and 11% of these (n = 50) had a different distinct synchronous pancreatic neoplasm. The majority of these, 62%, were con-PDAC, followed by neuroendocrine neoplasms (10%) and ampullary carcinoma (10%). Less frequently, mucinous (6%) as well as serous cystic neoplasms (6%), adenosquamous carcinoma (4%) and distal bile duct cancer (2%) were diagnosed. Among all patients with synchronous neoplasms, 66% harbored BD-IPMN, 28% combined IPMN and 6% main duct IPMN. Abdominal pain and/or jaundice were the leading symptoms in half of patients. Conclusion IPMN, mainly BD-IPMN, are associated with con-PDAC in about 7% of patients and account for 62% of all concurrent pancreatic/ampullary neoplasms. Other synchronous neoplasms may be found sporadically with IPMN without a suspected association.

IMPORTANCE: Sarcopenia and sarcopenic obesity have been associated with poor outcomes in unresectable pancreatic cancer (PC). Neoadjuvant treatment (NT) is used increasingly to improve resectability; however, its effects on fat and muscle body composition have not been characterized. OBJECTIVES: To evaluate whether NT affects muscle mass and adipose tissue in patients with borderline resectable PC (BRPC) and locally advanced PC (LAPC) and determine whether there were potential differences between patients who ultimately underwent resection and those who did not. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study conducted at 4 academic medical centers, 193 patients with BRPC and LAPC undergoing surgical exploration after NT who had available computed tomographic scans (both at diagnosis and preoperatively) and confirmed pancreatic ductal adenocarcinoma were evaluated. The study was conducted from January 2013 to December 2015. Data analysis was performed from September 2016 to May 2017. Measurement of body compartments was evaluated with volume assessment software before and after NT. A radiologist blinded to the patient outcome assessed the areas of skeletal muscle, total adipose tissue, and visceral adipose tissue through a standardized protocol. EXPOSURES: Receipt of NT. MAIN OUTCOMES AND MEASURES: Achievement of pancreatic resection at surgical exploration after the receipt of NT. RESULTS: Of the 193 patients with complete radiologic imaging available after NT, 96 (49.7%) were women; mean (SD) age at diagnosis was 64 (11) years. Most patients received combined therapy with fluorouracil, irinotecan, oxaliplatin, leucovorin, and folic acid (124 [64.2%]) and 86 (44.6%) received chemoradiotherapy as well. The median interval between pre-NT and post-NT imaging was 6 months (interquartile range [IQR], 4-7 months). All body compartments significantly changed. The adipose compound decreased (median total adipose tissue area from 284.0 cm(2); IQR, 171.0-414.0 to 250.0 cm(2); IQR, 139.0-363.0; P

The Third Sector in Italy records a slow but consta nt growth due to the increase of the number of enti ties but not of their dimension. The difficulties in fin ancial management, generated by a low attraction of debt and equity financial resources and a low level of m anagerial skills characterized the non profit organizations. Focused on the social cooperatives, the article describe the effects on the financial s tructure of innovative financial instruments as the particip ative loan. In the last years in Italy there has be en an increasing attention towards the ethical finance. T he consideration of the social co-ops as a part of the Third Sector allows them to have a privileged interlocuti on with the institutions of the ethical finance. Bu t the development of this institutions, although it is or iginated from the will to support the social respon sible development, at the moment seems not to support a substantial resolution of the financial needs relate d to the management of the social cooperatives. The arti cle shows an analysis on a particular financial intermediary, the Cooperazione Finanza Impresa (CFI). This institution is a private equity investor wh ich since twenty years is dedicated to worker cooperati ves and social cooperatives. The interest for this institution, besides the entities financed, is base d on a particular form of participative loan develo ped. The investigation start from the observation of a singu lar social cooperatives with the elaboration of a s et of indicators based on the financial ratio analysis. T he evaluation regard the financial structure previo us to the financing operation and its subsequent modification . Due to the first conclusions, the investigation enlarged the analysis to a sample of 10 social cooperatives in order to confirm the first results. The observat ion of modified financial structure up a period of five ye ars shows significative positive change that suppor t both the economic and the financial equilibrium, with a significant reduction of the average cost of the de bt in all the cooperatives financing by participative loans.

Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are being increasingly recognized, and often harbor cancer. Lymph node metastases are an important prognostic factor for patients with invasive intraductal papillary carcinoma (I-IPMC), but the role of lymph node ratio (LNR) in predicting survival after surgery for I-IPMC is unknown.Methods: The combined databases from the Surgical Department of Massachusetts General Hospital of Boston and the University of Verona were queried. We retrospectively reviewed clinical and pathologic data of all patients with resected, pathologically confirmed, I-IPMC between 1990 and 2007. Univariate and multivariate analysis were performed.Results: I-IPMCs were diagnosed in 104 patients (55 males and 49 females), median age was 69 years. Recurrent disease was identified in 49 patients (47.1%) and the median 5-year disease specific survival (DSS) was 60.1%. The median number of resected/ evaluated nodes was 15 (range, 5-60). There were 60 (57.7%) patients who had negative lymph nodes (N0), whereas 44 (42.3%) had lymph node metastases (N1). Patients with lymph node metastases had a shorter 5-year DSS (28.9%) compared with patients with negative lymph nodes (80.3%; P < 0.05) As the LNR increased, 5-year DSS decreased (LNR = 0, 86.5%; LNR >0 to 0.2, 34.4%; LNR >0.2, 11.1%; P < 0.05). On multivariate analysis, LNR, the presence of a family history of pancreatic cancer and a preoperative value of Ca 19.9 > 37 U/L were significant predictors of survival (P < 0.05).Conclusions: Lymph node ratio is a strong predictor of survival after resection for invasive intraductal papillary mucinous carcinoma.