Major Pancreatic Resection Increases Bone Mineral Density Loss, Osteoporosis, and Fractures.

OBJECTIVE: To assess whether long-term survivors of pancreatic surgery show increased risk to develop impaired bone mineral density, osteoporosis, and vitamin D deficiency. BACKGROUND: Pancreatic resection poses a risk for malabsorption of fat-soluble vitamins and other micronutrients essential for bone mineralization. Here, we evaluated the long-term effects of pancreatic resection on bone mineral density (BMD) and its clinical sequelae. METHODS: This was a two-pronged analysis of post-pancreatectomy patients with a follow-up period greater than 3 years comprising (1) a large, propensity score-matched, cohort study based on a multinational federated research network (FRN) and (2) a retrospective single institution review of clinical and radiographic patient data. In the FRN analysis, an initial cohort of 8,423 post-pancreatectomy patients were identified and propensity score-matched with normal controls. The primary endpoint was the 10-year risk of developing osteoporotic pathological fractures and secondary endpoints included diagnosis of osteoporosis, vitamin-D deficiency, and related therapies. The single institution retrospective analysis identified 224 patients who underwent pancreatic resection between 2005 and 2019. BMD was quantified in CT images acquired before and after surgery. BMD trends and related factors were assessed in a time-series mixed effect linear regression model. RESULTS: A total of 8,080 propensity score-matched pairs were included in the FRN analysis. The analysis revealed a 2.4-fold increase in pathological fractures (P<0.0001) and 1.4-1.5 fold increase in osteoporosis/osteomalacia (P<0.0001) and vitamin-D deficiency (P<0.0001) in post-pancreatectomy patients. Vitamin-D supplements were more common in the pancreatectomy group (OR 1.4, 95% CI 1.28-1.53, P<0.0001), as were specific osteoporosis/osteomalacia treatments such as calcitonin, denosumab, romosozumab, abaloparatide, and teriparatide (OR 2.24, 95%CI 1.69-2.95, P<0.0001). Retrospective analysis of CT imaging revealed that BMD declined more rapidly following pancreatic resection compared to normal historical controls (P=0.015). Older age, pancreatic cancer, and pancreaticoduodenectomy were associated with increased rates of BMD loss (P<0.05, each). CONCLUSIONS: After pancreatic resection, patients are at higher risk for BMD loss and subsequent fractures. As the cohort of pancreatic resection survivorship grows, attention will need to be paid to focused prevention efforts to reduce BMD loss, osteoporosis, and fractures in these vulnerable patients, with specific attention to the pancreatic cancer population.

Contemporary report of surgical outcomes after single-stage total pancreatectomy: A 10-year experience.

BACKGROUND: Surgeons rarely perform elective total pancreatectomy (TP). Our study seeks to report surgical outcomes in a contemporary series of single-stage (SS) TP patients. METHODS: Between the years 2013 to 2023 we conducted a retrospective review of 60 consecutive patients who underwent SSTP. Demographics, pathology, treatment-related variables, and survival were recorded and analyzed. RESULTS: SSTP consisted of 3% (60/1859) of elective pancreas resections conducted. Patient median age was 68 years. Ninety percent of these patients (n = 54) underwent SSTP for pancreatic ductal adenocarcinoma (PDAC). Conversion from a planned partial pancreatectomy to TP occurred intraoperatively in 31 (52%) patients. Fifty-nine patients (98%) underwent an R0 resection. Median length of hospital stay was 6 days. The majority of morbidities were minor, with 27% patients (n = 16) developing severe complications (Clavien-Dindo ≥3). Thirty and ninety-day mortality rates were 1.67% (one patient) and 5% (three patients), respectively. Median survival for the entire cohort was 24.4 months; 22.7 months for PDAC patients, with 1-, 3-, and 5-year survival of 68%, 43%, and 16%, respectively. No mortality occurred in non-PDAC patients (n = 6). CONCLUSION: Elective single-stage total pancreatectomy can be a safe and appropriate treatment option. SSTP should be in the armamentarium of surgeons performing pancreatic resection.

Implementation of an opioid reduction toolkit in pancreatectomy patients significantly increases patient awareness of safe practice and decreases amount prescribed and consumed.

