Long term quality of life amongst pancreatectomy patients with diabetes mellitus.

BACKGROUND: Pancreatogenic diabetes is common after pancreatectomy, and the impact on quality of life (QOL) is poorly understood. The objective of this study was to investigate QOL between diabetic and non-diabetic patients at least five years after pancreatectomy. METHODS: Patients were recruited from a prospectively maintained institutional database. Participants were administered the Audit of Diabetes-Dependent Quality of Life (ADDQOL). Quality of life was compared between diabetics and non-diabetics using validated European Organization for Research and Treatment of Cancer questionnaires. RESULTS: 80 individuals completed surveys. 55% were female, 80% non-Hispanic white, 44% underwent Whipple, 48% were cystic neoplasms and 39% were adenocarcinoma. Diabetic patients (42.5%) reported comparable EORTC QLQ-C30 and Pan26 scores to non-diabetic patients. Pre-operative diabetic patients reported more dyspnea (p = 0.02) and greater pain (p = 0.02) than new-onset diabetics. Diabetic patients reported an overall ADDQOL quality of life score 'very good' (IQR: excellent, good) though felt life would be much better without diabetes (IQR: very much better, little better). While operation type was not influential, patients diagnosed with cystic neoplasms were almost twice as likely as those with other pathologies to report that life would be much better without diabetes (p < 0.01). CONCLUSION: At a median of 9.3 years from pancreatic surgery, ADDQoL scores of patients were similar to cohorts of non-pancreatogenic diabetics in the general population. Patients without cancer were more likely to report that diabetes affected their overall QOL, regardless of operation. This study provides nuanced understanding of long-term QOL to improve the informed consent process and post-operative long-term care.

Long-term health after pancreatic surgery: the view from 9.5 years.

BACKGROUND: Discussing the impact of pancreatic surgery on long-term health is poorly understood, but necessary for informed consent. Given the increased number of pancreatic operations being performed annually, further investigation is necessary. METHODS: Patients surviving longer than 5 years after pancreatic surgery were surveyed for postoperative hospitalizations, operations, pain, nutrition and diabetes. Variables were analyzed according to patient and peri-operative variables, and validated using medical records. RESULTS: Eighty individuals completed the survey; median follow-up was 9.5 years (IQR:6.43,12.73). 47.5% underwent a pancreatoduodenectomy, and 25.0% a distal pancreatectomy; 40.0% had adenocarcinoma. 57.1% reported long-term weight loss, of which 65.9% was unintentional. While 1.3% took pancreatic enzymes before surgery, 38.8% utilized after. 12.5% had diabetes before, and 28.6% after surgery; 22 of 30 patients required insulin replacement therapy (73.3%). 41.3% reported hospitalizations, 17.5% required endoscopies and 28.8% additional operations after full recovery. Need for additional interventions were not related to pathology or post-operative complications, but were more common among patients undergoing a Whipple. CONCLUSION: More than half of patients will have a long-term medical complication attributable to pancreatectomy. In comparison to the literature, it may be inferred that consequences occur within the first few years after surgery, and do not compound over time.

Ras-dependent activation of BMAL2 regulates hypoxic metabolism in pancreatic cancer.

