Pancreatic resections: 30 and 90-day outcomes in octogenarians.

BACKGROUND: Pancreatic tumors are frequently found in a geriatric population. Given that the median age of patients with pancreatic cancer is 70 years at diagnosis and the ubiquity of CT and MRI imaging has increased the detection of pancreas masses, pancreatic surgeons often find themselves operating on patients of advanced age. This study sought to evaluate the outcomes of pancreatic resection in an octogenarian population at a single institution with a dedicated surgical oncology team. STUDY DESIGN: A retrospective chart review was performed for all patients undergoing pancreatic resection over a 13-year period at an academic community cancer center. Patient characteristics and operative outcomes were compared between patients aged 80 and older, and those younger than 80. Student t-tests, Fisher's exact test, and Kruskal-Wallis tests were used for univariate analyses. RESULTS: Over the 13-year period, a total of 48 patients of 403 undergoing pancreatic resections were aged 80 or older. Of these 48 patients, 35 underwent pancreaticoduodenectomy (Whipple) and 13 underwent distal pancreatectomy. Patient characteristics including ASA classification were similar among the two age groups. The procedures themselves were equally complicated with similar operative times, transfusion requirements, estimated blood losses, and portal vein resections. The number and severity of complications such as delayed gastric emptying and pancreatic leak were not statistically different between the two groups. Additionally, the 30-day reoperation, readmission, and mortality rates were not statistically different. Outcomes at 90-days revealed an increased rate of readmission amongst octogenarians who underwent Whipple without an increase in rates of major complications. The total number of deaths in the octogenarian group was 3 (6.2%) vs. 6 (1.7%) in the non-octogenarian group (p = 0.080). The median length of stay was similar amongst the two age groups. CONCLUSIONS: At a large-volume academic community cancer center with a dedicated surgical oncology team, highly selected octogenarians can undergo pancreatic resection safely with outcomes that do not differ significantly from their younger counterparts.

Characteristics of Gastrointestinal Stromal Tumors incidentally discovered during abdominal surgery.

BACKGROUND: Gastrointestinal Stromal Tumors (GISTs) are rare sarcomas with 5000 new cases arising in the United States each year. Despite their low incidence, general surgeons should be familiar with GISTs since a quarter of these neoplasms are encountered incidentally. METHODS: A retrospective medical records review was conducted to create a database of all GISTs resected from January 2005 to May 2019. We isolated patients who had incidental discovery of GISTs intraoperatively or within final pathology. Characteristics of patient (Age, gender), index procedure (malignant vs. benign, elective vs. emergent) and tumor (location, size and mitotic rate) were analyzed. RESULTS: A total 48 patients were incidentally discovered to have a GIST excised during index operation. The mean age of these patients was 62 years, with 27 females and 21 males. The primary location of tumors in descending frequency was stomach (30), small bowel (15), colon/rectum (2) and esophagus (1). The average size of all tumors was 1.2 cm, with the average size of the stomach, small bowel, colon/rectum and esophagus at 0.9 cm, 1.7 cm, 0.9 cm and 0.3 cm respectively. Mitotic rate was less than 5 mitosis per 50 HPF in 96% of patients. Incidental tumors were identified during both bariatric (13) and non-bariatric stomach surgery (8), colorectal surgery (14), hernia repair (4), ampullary/pancreatic surgery (5), esophageal surgery (2) liver surgery (1) and uterine surgery (1). Most incidental-GISTs were identified during elective surgery (81%, 39). Finally, 15 of the tumors were identified during surgery for other malignancies. CONCLUSIONS: One quarter (25%) of the GISTs encountered at our academic community cancer center over a 15-year period were discovered incidentally. These tumors had less malignant characteristics overall and were likely cured with surgical resection.

High volume pancreaticoduodenectomy performed at an academic community cancer center.