BACKGROUND: Postoperative opioid abuse following surgery is a major concern. This study sought to create an opioid reduction toolkit to reduce the number of narcotics prescribed and consumed while increasing awareness of safe disposal in pancreatectomy patients. METHODS: Prescription, consumption, and refill request data for postoperative opioids were collected from patients receiving an open pancreatectomy before and after the implementation of an opioid reduction toolkit. Outcomes included safe disposal practice awareness for unused medication. RESULTS: 159 patients were included in the study: 24 in the pre-intervention and 135 in the post-intervention group. No significant demographic or clinical differences existed between groups. Median morphine milliequivalents (MMEs) prescribed were significantly reduced from 225 (225-310) to 75 (75-113) in the post-intervention group (p < 0.0001). Median MMEs consumed were significantly reduced from 109 (111-207) to 15 (0-75), p < 0.0001), as well. Refill request rates remained equivalent during the study (Pre: 17% v Post: 13%, p = 0.9) while patient awareness of safe disposal increased (Pre: 25% v Post: 62%, p < 0.0001). DISCUSSION: An opioid reduction toolkit significantly reduced the number of postoperative opioids prescribed and consumed after open pancreatectomy, while refill request rates remained the same and patients' awareness of safe disposal increased.

KRAS mutation allele frequency threshold alters prognosis in right-sided resected pancreatic cancer.

BACKGROUND: Next-generation sequencing (NGS) provides information on genetic mutations and mutant allele frequency in tumor specimens. We investigated the prognostic significance of KRAS mutant allele frequency in patients with right-sided pancreatic ductal adenocarcinoma (PDAC) treated with surgical resection. METHODS: A retrospective study reviewed patients who underwent surgical resection for PDAC and analyzed tumors with an in-house mutational panel. Microdissected samples were studied using an NGS-based assay to detect over 200 hotspot mutations in 42 genes (Pan42) commonly involved in PDAC. RESULTS: A total of 144 PDAC right-sided surgical patients with a Pan42 panel were evaluated between 2015 and 2020; 121 patients (84%) harbored a KRAS mutation. Detected mutant allele frequencies were categorized as less than 20% (low mKRAS, n = 92) or greater than or equal to 20% (high mKRAS, n = 29). High mKRAS (KRAS ≥ 20%) patients were noted to have shorter disease-free survival after surgery (11.5 ± 2.1 vs. 19.5 ± 3.5 months, p = 0.03), more advanced tumor stage (p = 0.02), larger tumors (3.6 vs. 2.7 cm, p = 0.001), greater tumor cellularity (26% vs. 18%, p = 0.001), and higher rate of distant recurrence (p = 0.03) than low mKRAS patients. CONCLUSION: This study demonstrates the importance of KRAS mutant allele frequency on pathological characteristics and prognosis in right-sided PDAC treated with surgery.

Rare occurrence of pseudomyxoma peritonei (PMP) syndrome arising from a malignant transformed ovarian primary mature cystic teratoma treated by cytoreductive surgery and HIPEC: a case report.

BACKGROUND: Pseudomyxoma peritonei (PMP) syndrome is a disease process that typically occurs from ruptured appendiceal mucocele neoplasms. PMP syndrome arising from malignant transformation of an ovarian primary mature cystic teratoma (MCT) is a pathogenesis rarely encountered. CASE PRESENTATION: Herein, we report a 28-year-old patient evaluated and treated for a right ovarian mass and large volume symptomatic abdominopelvic mucinous ascites. Molecular profiling and genetic analysis revealed mutations in ATM, GNAS, and KRAS proteins while IHC demonstrated gastrointestinal-specific staining for CK20, CDX2, CK7, and SATB2. Peritoneal cytology showed paucicellular mucin. Diffuse peritoneal adenomucinosis (DPAM) variant of PMP arising from a ruptured ovarian primary MCT after malignant transformation to a low-grade appendiceal-like mucinous neoplasm was ultimately confirmed. Treatment included staged therapeutic tumor debulking and right salpingo-oophorectomy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). CONCLUSIONS: Our report builds upon the existing literature supporting this aggressive treatment option reserved for advanced abdominal malignancies utilized in this patient with a rare clinical entity.

Malate-aspartate shuttle promotes l-lactate oxidation in mitochondria.

