Pilot Study to Optimize Goal-directed Hemodynamic Management During Pancreatectomy.

INTRODUCTION: Intraoperative goal-directed hemodynamic therapy (GDHT) is a cornerstone of enhanced recovery protocols. We hypothesized that use of an advanced noninvasive intraoperative hemodynamic monitoring system to guide GDHT may decrease intraoperative hypotension (IOH) and improve perfusion during pancreatic resection. METHODS: The monitor uses machine learning to produce the Hypotension Prediction Index to predict hypotensive episodes. A clinical decision-making algorithm uses the Hypotension Prediction Index and hemodynamic data to guide intraoperative fluid versus pressor management. Pre-implementation (PRE), patients were placed on the monitor and managed per usual. Post-implementation (POST), anesthesia teams were educated on the algorithm and asked to use the GDHT guidelines. Hemodynamic data points were collected every 20 s (8942 PRE and 26,638 POST measurements). We compared IOH (mean arterial pressure <65 mmHg), cardiac index >2, and stroke volume variation <12 between the two groups. RESULTS: 10 patients were in the PRE and 24 in the POST groups. In the POST group, there were fewer minimally invasive resections (4.2% versus 30.0%, P = 0.07), more pancreaticoduodenectomies (75.0% versus 20.0%, P < 0.01), and longer operative times (329.0 + 108.2 min versus 225.1 + 92.8 min, P = 0.01). After implementation, hemodynamic parameters improved. There was a 33.3% reduction in IOH (5.2% ± 0.1% versus 7.8% ± 0.3%, P < 0.01, a 31.6% increase in cardiac index >2.0 (83.7% + 0.2% versus 63.6% + 0.5%, P < 0.01), and a 37.6% increase in stroke volume variation <12 (73.2% + 0.3% versus 53.2% + 0.5%, P < 0.01). CONCLUSIONS: Advanced intraoperative hemodynamic monitoring to predict IOH combined with a clinical decision-making tree for GDHT may improve intraoperative hemodynamic parameters during pancreatectomy. This warrants further investigation in larger studies.

Impact of Hospital Volume on Utilization of Minimally Invasive Surgery for Gastric Cancer.

BACKGROUND: Minimally invasive surgery (MIS) for gastric cancer is increasingly performed. The purpose of this study is to evaluate trends in utilization of laparoscopic and robotic techniques compared to open surgery as well as utilization based on hospital volume. METHODS: We used the National Cancer Database to query patients who underwent gastrectomy from 2010 to 2017 for adenocarcinoma. Regression analyses were used to determine associations between MIS and clinical factors, the trend of MIS over time, and survival. RESULTS: A total of 18,380 patients met inclusion criteria. The annual rates of MIS increased for all hospital volumes, though lower volume centers were less likely to undergo MIS. MIS was associated with a shorter length of stay compared to open, and robotic gastrectomy had a higher rate of obtaining at least 15 lymph nodes and lower rate of having a positive margin. CONCLUSIONS: MIS utilization for resection of gastric cancer increased over time, with robotic surgery increasing at a higher rate than laparoscopic surgery. Importantly, this occurred without increased in mortality or sacrificing adequate oncologic outcomes.

A Unique Presentation of Metastatic Gallbladder Carcinoma.

Gallbladder carcinoma can be challenging to diagnose and treat and usually leads to poor outcome, due to its aggressive nature and the nonspecific clinical presentation at early stage. We describe an interesting case of a 60-year-old female who presented with stage 3 appendiceal carcinoma after appendectomy was performed outside hospital. Further imaging workup demonstrated enlarged ovarian cysts and porcelain gallbladder. Upon exploration, she was found to have carcinomatosis and we proceeded with cytoreductive surgery (CRS) and hyperthermic intraperitoneal therapy (HIPEC). Final pathology demonstrated carcinoma from gallbladder primary.

A Rare Case of Pancreatic Endometriosis Masquerading as Pancreatic Mucinous Neoplasm.

Endometriosis is a relatively common condition among women, and pancreatic endometriosis has been reported on rare occasions. Such pancreatic lesions are difficult to diagnose and distinguish from other cystic lesions of the pancreas preoperatively. This report describes a case of pancreatic endometriosis in a 51-year-old female patient. Imaging demonstrated an enlarging cyst with findings concerning for a mucinous neoplasm. The patient underwent robotic distal pancreatectomy and splenectomy. Histopathology revealed an endometriotic cyst. Pancreatic endometriosis can be difficult to distinguish from other lesions of the pancreas. Surgical resection should be undertaken in cases where malignancy is suspected.

Patient Comorbidities Drive High Mortality Rates Associated with Major Liver Resections Irrespective of Hospital Volume.