To identify novel drivers of malignancy in pancreatic ductal adenocarcinoma (PDAC), we employed regulatory network analysis, which calculates the activity of transcription factors and other regulatory proteins based on the integrated expression of their positive and negative target genes. We generated a regulatory network for the malignant epithelial cells of human PDAC using gene expression data from a set of 197 laser capture microdissected human PDAC samples and 45 low-grade precursors, for which we had matched histopathological, clinical, and epidemiological annotation. We then identified the most highly activated and repressed regulatory proteins (e.g. master regulators or MRs) associated with four malignancy phenotypes: precursors vs. PDAC (initiation), low-grade vs. high grade histopathology (progression), survival post resection, and association with KRAS activity. Integrating across these phenotypes, the top MR of PDAC malignancy was found to be BMAL2, a member of the PAS family of bHLH transcription factors. Although the canonical function of BMAL2 is linked to the circadian rhythm protein CLOCK, annotation of BMAL2 target genes highlighted a potential role in hypoxia response. We previously demonstrated that PDAC is hypovascularized and hypoperfused, and here show that PDAC from the genetically engineered KPC model exists in a state of extreme hypoxia, with a partial oxygen pressure of <1mmHg. Given the close homology of BMAL2 to HIF1ß (ARNT) and its potential to heterodimerize with HIF1A and HIF2A, we investigated whether BMAL2 plays a role in the hypoxic response of PDAC. Indeed, BMAL2 controlled numerous hypoxia response genes and could be inhibited following treatment with multiple RAF, MEK, and ERK inhibitors, validating its association with RAS activity. Knockout of BMAL2 in four human PDAC cell lines led to defects in growth and invasion in the setting of hypoxia. Strikingly, BMAL2 null cells failed to induce glycolysis upon exposure to severe hypoxia and this was associated with a loss of expression of the glycolytic enzyme LDHA. Moreover, HIF1A was no longer stabilized under hypoxia in BMAL2 knockout cells. By contrast, HIF2A was hyper-stabilized under hypoxia, indicating a dysregulation of hypoxia metabolism in response to BMAL2 loss. We conclude that BMAL2 is a master regulator of hypoxic metabolism in PDAC, serving as a molecular switch between the disparate metabolic roles of HIF1A- and HIF2A-dependent hypoxia responses.

Multiplexed single-cell analysis reveals prognostic and nonprognostic T cell types in human colorectal cancer.

Clinical outcomes in colorectal cancer (CRC) correlate with T cell infiltrates, but the specific contributions of heterogenous T cell types remain unclear. To investigate the diverse function of T cells in CRC, we profiled 37,931 T cells from tumors and adjacent normal colon of 16 patients with CRC with respect to transcriptome, TCR sequence, and cell surface markers. Our analysis identified phenotypically and functionally distinguishable effector T cell types. We employed single-cell gene signatures from these T cell subsets to query the TCGA database to assess their prognostic significance. We found 2 distinct cytotoxic T cell types. GZMK+KLRG1+ cytotoxic T cells were enriched in CRC patients with good outcomes. GNLY+CD103+ cytotoxic T cells with a dysfunctional phenotype were not associated with good outcomes, despite coexpression of CD39 and CD103, markers that denote tumor reactivity. We found 2 distinct Treg subtypes associated with opposite outcomes. While total Tregs were associated with good outcomes, CD38+ Tregs were associated with bad outcomes independently of stage and possessed a highly suppressive phenotype, suggesting that they inhibit antitumor immunity in CRC. These findings highlight the potential utility of these subpopulations in predicting outcomes and support the potential for novel therapies directed at CD38+ Tregs or CD8+CD103+ T cells.

Proximal Gastrectomy Is a Viable Alternative to Total Gastrectomy in Early Stage Proximal Gastric Cancer.

BACKGROUND: Total gastrectomy with Roux-en-Y esophagojejunostomy is a life-extending procedure for patients with nonmetastatic proximal gastric and gastroesophageal junction adenocarcinoma, yet it can be a life-altering procedure with negative impact on quality of life.1 Perioperative recovery often involves the need for supplemental nutrition (either enteral or parenteral). Furthermore, long-term effects of early satiety, dysphagia, sustained weight loss, and difficulty in maintaining a healthy weight, dumping syndrome, and intestinal overgrowth are not unusual. Although the alternative of untreated cancer is clearly unacceptable, these lifestyle consequences are not benign. METHODS: A retrospective review of patients who had undergone laparoscopic total and proximal gastrectomy for gastric adenocarcinoma was conducted. Patient demographic data, pathologic parameters, and short-term and long-term clinical data were compared between total gastrectomy and proximal gastrectomy cohorts. RESULTS: Seventeen patients were included in the study: 13 had undergone laparoscopic total gastrectomy (LTG) and 4 had undergone laparoscopic proximal gastrectomy (LPG). Patients who had LPG, given the nature of the procedure, were confined to early stage (up to T2) tumors in the gastric cardia or GE junction. Patients who had LTG tended to be larger, later stage tumors (but not exclusively). The mean operative time was greater for LTG than for LPG (247 ± 54 versus 181 ± 49 min, respectively, P = .036). Length of hospital stay (9.0 ± 3.2 versus 5.0 ± 0.8 days, P < .001) and readmission for postoperative complication (38.5 versus 0%, P = .009) were also higher in the LTG group. There was no significant difference in terms of mean estimated blood loss or blood transfusion rates, overall complications, or anastomotic stricture requiring endoscopic dilation between the patients who underwent LTG and those who underwent LPG. CONCLUSION: In early stage tumors (T1b or T2), proximal gastrectomy (PG) should be considered to mitigate diminished quality of life. PG with esophagogastrostomy, which can easily be performed minimally invasively, can be more tolerable for the patient, with no anatomic basis for dumping syndrome or small intestinal bacterial overgrowth (SIBO), and a greater reservoir for more normal meal habits when compared to total gastrectomy (TG) with Roux-en-Y reconstruction.