Metabolism in cancer cells is rewired to generate sufficient energy equivalents and anabolic precursors to support high proliferative activity. Within the context of these competing drives aerobic glycolysis is inefficient for the cancer cellular energy economy. Therefore, many cancer types, including colon cancer, reprogram mitochondria-dependent processes to fulfill their elevated energy demands. Elevated glycolysis underlying the Warburg effect is an established signature of cancer metabolism. However, there are a growing number of studies that show that mitochondria remain highly oxidative under glycolytic conditions. We hypothesized that activities of glycolysis and oxidative phosphorylation are coordinated to maintain redox compartmentalization. We investigated the role of mitochondria-associated malate-aspartate and lactate shuttles in colon cancer cells as potential regulators that couple aerobic glycolysis and oxidative phosphorylation. We demonstrated that the malate-aspartate shuttle exerts control over NAD+ /NADH homeostasis to maintain activity of mitochondrial lactate dehydrogenase and to enable aerobic oxidation of glycolytic l-lactate in mitochondria. The elevated glycolysis in cancer cells is proposed to be one of the mechanisms acquired to accelerate oxidative phosphorylation.

Slippery Nanoparticles as a Diffusion Platform for Mucin Producing Gastrointestinal Tumors.

BACKGROUND: Treatment failure in pseudomyxoma peritonei (PMP) is partly attributed to the ineffective delivery of therapeutics through dense mucinous tumor barriers. We modified the surface of Poly (lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG-NPs) with a low-density, second PEG layer (PLGA-TPEG-NPs-20) to reduce their binding affinity to proteins and improve diffusion through mucin. METHODS: Nanoprecipitation was used to fabricate PLGA-PEG-NPs. To construct the second PEG layer of PLGA-TPEG-NPs-20, PEG-Thiol was conjugated to PLGA-PEG-NPs composed of 80% methoxy PLGA-PEG and 20% of PLGA-PEG-Maleimide. DiD-labeled nanoparticles (NPs) were added to the inner well of a trans-well system containing cultured LS174T or human PMP tissue. Diffusion of NPs was measured via fluorescence signal in the bottom well. In an ex vivo rat model, small intestine was treated with DiD-labeled NPs. In an in vivo murine LS174T subcutaneous tumor model, Nu/Nu nude mice received supratumoral injections (subcutaneous injection above the tumor) of DiD-labeled NPs. Thirty minutes after injection, mice were sacrificed, and tumors were collected. All tissue was cryosectioned, mounted with DAPI-containing media, and inspected via confocal microscopy. RESULTS: Diffusion profiles of NPs through PMP and cultured LS174T cells were generated. PLGA-TPEG-NPs-20 diffused faster with ~ 100% penetration versus PLGA-PEG-NPs with ~ 40% penetration after 8 h. Increased diffusion of PLGA-TPEG-NPs-20 was further observed in ex vivo rat small intestine as evidenced by elevated luminal NP fluorescence signal on the luminal surface. Subcutaneous LS174T tumors treated with PLGA-TPEG-NPs-20 demonstrated greater diffusion of NPs, showing homogenous fluorescence signal throughout the tumor. CONCLUSIONS: PLGA-TPEG-NPs-20 can be an effective mucin penetrating drug delivery system.

Case report of rhabdomyosarcomatous transformation of a primary gastrointestinal stromal tumor (GIST).

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal neoplasm of the gastrointestinal tract. Mutations of KIT and platelet-derived growth factor receptor alpha have been well characterized in GISTs. Patients with KIT mutations are generally sensitive to treatment with tyrosine kinase inhibitors. However, some patients with GIST, while initially sensitive to TKIs, gain resistance in later stages of treatment. Heterologous rhabdomyomsarcomatous dedifferentiation of advanced GISTs after long-term imatinib mesylate (IM) therapy has been reported. In these cases, the underlying molecular mechanism of tumor progression and transformation is unclear. CASE PRESENTATION: We report one such patient with rhabdomyosarcomatous dedifferentiation of a GIST without metastatic disease after brief 3-month therapy with IM. The tumor was composed of two distinct phenotypes, a CD117 negative region with rhabdomyosarcomatous differentiation directly adjacent to a CD117 positive classic GIST region. Molecular analysis identified the activating KIT exon 11 mutation in both regions, indicating a common origin for both phenotypes. Additionally, the dedifferentiated component contained two synonymous variants in platelet-derived growth factor receptor alpha and KIT. The increased number of synonymous variants in the rhabdomyosarcomatous region may reflect increased genetic instability of this tumor that may have resulted in the loss of CD117 expression in the dedifferentiated component. CONCLUSION: This study adds to the growing consensus that rhabdomyosarcomatous GIST progresses from a common GIST primary tumor. The role of IM in this progression is uncertain; however short duration of IM treatment in this study supports the hypothesis that rhabdomyosarcomatous GIST progression is not a consequence of IM therapy. Furthermore, we provide additional information supporting the observation that CD117 negative rhabdomyosarcomatous transformation maintains the activating KIT variant without KIT expression.