BACKGROUND: We sought to evaluate the post-operative outcomes of patients undergoing pancreaticoduodenectomy at a high volume academic community cancer center. METHODS: A retrospective review was performed of patients undergoing pancreaticoduodenectomy over a 10-year period. RESULTS: Over 10 years, 213 patients underwent pancreaticoduodenectomy. Median age was 66y. Most patients had significant comorbidities (median ASA = 3) and were overweight (median BMI = 27). Median operative time and blood loss were 253 min and 500 ml, respectively. 160 (75%) out of 213 patients had a malignant lesion on final pathology. 121 (76%) out of 160 had R0 resection. Median lymph nodes harvested was 13. Overall incidence of DGE was 31% (67/213), with clinically significant DGE in 15% (32/213). Pancreatic leak rate was 18% (37/213), with clinically significant leaks in 10% (21/213). Median length of stay was 8 days. Grade 3/4 morbidity rate was 21% (44/206), and 30-day mortality was 2% (5/213). CONCLUSIONS: At a high volume academic community cancer center, pancreaticoduodenectomy can be performed with excellent outcomes on par with any academic center or university hospital.

Complex distal pancreatectomy outcomes performed at a single institution.

OBJECTIVE: Discuss the outcomes of distal pancreatectomy in a high volume academic community cancer center. INTRODUCTION: Distal pancreatectomy can be done with minimal morbidity and mortality in high volume centers. However, there are limited reports of distal pancreatectomy being performed in the community. This study sought to define the experience with distal pancreatectomy at a high volume community cancer center with a dedicated surgical oncology team. METHODS: A retrospective chart review was performed for patients undergoing distal pancreatectomy performed over a twelve year period (2005-2017) at an academic community cancer center. RESULTS: 157 patients underwent distal pancreatectomy. The distribution of open, laparoscopic and robotic resections were 96 (61%), 42 (27%) and 19 (12%) respectively. Concomitant organ resection other than splenectomy was performed in 54 (34%) patients. Spleen sparing resections were performed in 6 (4%) patients. 84 (54%) out of the 157 resections had a malignant lesion on final pathology. Median length of stay was 6 days with 25 (16%) patients readmitted within 30 days. Grade 3 or 4 morbidity rate was 18% (28/157). The incidence of clinically significant pancreatic fistula (Grade B/C) was 8% (13/157). The reoperative rate was 3% (5/157). Overall 30 day mortality in all patients was 0.6% (1/157). CONCLUSION: This is the largest series of distal pancreatic resections reported in a community cancer hospital. In a high volume academic community cancer center with a dedicated surgical oncology team, distal pancreatic resections can be performed with short hospital stays, minimal morbidity, and a mortality rate of less than 1%.

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma.

Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.

Clinical Presentation and Diagnosis of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors are a rare group of neoplasms that arise from multipotent stem cells in the pancreatic ductal epithelium. Although they comprise only 1% to 2% of pancreatic neoplasms, their incidence is increasing. Most pancreatic neuroendocrine tumors are nonfunctioning, but they can secrete various hormones resulting in unique clinical syndromes. Clinicians must be aware of the diverse manifestations of this disease, as the key step to management of these rare tumors is to first suspect the diagnosis.

Outcomes of gastric cancer resections performed in a high volume community cancer center.

BACKGROUND: Large University Hospitals are usually the referral centers for complex surgical procedures. However, the majority of cancer care takes place in the community hospital. The aim of this study was to analyze the morbidity, mortality and long-term survival of gastric cancer patients after the establishment of a multidisciplinary gastric cancer team in an academic community hospital. METHODS: A retrospective review of medical records was performed for patients who presented with gastric cancer from 2005 to 2013. Thirty-day morbidity and mortality were assessed for patients who underwent gastrectomy with curative intent. Long-term survival was determined by Kaplan-Meier analysis. RESULTS: Ninety-one patients underwent curative resection over an 8-year period. Eighty-seven patients (96%) had an R0 resection. Mean lymph node recovery was 20. Serious morbidity rate was reported in 10/91 (11%). Mortality in the series was 3/91 (3%). Five-year survival by stage was similar to AJCC reported survival. CONCLUSION: Complex surgical resections for gastric cancer can be safely performed at a high volume community cancer center with minimal morbidity and mortality.

Multidisciplinary management of gastric cancer.