Long-term quality of life and global health following pancreatic surgery for benign and malignant pathologies.

BACKGROUND: While the frequency of pancreatic operations are increasing, understanding quality of life is still insufficient. The aim was to evaluate global health and quality of life of long-term survivors from a range of pancreatic operations using internationally validated instruments. METHODS: Patients surviving longer than 5 years after pancreatic operations were surveyed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Cancer-30 and Pancreatic Cancer-26 modules. Variables were analyzed according to demographic and clinical features. RESULTS: Eighty patients completed questionnaires. The median follow-up was 9.3 years from the time of operation. The mean scores of global health status/quality of life, physical function, role function, emotional function, cognitive function, and social functioning were 73.9, 83.7, 84.6, 81.1, 80.2, and 86.3, respectively. The participants' reported quality of life was comparable or better than the general United States population. The summary score, which was defined as weighted average of function and symptom scores (excluding global health status/quality of life and financial impact scores), showed significant differences according to the level of education (70.1 no college vs 85.2 college and 85.7 grad school, P = .049), operation type (79.9 pancreatoduodenectomy vs 91.1 total, P = .043), additional endoscopic retrograde cholangiopancreatography (77.3 vs 86.0, P = .029), and additional abdominal operations related to the primary operation (79.0 vs 86.6, P = .026). CONCLUSION: Long-term survivors of pancreatectomy had comparable or better global health status/quality of life, function scale, and lower symptom scores than the general population of the United States, though persistent gastrointestinal symptoms are common. These findings should help inform patients of the long-term consequences of pancreatectomy, so they can make better decisions especially when considering prophylactic operations.

Noninvasive Young's modulus visualization of fibrosis progression and delineation of pancreatic ductal adenocarcinoma (PDAC) tumors using Harmonic Motion Elastography (HME) in vivo.

Background and aims: Poor specificity and predictive values of current cross-sectional radiological imaging methods in evaluation of pancreatic adenocarcinoma (PDAC) limit the clinical capability to accurately stage the tumor pre-operatively and provide optimal surgical treatment and improve patient outcomes. Methods: In this study, we applied Harmonic Motion Elastography (HME), a quantitative ultrasound-based imaging method to calculate Young's modulus (YM) in PDAC mouse models (n = 30) and human pancreatic resection specimens of PDAC (n=32). We compared the YM to the collagen assessment by Picrosirius red (PSR) stain on corresponding histologic sections. Results: HME is capable of differentiating between different levels of fibrosis in transgenic mice. In mice without pancreatic fibrosis, the measured YM was 4.2 ± 1.3 kPa, in fibrotic murine pancreata, YM was 5.5 ± 2.0 kPa and in murine PDAC tumors, YM was 11.3 ± 1.7 kPa. The corresponding PSR values were 2.0 ± 0.8 %, 9.8 ± 3.4 %, and 13.2 ± 1.2%, respectively. In addition, three regions within each human surgical PDAC specimen were assessed: tumor, which had both the highest Young's modulus (YM > 40 kPa) and collagen density (PSR > 40 %); non-neoplastic adjacent pancreas, which had the lowest Young's modulus (YM < 15 kPa) and collagen density (PSR < 10%) and a transitional peri-lesional region between the tumor and non-neoplastic pancreas with an intermediate value of measured Young's modulus (15 kPa < YM < 40 kPa) and collagen density (15% < PSR < 35 %). Conclusion: In conclusion, a non-invasive, quantitative imaging tool for detecting, staging and delineating PDAC tumor margins based on the change in collagen density was developed.