Non-Thermal Plasma-Induced Immunogenic Cell Death in Cancer: A Topical Review.

Recent advances in biomedical research in cancer immunotherapy have identified the use of an oxidative stress-based approach to treat cancers, which works by inducing immunogenic cell death (ICD) in cancer cells. Since the anti-cancer effects of non-thermal plasma (NTP) are largely attributed to the reactive oxygen and nitrogen species that are delivered to and generated inside the target cancer cells, it is reasonable to postulate that NTP would be an effective modality for ICD induction. NTP treatment of tumors has been shown to destroy cancer cells rapidly and, under specific treatment regimens, this leads to systemic tumor-specific immunity. The translational benefit of NTP for treatment of cancer relies on its ability to enhance the interactions between NTP-exposed tumor cells and local immune cells which initiates subsequent protective immune responses. This review discusses results from recent investigations of NTP application to induce immunogenic cell death in cancer cells. With further optimization of clinical devices and treatment protocols, NTP can become an essential part of the therapeutic armament against cancer.

Case report: optimal tumor cytoreduction and octreotide with durable disease control in a patient with MEN-1 and Zollinger-Ellison syndrome-over a decade of follow-up.

BACKGROUND: Zollinger-Ellison syndrome (ZES) is a rare condition characterized by hypersecretion of gastrin by gastrinoma tumors leading to severe peptic ulcer disease with potential development of gastric carcinoid tumors. Herein, we report the clinical course of a 68-year-old patient with multiple endocrine neoplasia type 1 (MEN-1) who underwent several surgeries to ultimately undergo optimal tumor cytoreduction of locally advanced gastrinomas and symptomatic gastric carcinoids. The patient was subsequently maintained on octreotide long-acting release (LAR). This case report supports consideration for aggressive tumor cytoreduction and octreotide in similar patients with MEN-1-associated ZES for durable disease control and symptom management. CASE PRESENTATION: The patient is a 68-year-old male with multiple endocrine neoplasia type 1 (MEN-1), diagnosed in 1993 after presenting with recurrent renal calculi and hypercalcemia. Soon thereafter, he presented with symptoms and elevated gastrin levels suggestive of ZES prompting abdominal exploration with partial resection of the duodenum to remove gastrinoma tumor nodules. Within 4 years of the operation, he represented with intractable hypergastrinemia despite optimal medical management with peak gastrin levels exceeding 29,000 pg/mL, in 2006. In January 2007, the patient returned to the operating room for resection of regional peripancreatic and perigastric lymph nodes and enucleation of pancreatic body and tail gastrinoma tumors. Although his gastrin level decreased to 5000 pg/mL with resultant improvement of symptoms, in less than 2 years, he developed disease progression with obstructive symptomatology from enlarging gastric carcinoids and rising gastrin levels. In May of 2008, he underwent pancreaticoduodenectomy and near-total gastrectomy. Since June of 2008, the patient shows no demonstrable progression of disease and remains asymptomatic on LAR octreotide (30 mgs). Gastrin levels have been well controlled (range, 100-624 pg/mL; current 114 pg/mL). CONCLUSION: Success of this procedure in our case report highlights the potential role for optimal tumor cytoreduction and LAR octreotide to control disease progression in a patient with MEN-I and Zollinger-Ellison syndrome with locally advanced gastrinoma and secondary large gastric carcinoids.

Patient-specific predictors of failure to rescue after pancreaticoduodenectomy.