Treatment of gastric cancer involves a multidisciplinary approach to achieve long-term outcome, including surgery, chemotherapy, and radiation therapy. Most patients present with advanced disease and are not candidates for a curative approach. Palliative chemotherapy is recommended for symptom control and for short-term advances in survival. Surgery combined with different chemotherapy and chemoradiation options improves survival. Initial studies focused on adjuvant chemoradiation and showed improved survival. More recent trials have demonstrated that perioperative chemotherapy before and after surgery provides a survival advantage. Such an approach may also downstage marginal patients who can then be selected to undergo curative resection and complete adjuvant chemotherapy.

Gastrointestinal stromal tumors of the stomach.

Gastrointestinal stromal tumors (GISTs) are relatively rare mesenchymal tumors located within the submucosa of the GI tract. The defining characteristic of GISTs is the presence of the cell-surface antigen CD117 receptor tyrosine kinase, identified by immunohistochemistry. Currently the only cure for GIST is complete surgical resection. Imatinib has revolutionized the treatment of GISTs and has been used as adjuvant treatment after resection, and as treatment for locally advanced, recurrent, and metastatic GIST. Imatinib resistance has become a significant concern in the treatment of GISTs and other tyrosine kinase inhibitors that target different pathways are currently being studied.

Peritoneal surface malignancies and regional treatment: a review of the literature.

Recent studies have lead to a renewed interest in cytoreductive surgery and intraperitoneal chemotherapy as a regional treatment modality for patients with peritoneal surface malignancies. There have been multiple phase III randomized trials that have shown a survival advantage with intraperitoneal chemotherapy in certain patients. More well designed phase III studies are needed to further define which groups of patients may benefit from cytoreductive surgery and intraperitoneal chemotherapy.

Tumor necrosis factor-α treatment of HepG2 cells mobilizes a cytoplasmic pool of ERp57/1,25D3-MARRS to the nucleus.

ERp57/PDIA3/1,25-MARRS has diverse functions and multiple cellular locations in various cell types. While classically described as an endoplasmic reticulum (ER) resident protein, ERp57 has a nuclear location sequence (NLS) and can enter the nucleus from the cytosol to alter transcription of target genes. Dysregulation and variable expression of ERp57 is associated with a variety of cancers including hepatocellular carcinoma (HCC). We investigated the dynamic mobility of ERp57 in an HCC cell line, HepG2, to better understand the movement and function of the non-ER resident pool of ERp57. Subcellular fractionation indicated ERp57 is highly expressed in the ER with a smaller cytoplasmic pool in HepG2 cells. Utilizing an ERp57 green fluorescent protein fusion construct created with and without a secretory signal sequence, we found that cytoplasmic ERp57 translocated to the nucleus within 15 min after tumor necrosis factor-α (TNF-α) treatment. Protein kinase C activators including 1,25-dihydroxyvitamin D(3) and phorbol myristate acetate did not trigger nuclear translocation of ERp57, indicating translocation is PKC independent. To determine if an interaction between the rel homology binding domain in ERp57 and the nuclear factor-κB subunit, p65, occurred after TNF-α treatment and could account for nuclear movement, co-immunoprecipitation was performed under control and conditions that stabilized labile disulfide bonds. No support for a functional interaction between p65 and ERp57 after TNF-α treatment was found in either case. Immunostaining for both ERp57-GFP and p65 after TNF-α treatment indicated that nuclear translocation of these two proteins occurs independently in HepG2 cells.

Malignant masquerade: dilemmas in diagnosing biliary obstruction.

The hepatobiliary surgeon must be as familiar with the nonmalignant processes that can affect the extrahepatic biliary tree as they are with the malignant causes. Subtleties in the patient's history, presentation, and imaging studies may prevent unnecessary extensive hepatobiliary resection. The focus of this article deals with the etiology of nonmalignant obstruction at the biliary bifurcation and hilum and the mid-bile duct. It does not focus on either choledocholithiasis or pancreatitis, the two most common causes of distal bile duct obstruction. Obstruction from pancreatic cancer is also not the focus of this discussion.

Perihepatic lymph node micrometastases impact outcome after partial hepatectomy for colorectal metastases.

