Prognosis Based Definition of Resectability in Pancreatic Cancer: A Road Map to New Guidelines.

OBJECTIVE: To identify objective preoperative prognostic factors that are able to predict long-term survival of patients affected by PDAC. SUMMARY OF BACKGROUND DATA: In the modern era of improved systemic chemotherapy for PDAC, tumor biology, and response to chemotherapy are essential in defining prognosis and an improved approach is needed for classifying resectability beyond purely anatomic features. METHODS: We queried the National Cancer Database regarding patients diagnosed with PDAC from 2010 to 2016. Cox proportional hazard models were used to select preoperative baseline factors significantly associated with survival; final models for overall survival (OS) were internally validated and formed the basis of the nomogram. RESULTS: A total of 7849 patients with PDAC were included with a median follow-up of 19 months. On multivariable analysis, factors significantly associated with OS included carbohydrate antigen 19-9, neoadjuvant treatment, tumor size, age, facility type, Charlson/Deyo score, primary site, and sex; T4 stage was not independently associated with OS. The cumulative score was used to classify patients into 3 groups: good, intermediate, and poor prognosis, respectively. The strength of our model was validated by a highly significant randomization test, Log-rank test, and simple hazard ratio; the concordance index was 0.59. CONCLUSION: This new PDAC nomogram, based solely on preoperative variables, could be a useful tool to patients and counseling physicians in selecting therapy. This model suggests a new concept of resectability that is meant to reflect the biology of the tumor, thus partially overcoming existing definitions, that are mainly based on tumor anatomic features.

Controversial Role of Adjuvant Therapy in Node-Negative Invasive Intraductal Papillary Mucinous Neoplasm.

BACKGROUND: Adjuvant chemotherapy and/or chemoradiation [chemo(radiation)] is considered the standard of care for resected patients with pancreatic adenocarcinoma. However, invasive carcinoma arising from an intraductal papillary mucinous neoplasm (IPMN) seems to have different biologic behavior and prognosis. Retrospective data suggest a survival benefit of adjuvant chemo(radiation) for resected invasive IPMNs with metastatic nodal disease; however, it is unclear whether this remains valid for node-negative patients. PATIENTS AND METHODS: To compare the outcome of patients with invasive IPMNs who received adjuvant chemo(radiation) with that of those treated with surgery alone, we queried the National Cancer Database regarding data of patients who underwent pancreatic resection for invasive IPMN between 2006 and 2015. A propensity score analysis was conducted to balance covariates between treatment groups. RESULTS: For the study, 492 patients were eligible, of whom 267 (54.3%) received adjuvant chemo(radiation). Estimated 1- and 3-year overall survival rates were 88.9% and 73.5% versus 93.2% and 72.8% for patients who did or did not receive adjuvant chemo(radiation), respectively. Among patients with negative nodal stage, there was no difference in overall survival between patients who received versus patients who did not receive adjuvant chemo(radiation) (P = 0.973). In contrast, among patients with positive nodal disease, those who received adjuvant chemo(radiation) had significantly better OS compared with those who did not (P = 0.001). CONCLUSIONS: In patients with resected invasive IPMNs, adjuvant chemo(radiation) was associated with significantly improved overall survival only in presence of nodal metastases. This finding can help clinicians to select adjuvant treatment in a patient-tailored fashion.

Vitamin D status in primary hyperparathyroidism: a Southern European perspective.

BACKGROUND: Vitamin D deficiency (VDD) is common in patients with primary hyperparathyroidism (pHPT), and this could affect the clinical expression of the disease. However, few North American or North European studies have addressed this issue, showing vitamin D repletion in only about one-third of the patients. SUBJECTS AND METHODS: Vitamin D status was evaluated both in an observational study in a series of 206 consecutive patients with pHPT at diagnosis and in a case-control analysis with 113 age- and sex-matched healthy blood donors. Vitamin D status was assessed by measuring plasma 25-hydroxy-vitamin D (25OHD) levels and was defined as VDD or severe VDD if 25OHD was <20 ng/ml (<50 nm) and <10 ng/ml (<25 nm), respectively. RESULTS: No seasonal variability was observed in 25OHD levels. VDD was observed in 75 of 206 patients (36·4%). The VDD was severe in 24 of 75 patients (11·7%). There was no difference in prevalence of VDD between men and women nor between asymptomatic and 'bone and stone' symptomatic patients. 25OHD levels was negatively correlated with parathyroid hormone, ionized calcium, and bone turnover markers, and positively correlated with phosphate. 25OHD levels were also positively correlated with bone mineral density at all sites measured. In the case-control study, the overall prevalence of VDD and severe VDD was higher in patients with pHPT compared with controls (33·6% vs 10·6%, P < 0·0001, and 8·8% vs 1·8%, P = 0·0337, respectively). CONCLUSIONS: Our study shows that VDD occurs in about one-third of patients with pHPT resident in a Southern European area, a lower figure than previously reported. Moreover, VDD is related to a more severe bone disease, and its prevalence is higher in patients with pHPT than in healthy matched subjects.