BACKGROUND: Failure to rescue (FTR) is a recently described outcome metric for quality of care. However, predictors of FTR have not been adequately investigated, particularly after pancreaticoduodenectomy. We aim to identify predictors of FTR after pancreaticoduodenectomy. METHODS: We reviewed all patients who developed serious morbidity after pancreaticoduodenectomy from 2005 to 2012 in the ACS-NSQIP database. Logistic regression was used to identify preoperative and postoperative risks for 30-day mortality within a development cohort (randomly selected 80%). A score was created using weighted beta coefficients. Predictive accuracy was assessed on the validation cohort (remaining 20%) using a receiver operator characteristic curve and calculating the area under the curve (AUC). RESULTS: The FTR rate was 7.2% after pancreaticoduodenectomy (n = 5,027). We identified 5 independent risk factors: age ≥65 and albumin ≤3.5 g/dL, preoperatively; and development of shock, renal failure, and reintubation, postoperatively. The generated score had an AUC = 0.83 (95% CI, 0.77-0.89) in the validation cohort. Using the score: 1*Albumin ≤3.5 g/dL + 2*Age ≥ 65 + 2*Shock + 5*Renal failure + 5*Reintubation, FTR rates increased with increasing score (p < 0.001). CONCLUSION: FTR rates have previously been shown to be associated with hospital factors. We show that FTR is also associated with preoperative and postoperative patient-specific factors.

Multidisciplinary strategies in bloodless medicine and surgery for patients undergoing pancreatectomy.

BACKGROUND: Bloodless pancreatic surgery (BPS) is rarely performed and/or reported. We aim to characterize perioperative and anesthetic strategies in BPS. MATERIALS AND METHODS: A literature search was performed on MEDLINE looking for case reports/case series using search terms ("Jehovah's Witness" [All Fields]) AND ("Pancreatic Surgery" [All Fields] OR "Pancreaticoduodenectomy" [All Fields] OR "Distal Pancreatectomy" [All Fields]). Data regarding categorical variables are reported as proportions and quantitative continuous variables as medians with ranges or means with standard deviation. Forty-one patients requiring BPS are reported in the literature with three additional cases from our institution (n = 44). The data analyzed included clinicopathologic factors, BPS strategies, patient complications, and in-hospital mortality. RESULTS: The most common procedure and diagnosis were pancreaticoduodenectomy (n = 34, 77.3%) and pancreatic ductal adenocarcinoma (n = 12, 27.3%), respectively. Transfusion reduction strategies in BPS fell into three categories: preoperative, intraoperative, and postoperative. Preoperative strategies included iron supplementation (n = 24, 54.5%) and erythropoietin administration (n = 14, 41.2%). Intraoperative strategies included acute normovolemic hemodilution (n = 30, 68%) and cell saver (n = 4, 9.1%). Postoperative strategies included erythropoietin (n = 16, 48.5%) and iron supplementation (n = 16, 48.5%). Complications occurred in 21 (60%) patients. There was no in-hospital mortality among the 44 patients in this cohort. CONCLUSIONS: A broad spectrum of bloodless medicine and surgery practices were used based on patient selection, multidisciplinary practice, and preference. With careful perioperative and anesthetic management, BPS can be performed with good outcomes.

Clinical studies in CRS and HIPEC: Trials, tribulations, and future directions-A systematic review.

BACKGROUND: The field of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has suffered from a lack of clinical trials to validate its expanding use. OBJECTIVE: To evaluate published and ongoing clinical trials seeking to better define role of CRS/HIPEC in the treatment of peritoneal surface malignancies. METHODS: Systematic review by PubMed search was performed using terms "Clinical trial," "intraperitoneal chemotherapy," and "HIPEC." ClinicalTrials.gov and EudraCT registries were searched for active clinical trials. Eligibility included CRS/HIPEC trials investigating adult patient populations from published clinical reports and/or trials currently accruing or at completion. RESULTS: Thirteen published trials and 57 active clinical trials were included for review. CONCLUSIONS: Published and ongoing U.S. and international clinical trials for CRS and HIPEC are defining important parameters that include improving patient selection, strategic sequences of treatment, cytoreductive strategies, chemotherapeutics, optimal hyperthermic temperature and timing, and toxicity profiles. Main barriers or limitations to trial development remain patient enrollment, trial design, and oncologic community collaboration. Overall progress is positive with increasing number of clinical trials throughout the world. Collaboration between surgeons and the wider oncologic community will be crucial to validate this important treatment strategy.

Reconstruction options following pancreaticoduodenectomy after Roux-en-Y gastric bypass: a systematic review.