BACKGROUND: Hepatectomy for resectable colorectal liver metastases provides a survival advantage but is usually reserved for patients without extrahepatic disease. Metastases to perihepatic lymph nodes (LN) occur with controversial significance. This study uses standard pathologic analysis and immunohistochemistry (IHC) to determine the impact of occult metastatic disease to perihepatic LN in patients with colorectal cancer undergoing hepatectomy. METHODS: Fifty-nine patients with liver metastases from colon or rectal primary cancer were studied prospectively. Perihepatic LN were sampled from the portocaval, pancreaticoduodenal, and common hepatic artery regions. All LN were analyzed using hematoxylin and eosin (H&E), and those negative by H&E were analyzed using IHC for cytokeratin. Recurrence and survival were compared amongst LN groups. RESULTS: Median follow-up was 42 months for survivors. There were eight patients with metastatic disease to at least one perihepatic LN identified by H&E and fourteen patients with metastases identified by IHC only. Forty-one patients (70%) recurred after resection, and patients with LN metastases, regardless of detection method, had a shorter recurrence-free survival compared to node negative patients. However, patterns of recurrence differed by LN group. Compared to H&E-positive patients, IHC-positive patients had a better overall survival and were more likely to recur at a single site amenable to salvage resection. CONCLUSIONS: In patients with hepatic colorectal metastases, IHC analysis of perihepatic LN adds prognostic value regarding the timing and burden of recurrence after resection. Routine IHC assessment of perihepatic LN is reasonable since the information garnered would potentially influence postresection chemotherapy recommendations.

Total mesorectal excision and pelvic node dissection for rectal cancer: an appraisal.

Total mesorectal excision has revolutionized the surgical treatment of rectal cancer since its introduction in the 1980s. The rationale, technique, and outcomes of total mesorectal excision in rectal cancer are explored. Lateral pelvic lymph node dissection is used by the Japanese in selected patients and has remained a controversial approach in the management of rectal cancer. The technique, controversies, and outcomes are summarized.

Is detection of asymptomatic recurrence after curative resection associated with improved survival in patients with gastric cancer?

BACKGROUND: It is not clear if more intense surveillance is associated with improved survival after curative resection for cancer. In the context of a followup program after curative gastrectomy, recurrence and survival were investigated for patients presenting with either symptomatic or asymptomatic recurrence. STUDY DESIGN: A prospectively maintained gastric cancer database was used to identify all patients who underwent a curative (R0) gastrectomy from July 1985 to June 2000. Survival curves were generated for patients with either symptomatic or asymptomatic recurrence, and the prognostic variables associated with outcomes were identified. RESULTS: Of 1,172 patients who underwent a curative (R0) gastrectomy, 561 patients (48%) had documented recurrence and 382 patients had complete data about symptoms. Median time to recurrence was 10.8months for asymptomatic patients and 12.4months for symptomatic patients (p = NS). Median postrecurrence survival was 13.5months for asymptomatic patients and 4.8months for symptomatic patients (p < 0.01). Median disease-specific survival was 29.4months for asymptomatic patients and 21.6months for symptomatic patients (p < 0.05). Variables predictive of poor postrecurrence survival included symptomatic recurrence, advanced stage (III/IV), poor differentiation, short disease-free interval (<12months), and multiple sites of recurrence. CONCLUSIONS: Followup did not identify asymptomatic recurrence earlier than symptomatic recurrence. Patients with symptomatic recurrence have more aggressive disease with a shorter postrecurrence survival. The impact of detecting asymptomatic recurrence in the course of followup after curative gastrectomy could not be distinguished from the effects of four powerful biologic variables that also interact to govern outcomes.

Determinants of unresectability and outcome of patients with occult colorectal hepatic metastases.