Harmonic Motion Imaging of Pancreatic Tumor Stiffness Indicates Disease State and Treatment Response.

PURPOSE: Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment. EXPERIMENTAL DESIGN: Harmonic motion imaging (HMI) is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens. RESULTS: In mice, we learned that stiffness increased during progression from preneoplasia to adenocarcinoma and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2-mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients. CONCLUSIONS: These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in PDA.

Resection of Locally Advanced Pancreatic Cancer without Regression of Arterial Encasement After Modern-Era Neoadjuvant Therapy.

INTRODUCTION: Modern-era systemic therapy for locally advanced pancreatic adenocarcinoma (LAPC) offers improved survival relative to historical regimens but not necessarily improved radiographic downstaging to allow more patients to undergo resection. The aim of this study was to evaluate the survival, progression, and pathologic outcomes after resection of LAPC that did not regress from > 180 degrees arterial encasement after neoadjuvant therapy. METHODS: Sixty-one LAPC patients were brought to the operating room after neoadjuvant therapy for NCCN-defined unresectable pancreatic cancer between 2012 and 2017. Pts were explored with intent of pancreatectomy and irreversible electroporation for margin extension; 5 (8%) had metastatic lesions on exploratory laparoscopy and were excluded from analyses. Imaging was re-examined to confirm LAPC prior to surgery. Data were analyzed from a prospective pancreatic cancer database. RESULTS: Patients had arterial involvement of the celiac axis (37.5%) and/or superior mesenteric artery (42.9%) and/or an extended length of the common hepatic (n = 44.6%) artery. Twenty-nine males and 27 females, median 65 years of age, received neoadjuvant gemcitabine-based (58.9%) or FOLFIRINOX (35.7%) chemotherapy and stereotactic body (42.9%) or intensity-modulated (51.8%) radiation therapy. Median months from initiation of neoadjuvant therapy to surgery was 7.5. Sixty-one percent underwent Whipple, 21% distal, and 18% modified Appleby procedures; 57% patients underwent venous reconstruction. Ninety-day mortality was 2%. An R0 margin was achieved in 80%, and 53% were N0. Median overall and progression-free survival was 18.5 (95%CI 12.27-32.33) and 8.5 months (95%CI 6.0-15.0), respectively. One- and 3-year survival from surgery was 68.5% (95%CI 53.0-79.7) and 39.0% (95%CI 23.7-53.8), respectively. CONCLUSION: With modern-era neoadjuvant therapy, R0 resections can be achieved in a majority of non-metastatic patients with locally advanced, unresectable disease based on cross-sectional imaging.

Routine chest X-ray is unnecessary after ultrasound-guided central venous line placement in the operating room.

BACKGROUND: Central venous catheters (CVC) can be useful for perioperative monitoring and insertion has low complication rates. However, routine post insertion chest X-rays have become standard of care and contribute to health care costs with limited impact on patient management. METHODS: 200 patient charts who underwent pancreaticoduodenectomy with central line placement and early line removal were reviewed for clinical complications related to central line placement as well as radiographic evidence of malpositioning. A cost analysis was performed to estimate savings if CXR had not been performed across routine surgical procedures requiring central access. RESULTS: In 200 central line placements for Whipple procedures, 198 lines were placed in the right internal jugular and 2 were placed in the subclavian. No cases of pneumothorax or hemothorax were identified and 30 (15.3%) of CVCs were improperly positioned. Only 1 (0.5%) of these was deemed clinically significant and repositioned after the CXR was performed. CONCLUSION: Routine CXR consumes valuable time and resources (≅$155,000 annually) and rarely affects management. Selection should be guided by clinical factors.