BACKGROUND: Obesity is a risk factor for pancreatic cancer which may be treated with Roux-en-Y gastric bypass and represents an increasing morbidity. Post-RYGB anatomy poses considerable challenges for reconstruction after pancreaticoduodenectomy (PD), a growing problem encountered by surgeons. We characterize specific strategies used for post-PD reconstruction in the RYGB patient. METHODS: PubMed search was performed using MeSH terms "Gastric Bypass" and "Pancreaticoduodenectomy" between 2000 and 2018. Articles reporting cases of pancreaticoduodenectomy in post-RYGB patients were included and systematically reviewed for this study. RESULTS: Three case reports and five case series (25 patients) addressed PD after RYGB; we report one additional case. The typical post-gastric bypass PD patient is a woman in the sixth decade of life, presenting most commonly with pain (69.2%) and/or jaundice (53.8%), median 5 years after RYGB. Five post-PD reconstructive options are reported. Among these, the gastric remnant was resected in 18 cases (69.2%), with reconstruction of biliopancreatic drainage most commonly achieved using the distal jejunal segment of the pre-existing biliopancreatic limb (73.1%). Similarly, in the eight cases where the gastric remnant was spared (30.8%), drainage was most commonly performed using the distal jejunal segment of the biliopancreatic limb (50%). Among the 17 cases reporting follow-up data, median was 27 months. CONCLUSION: Reconstruction options after PD in the post-RYGB patient focus on resection or preservation gastric remnant, as well as creation of new biliopancreatic limb. Insufficient data exists to make recommendations regarding the optimal reconstruction option, yet surgeons must prepare for the possible clinical challenge. PD reconstruction post-RYGB requires evaluation through prospective studies.

Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy.

One of the major challenges in applying nanomedicines to cancer therapy is their low interstitial diffusion in solid tumors. Although the modification of nanocarrier surfaces with enzymes that degrade extracellular matrix is a promising strategy to improve nanocarrier diffusion in tumors, it remains challenging to apply this strategy in vivo via systemic administration of nanocarriers due to biological barriers, such as reduced blood circulation time of enzyme-modified nanocarriers, loss of enzyme function in vivo, and life-threatening side effects. Here, we report the conjugation of recombinant human hyaluronidase PH20 (rHuPH20), which degrades hyaluronic acid, on the surfaces of poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) nanoparticles followed by anchoring a relatively low density layer of PEG, which reduces the exposure of rHuPH20 for circumventing rHuPH20-mediated clearance. Despite the extremely short serum half-life of rHuPH20, our unique design maintains the function of rHuPH20 and avoids its effect on shortening nanocarrier blood circulation. We also show that rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. The facile surface modification quadruples the accumulation of conventional PLGA-PEG nanoparticles in 4T1 syngeneic mouse breast tumors and enable their uniform tumor distribution. The rHuPH20-modified nanoparticles encapsulating doxorubicin efficiently inhibit the growth of aggressive 4T1 tumors under a low drug dose. Thus, our platform technology may be valuable to enhance the clinical efficacy of a broad range of drug nanocarriers. This study also provides a general strategy to modify nanoparticles with enzymes that otherwise may reduce nanoparticle circulation or lose function in the blood.

Pancreatic mucinous cystic neoplasm in a transgender patient.

BACKGROUND: Cystic pancreatic lesions are increasingly more frequent detected clinical entities. Mucinous cystic neoplasm (MCN) is a hormone-related pancreatic tumor (HRTP) with a strong predominance in young and middle-aged females. CASE PRESENTATION: Here, we present the case of a 31-year-old surgically transgendered female-to-male patient with a history of alcoholic pancreatitis, on chronic testosterone therapy. He was found to have a pancreatic MCN and underwent distal pancreatectomy and splenectomy. CONCLUSION: To our knowledge, this is the first reported case of a transgender patient with a history of hormone replacement therapy (HRT) and pancreatic MCN. We consider possible mechanisms for the pathogenesis to explain this patient's neoplasm.

Retroperitoneal Castleman's disease: advocating a multidisciplinary approach for a rare clinical entity.

BACKGROUND: Castleman's disease is a rare and poorly understood disease entity that may resemble more common conditions and represents a clinical challenge to the treating surgeon. CASE PRESENTATION: In this report, we describe a case of a 61-year-old Caucasian woman with a symptomatic retroperitoneal mass. The specimen obtained from her resection contained a protuberant encapsulated mass, exhibiting microscopic features consistent with localized, unicentric Castleman's disease. These characteristics included architectural features and immunohistochemical findings consistent with the hyaline vascular variant of Castleman's disease. CONCLUSION: We report a very rare case of a retroperitoneal hyaline vascular type of Castleman's disease. We discuss the diagnostic dilemma Castleman's disease may present to the surgeon, with an emphasis on multidisciplinary management of these patients. We also review current data on pathogenesis, treatment and outcomes.