Central pancreatectomy with inframesocolic pancreatojejunostomy.

PURPOSE: Pancreatic fistula (PF) occurs frequently after central pancreatectomy (CP), but it is not clear from which pancreatic stump it arises and, consequently, which interventions can reduce its incidence and severity. The information could be obtained if the two pancreatic remnants were segregated into different body compartments. METHODS: In eight consecutive patients, the cut end of the distal pancreatic stump after CP was brought in the inframesocolic compartment through a small defect created in the transverse mesocolon. Pancreatojejunostomy was hence constructed in the intraperitoneal compartment, being divided by the retroperitoneal right-sided pancreatic stump by the transverse mesocolon itself. Five patients were operated on open, and three by robot-assisted laparoscopy. PF was defined according to the criteria proposed by the International Study Group on Pancreatic Fistula. RESULTS: PF fistula developed in five out eight patients (three grade A and two grade B). Amylase concentration in the fluid obtained from surgical drains showed that the two pancreatic remnants were actually segregated into different body compartments and that four out of five PF originated from the right remnant. Mean hospital stay was 12.5 days. No patient was readmitted, developed peripancreatic fluid collections, required interventional radiology procedures, or underwent repeat surgery. CONCLUSIONS: In CP, interposing an anatomic barrier, such as the transverse mesocolon, between the two pancreatic remnants is a simple maneuver that, if on one hand, adds little to the complexity of the operation, on the other, provides insights into the origin of PF after CP.

Current perspectives on laparoscopic robot-assisted pancreas and pancreas-kidney transplantation.

Pancreas transplant recipients continue to suffer high surgical morbidity. Current robotic technology provides a unique opportunity to test whether laparoscopy can improve the post-operative course of pancreas transplantation (PT). Current knowledge on robotic pancreas and renal transplantation was reviewed to determine feasibility and safety of robotic PT. Information available from literature was included in this review, together with personal experience including three PT, and two renal allotransplants. As of April 2011, the relevant literature provides two case reports on robotic renal transplantation. The author's experience consists of one further renal allotransplantation, two solitary PT, and one simultaneous pancreas-kidney transplantation. Information obtained at international conferences include several other renal allotransplants, but no additional PT. Preliminary data show that PT is feasible laparoscopically under robotic assistance, but raises concerns regarding the effects of increased warm ischemia time on graft viability. Indeed, during construction of vascular anastomoses, graft temperature progressively increases, since maintenance of a stable graft temperature is difficult to achieve laparoscopically. There is no proof that progressive graft warming produces actual damage to transplanted organs, unless exceedingly long. However, this important question is likely to elicit a vibrant discussion in the transplant community.

Prognostic implications of tumor invasion or adhesion to peripancreatic vessels in resected pancreatic cancer.

BACKGROUND: The purpose of this study was to evaluate the operative risk and the prognostic implications of pancreatectomy plus resection and reconstruction of peripancreatic vessels (PPV) in patients with pancreatic adenocarcinoma. METHODS: One hundred ten patients who underwent pancreatectomy with PPV resection and reconstruction (Study Group; SG) were retrospectively compared with 62 patients without distant metastasis who were palliated, (Control Group 1; CG-1), as well as 197 patients who underwent "conventional"pancreatectomy (Control Group 2; CG-2). RESULTS: Postoperative morbidity and mortality were similar in SG (33% and 3%), in CG-1 (26% and 3%), and in CG-2 (40% and 6%) patients. Median survival time (MST) of SG patients (15 months) was longer than that of CG-1 patients (6 months; P < .0001) and similar to that of CG-2 patients (18 months). Patients undergoing isolated venous resection (n = 84) had the best outcome (MST: 15 months) ( P < .0001 vs CG-1 patients), while patients undergoing resection of multiple PPV (n = 14) had the worst outcome (MST: 8 months). PPV infiltration, histologically proven in 64 patients (65%), was associated with decreased MST only if the tunica intima was infiltrated (26%) (11 months; P < .001). Multivariate analysis showed that no adjuvant therapy, intimal invasion, and poorly differentiated histology were associated with a higher hazard of death by 2.2, 2.2, and 2.5-fold, respectively. CONCLUSION: In properly selected patients, pancreatectomy plus resection and reconstruction of PPV was performed as safely as palliation or "conventional" pancreatectomy and was associated with better survival when compared to palliation.