BACKGROUND: Patients chosen for liver resection of colorectal liver metastases are a select group with minimal disease, favorable tumor biology and earlier presentation when compared to unresectable patients. Despite intense preoperative assessments, operative detection of occult unresectable disease is inevitable for a small group of patients. The aim of this study was to evaluate determinants of occult unresectability, and to establish if patients with occult unresectable disease demonstrate survival benefits similar to resected patients, or more similar to patients diagnosed with metastatic disease who were never explored. METHODS: A retrospective medical record review was performed on 171 patients with colorectal hepatic metastases who underwent exploration with the intent of performing a curative liver resection. Patient and tumor characteristics, operative findings and survival were evaluated. Univariate and multivariate analysis were performed to evaluate determinants of unresectability, and survival was determined by Kaplan-Meier analysis. RESULTS: One hundred forty-six patients were completely resected and 25 patients were found to have occult unresectable disease during exploration. Of these 25 patients, 10 had more extensive hepatic disease than expected which precluded resection, while 15 patients had unexpected extrahepatic disease. Of the 15 patients with extrahepatic disease, 7 had otherwise resectable liver metastases. Only bilobar disease was a statistically significant finding associated with occult unresectability on multivariate analysis (P = 0.05). Resected patients had a median survival of 37 months, while unresected patients had a median survival of 17 months (P < 0.005). At 3 and 5 years, the overall survival for resected patients was 52% and 29%. The survival at 3 years for patients with occult unresectable disease was only 5%, with no 5 year survivors. CONCLUSIONS: The majority of patients with occult unresectable colorectal hepatic metastases had bilobar disease or extrahepatic spread. Despite the process of patient selection that leads to an attempt for curative resection, patients with occult unresectable disease identified at exploration suffer from poor survival that approximates the outcome of patients never considered for resection.

Effect of murine liver cell proliferation on herpes viral behavior: implications for oncolytic viral therapy.

Replication-competent herpes simplex oncolytic viruses are promising anticancer agents that partly target increased DNA synthesis in tumor cells. Investigators have proposed that these DNA viruses may be combined with liver resection to enhance killing of liver malignancies. Whether or not the cellular alterations associated with hepatic regeneration affect the efficacy and toxicity of these promising anticancer agents is unknown. This study examined the behavior of two oncolytic viruses, NV1020 and G207, during liver regeneration. When delivered during the peak of liver regeneration, replication and appearance of both G207 and NV1020 in hepatic tissue are enhanced as demonstrated by histochemical staining for the marker gene lac Z, immunohistochemical staining, and quantitative polymerase chain reaction. This increased appearance of virus in liver tissue correlates with increases in cellular ribonucleotide reductase activity and DNA synthesis and is also associated with increased viral binding. However, increased viral presence is transient, and viral detection declines to baseline within 7 days. When these viruses were delivered to animals even as early as 7 days after hepatectomy, there proved to be no measurable viral replication in any organ and no increased morbidity or mortality. In conclusion, the early stages of hepatic regeneration after resection provide an environment suitable for viral replication. Administration of replication-competent herpes simplex virus during the peak of hepatocyte regeneration (24-48 hours) permits viral productivity in tissue that otherwise does not support viral growth. The increase in hepatotoxicity after hepatectomy is short-lived and can be predicted by peak hepatocyte DNA synthesis.

Up-regulation of GADD34 mediates the synergistic anticancer activity of mitomycin C and a gamma134.5 deleted oncolytic herpes virus (G207).

Oncolytic viruses used for gene therapy have been genetically modified to selectively target tumor cells while sparing normal host tissue. The multimutant virus G207 has been attenuated by inactivation of viral ribonucleotide reductase and by deletion of both viral gamma134.5 genes. Deletion of gamma134.5 greatly decreases the neurovirulence of this mutant virus but also reduces its antitumor efficacy. The mammalian homologue to the gamma134.5 gene product is the GADD34 protein. This protein can functionally substitute for the gamma134.5 gene and is also up-regulated during DNA damage. We postulated that combining use of the chemotherapy agent mitomycin C (MMC) with G207 will selectively up-regulate GADD34 in tumor that may complement the gamma134.5 gene deletion and augment viral antitumor efficacy. This hypothesis was tested in human gastric cells in vitro and in vivo. Using both the isobologram method and combination-index method of Chou-Talalay, significant synergism was demonstrated between MMC and G207. As a result of such synergism, a dose-reduction for each agent can be accomplished over a wide range of drug-effect levels without sacrificing tumor cell kill. Northern blot analysis confirmed that expression of GADD34 mRNA was increased by MMC treatment. SiRNA directed at GADD34 decreased MMC-associated enhancement of viral proliferation and resulted in decreased viral synergy with MMC. These data indicate that induction of GADD34 selectively restores the virulent phenotype of the deleted gene in G207 and thus provides a cellular basis for the combined use of DNA-damaging agents and gamma134.5 HSV mutants in the treatment of cancer.