Poptosis or Peptide-Induced Transmembrane Pore Formation: A Novel Way to Kill Cancer Cells without Affecting Normal Cells.

Recent advances in cancer treatment like personalized chemotherapy and immunotherapy are aimed at tumors that meet certain specifications. In this review, we describe a new approach to general cancer treatment, termed peptide-induced poptosis, in which specific peptides, e.g., PNC-27 and its shorter analogue, PNC-28, that contain the segment of the p53 transactivating 12-26 domain that bind to HDM-2 in its 1-109 domain, bind to HDM-2 in the membranes of cancer cells, resulting in transmembrane pore formation and the rapid extrusion of cancer cell contents, i.e., tumor cell necrosis. These peptides cause tumor cell necrosis of a wide variety of solid tissue and hematopoietic tumors but have no effect on the viability and growth of normal cells since they express at most low levels of membrane-bound HDM-2. They have been found to successfully treat a highly metastatic pancreatic tumor as well as stem-cell-enriched human acute myelogenous leukemias in nude mice, with no evidence of off-target effects. These peptides also are cytotoxic to chemotherapy-resistant cancers and to primary tumors. We performed high-resolution scanning immuno-electron microscopy and visualized the pores in cancer cells induced by PNC-27. This peptide forms 1:1 complexes with HDM-2 in a temperature-independent step, followed by dimerization of these complexes to form transmembrane channels in a highly temperature-dependent step parallel to the mode of action of other membranolytic but less specific agents like streptolysin. These peptides therefore may be effective as general anti-cancer agents.

The Clinical Implications of KRAS Mutations and Variant Allele Frequencies in Pancreatic Ductal Adenocarcinoma.

The KRAS proto-oncogene is a major driver of pancreatic tumorigenesis and is nearly ubiquitously mutated in pancreatic ductal adenocarcinoma (PDAC). KRAS point mutations are detected in over 90% of PDAC cases, and these mutations have been shown to be associated with worse therapy response and overall survival. Pathogenic KRAS mutations are mostly limited to codons 12, 13 and 61, with G12D, G12V, G12R, Q61H, and G13D accounting for approximately 95% of the mutant cases. Emerging data have shown the importance of specific mutant subtypes, as well as KRAS variant allele frequency on clinical prognosis. Furthermore, novel technologies and therapies are being developed to target specific mutant subtypes, with encouraging early results. In this paper, we aim to review the recent studies regarding the relative impact of specific mutant KRAS subtypes on oncologic outcomes, the application of variant allele frequency in next generation sequencing analyses, and the ongoing research into therapies targeting specific mutant KRAS subtypes.

Peripancreatic fluid collections following distal pancreatectomy and splenectomy-when is intervention warranted?

BACKGROUND: Peripancreatic fluid collections after distal pancreatectomy and splenectomy are commonly identified on postoperative cross-sectional imaging. This study aimed to determine the incidence, natural history, and indications for intervention. METHODS: We conducted a retrospective review of patients with peripancreatic fluid collections after distal pancreatectomy with or without splenectomy between 2013 and 2018, approved by our institutional review board. The chi-square test was used for categorical variables, the Mann-Whitney U test for continuous variables, and Fisher's exact test was used for values in which the sample size was less than 5 to compare data. RESULTS: During the study period, 235 patients underwent distal pancreatectomy with or without splenectomy, and 182 patients with postoperative imaging were included. In the cohort of patients with postoperative imaging, 83 (46%) had peripancreatic fluid collections, of which 46 (55%) were symptomatic fluid collections (SFCs) and 37 (45%) were asymptomatic fluid collections (AFCs). Those with SFC had a higher incidence of postoperative morbidity (46% vs 8%; P = .0002), most commonly postoperative pancreatic fistula (90%). Of patients with SFC, 34 (74%) underwent treatment via percutaneous drainage (n = 26), endoscopic drainage (n = 7), or antibiotics alone (n = 1). AFCs (n = 37) were observed. Collections that were intervened upon resolved significantly faster than those observed, 3.5 months vs 13.2 months (P < .0001), respectively. CONCLUSION: Asymptomatic patients may be observed with or without serial imaging and the AFC will typically resolve spontaneously with time. Patients who develop symptoms should generally be intervened upon with drainage if deemed feasible, given that this reduces the time to resolution.