Vascular complications of pancreatectomy.

Despite decreased postoperative mortality, pancreatic resections continue to be associated with high morbidity rates. Vascular complications and, in particular, erosive bleeding from the large retroperitoneal vasculature are particularly difficult to treat and account for a large percentage of the residual postoperative mortality of pancreatic resections. We herein analyze the pathogenesis, diagnosis, preventive measures and possible remedies of either hemorrhagic or occlusive complications of pancreatic resections through a review of the literature and of our institutional experience consisting of 818 pancreatectomies.

The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index.

OBJECTIVE: The diagnosis of growth hormone (GH) deficiency (GHD) in adults is based on a reduced peak GH response to provocative tests, such as the insulin tolerance test (ITT) and the GH-releasing hormone-arginine (GHRH-ARG) test. However, the cut-off limits of peak GH response in lean subjects are not reliable in obese patients; this is noteworthy since adult GHD is often associated with obesity. Aim of this study was to evaluate the diagnostic cut-off limits of peak GH response to the GHRH-ARG test in overweight and obese as well as in lean population. DESIGN AND METHODS: The GH responses to the GHRH-ARG test were studied in 322 patients with organic hypothalamic-pituitary disease and in 318 control subjects. Patients were subdivided into two groups on the basis of the number of pituitary hormone deficits, except for GH deficiency: (a) patients with total pituitary hormone deficit (TPHD) and (b) patients without or with no more than two pituitary hormone deficits (PHD). Both patients and control subjects were divided into three subgroups according to body mass index (BMI): lean (BMI <25 kg/m(2)), overweight (BMI > or = 25 and <30 kg/m(2)) and obese (BMI > or =30 kg/m(2)). TPHD patients were assumed to be GH deficient, whereas PHD patients may include subjects with either normal or impaired GH secretion. The statistical analysis was carried out by the Receiver-Operating Characteristic curve analysis (Medcalc 7.2). The diagnostic cut-off points were calculated for lean, overweight and obese subjects to provide optimal separation of GH-deficient patients and control subjects according to two criteria: (1) a balance between high sensitivity and high specificity; (2) to provide the highest pair of sensitivity/specificity values for GH deficiency. RESULTS: In the lean population the best pair of values, with highest sensitivity as 98.7% and highest specificity as 83.7%, was found using a peak GH cut-off point of 11.5 mug/l. In the overweight population the best pair of values, 96.7 and 75.5%, respectively, was found using a peak GH cut-off point of 8.0 mug/l. In the obese population the best pair of values, 93.5 and 78.3%, respectively, was found using a peak GH cut-off point of 4.2 mug/l. Applying the above mentioned cut-off points, among PHD patients we found that 80 subjects (72%) were GHD whereas 31 (28%) had normal GH secretion. CONCLUSIONS: In conclusion the GHRH-ARG test is a reliable tool for the diagnosis of adult GH deficiency in lean, overweight and obese patients, provided that specific BMI-related cut-off limits are assumed.

Endovascular repair of an aorto-left renal vein fistula due to a ruptured abdominal aortic aneurysm after EVAR.

PURPOSE: To report an unusual late complication of endovascular aneurysm repair: an arteriovenous fistula between the aneurysm sac and a retro-aortic left renal vein following sac expansion due to a type III endoleak. CASE REPORT: A 79-year-old man developed an arteriovenous fistula between the aneurysm sac and a retro-aortic left renal vein 67 months after endovascular aneurysm exclusion (EVAR). Aneurysm rupture was due to disconnection between the right iliac limb and an extender cuff. The problem was repaired percutaneously with another endograft bridging the two prostheses. At 16 months, the aneurysm sac diameter was decreased; there was no evidence of the AV fistula, and the patient was free from any complication related to the EVAR. CONCLUSIONS: This case emphasizes the need of close surveillance even in the late postoperative course of these patients. Moreover, this rare event confirmed that endovascular techniques can play an important role in treating emergent complications.

IGFs and IGFBPs in adult growth hormone deficiency.

In the current guidelines for the diagnosis of adult GH deficiency (GHD) it is stated that, within the appropriate clinical context, it has to be shown by provocative tests only. But the diagnostic value of measuring IGF-I levels has been recently revisited. It has been confirmed that normal IGF-I levels do not rule out severe GHD in adults. However, it has also been emphasized that very low IGF-I levels in patients highly suspected for GHD (and without malnutrition, liver disease or hypothyroidism) could be considered definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitarism acquired in adulthood. The value of measuring IGF-I levels for monitoring the efficacy and the adequacy of rhGH replacement remains definitely accepted.

Pancreas preservation with University of Wisconsin and Celsior solutions: a single-center, prospective, randomized pilot study.

BACKGROUND: Celsior is an extracellular-type, low-viscosity, preservation solution already used for heart, lung, liver, and kidney transplantation. We report the results of a single-center, prospective, randomized pilot study specifically designed to compare the safety profile of Celsior solution with University of Wisconsin (UW) solution in clinical pancreas transplantation. METHODS: A total of 105 consecutive procurements were randomized to graft preservation with UW (n=53) solution or Celsior (n=52) solution. The groups were comparable with regard to all donor and recipient characteristics. RESULTS: Five grafts were discarded and 100 grafts (50 UW vs. 50 Celsior) were transplanted. Mean cold and warm ischemia times were 11.0 +/- 2.1 hr and 37.2 +/- 6.0 min for UW compared with 10.8 +/- 1.8 hr and 38.1 +/- 5.9 min for Celsior (P =not significant). Delayed endocrine pancreas function was recorded in one graft preserved with UW solution. Eleven recipients (UW 12% vs. Celsior 10%, P =not significant) required a relaparotomy. The mean serum levels of glucose, amylase, and lipase remained comparable between the study arms at equivalent intervals after transplantation. One recipient died with functioning grafts in each study arm; two further grafts were lost to arterial thrombosis (Celsior) and chronic rejection (UW), respectively. Actuarial 1-year patient and graft survival rates overlapped in the two study arms (98% and 96%, respectively). CONCLUSIONS: Within the range of cold ischemia time reported in this study, UW and Celsior solutions have similar safety profiles for pancreas preservation.

GHRH and GH secretagogues: clinical perspectives and safety.

The diagnosis and treatment of growth hormone deficiency (GHD), as well as the possibility of counteracting somatopause and age-related changes in body composition, structural functions, and metabolism, prompted interest in potential clinical uses of GH-releasing hormone (GHRH) and GH secretagogues (GHS). GHD often reflects hypothalamic GHRH deficiency and it has been clearly demonstrated that the age-related decline in the function of the GH/IGF-I axis reflects a reduction in hypothalamic function as evidenced by the preservation of the releasable pool of pituitary GH in aged subjects. The effectiveness of recombinant human GH (rhGH) is well established, but it is also recognized that GH replacement does not mimic physiological GH secretion which theoretically would be restored by GHRH and/or GHS. At present, it has been clearly demonstrated that GHRH and/or GHS represent reliable tools for the diagnosis of GHD. On the other hand, neither GHRH nor GHS has been shown to provide effective alternatives to rhGH for the treatment of GHD. Although GHRH and/or GHS represent the most logical approaches for the restoration of the GH/IGF-I axis to a youthful level of activity and for counteracting the somatopause, this hypothesis has never been proven definitively. Conceptually, GHRH replacement would be the most physiological approach and its safety is guaranteed, provided an appropriate dose is used, in order to avoid hyperactivity of the GH/IGF-I axis. However, a long-acting preparation is needed. On the other hand, GHS, e.g., ghrelin analogues, could be considered as a function of their selectivity of action. However, ghrelin has a wide spectrum of endocrine and non-endocrine actions at both central and peripheral levels. Thus, non-selective GHS, although available in orally active forms, could elicit unforeseen side effects. Previous studies with GHRH and/or GHS in aging patients provided encouraging results. However, it still remains to be definitively demonstrated that aged subjects would benefit from chronic treatment with these molecules.