INTRODUCTION: Major hepatectomies are utilized to manage primary hepatic malignancies. Reports from high-volume centers (HVCs) with minimal perioperative mortality focus on multiple aspects of perioperative care, although patient-specific factors remain unelucidated. We identified patient factors associated with outcomes and examined whether these contribute to survival differences. METHODS: We queried the National Cancer Database (2006-2015) for patients with primary liver malignancies managed with major hepatectomy. Facilities were dichotomized by volume (high volume: >15 hepatectomies/year). Perioperative outcomes were compared based on patient demographic and clinical characteristics as well as center volume. RESULTS: 4263 patients were included with 78.5% receiving care in low-volume centers (LVCs). 90-day postoperative mortality was higher in LVCs vs. HVCs (12% vs. 7.5%; P < .001). Factors associated with undergoing surgery in LVCs included: living in areas with lower income (P = .006) and education (P < .001), having nonprivate insurance (P < .001), residing near the care center (P < .001), and having a comorbidity score (CDS) >1 (P = .014). Patients with CDS ≤ 1 had higher 90-day mortality in LVCs (11.3% vs. 6.6%; P < .001) and had similar outcomes in LVCs and HVCs (15.6% vs. 13.7% P = .6). Patients with CDS > 1 were more likely to receive care in LVCs (16.3% vs. 12.7%; P < .001). CONCLUSION: Reduced perioperative mortality following major hepatectomy in HVCs is driven by optimal management of patients with low CDS. However, nearly 1 in 5 patients who undergo major hepatectomies have a high CDS and approximately 15% of them succumb in the perioperative period irrespective of the treating centers' experience.

Characterization of alveolar soft part sarcoma using a large national database.

BACKGROUND: Alveolar soft part sarcoma is a rare, histologic subtype of soft tissue sarcoma that remains poorly defined. We aimed to describe patient characteristics and treatment patterns and to examine factors associated with survival for patients with alveolar soft part sarcoma. METHODS: After identifying patients with alveolar soft part sarcoma in the National Cancer Database, we recorded their clinicopathologic characteristics. Univariable log-rank survival analysis and Cox proportional hazards model were employed. For context, survival comparisons were included for patients with other sarcoma subtypes. RESULTS: Overall, 293 patients with alveolar soft part sarcoma were identified. Interestingly, patients with head and neck tumors were least likely to present with distant disease (40%, P = .025). The majority of patients underwent resection (n = 183, 63%). Among those, no predictors of lesser survival were identified other than the presence of metastases (hazard ratio 6.04, P ≤ .001). Patients with stage IV alveolar soft part sarcoma who underwent resections experienced improved survival relative to similar patients with more common subtypes of soft tissue sarcomas (P ≤ .001). CONCLUSION: Alveolar soft part sarcoma is exceedingly rare, and patients often present with metastases. Primary tumors can occur anywhere in the body, and location impacts the rates of metastases at presentation. Resection is associated with a favorable survival advantage when compared to other, more common histologic subtypes of soft tissue sarcomas.

Gallbladder squamous cell carcinoma: An analysis of 1084 cases from the National Cancer Database.

BACKGROUND/OBJECTIVES: Gallbladder squamous cell carcinoma (SCC) is an uncommon malignancy whose rarity has made it particularly challenging to study. We utilized a national database to shed light on the clinicopathologic characteristics, management patterns, and survival associated with these tumors. METHODS: Patients with gallbladder SCC were identified in the National Cancer Database. Clinicopathologic and treatment characteristics were recorded and compared with adenocarcinoma for context. Univariate and multivariable survival analyses were completed for patients who underwent resection. RESULTS: Overall, 1084 patients with SCC and 23 958 patients with adenocarcinoma were identified. Compared with those with adenocarcinoma, patients with SCC had higher grade tumors (P < .001) and were diagnosed at a later stage (P < .001). Patients with SCC were more likely to undergo radical cholecystectomy (17% vs 9%; P < .001), but had a higher rate of margin positivity (36% vs 29%; P < .001). SCC histology was associated with worse survival compared with adenocarcinoma, even after adjusting for R0 resections (13 vs 29 months; P < .001). On multivariable analysis, SCC histology was independently associated with abbreviated survival (P = .003). CONCLUSIONS: Gallbladder SCCs are aggressive cancers that often present at an advanced stage. Complete surgical extirpation should be pursued when feasible. However, prognosis is worse than that of adenocarcinoma, even after R0 resection.

Primary Gallbladder Neuroendocrine Tumors: Insights into a Rare Histology Using a Large National Database.

BACKGROUND: Primary gallbladder neuroendocrine tumors (NETs) are rare, poorly understood cancers infrequently encountered at even the largest of tertiary referral centers. We therefore sought to identify a large cohort of patients with gallbladder NETs using a national database, with the aim of defining treatment modalities employed and survival associated with these uncommon malignancies. METHODS: Patients with primary gallbladder NETs were identified in the National Cancer Database, and clinicopathologic characteristics were recorded. A univariate log-rank survival analysis was completed for patients who underwent resection. Parameters found to be significant were entered into a multivariate accelerated failure time analysis. For context, survival comparisons were included for patients who underwent resections for NETs at any gastrointestinal site and for gallbladder adenocarcinoma. RESULTS: Overall, 754 patients with gallbladder NETs were identified. Patients were predominantly female (n = 518, 69%), White (n = 503, 67%), presented with stage IV disease (n = 295, 39%) and had high-grade lesions (n = 312, 41%). The majority underwent resection (n = 480, 64%), primarily simple cholecystectomy (n = 431, 90%), whereas a minority received multimodal therapy (n = 145, 21%). Among patients who underwent resection, older age (p = 0.001), large cell histology (p = 0.012), and positive margins (p = 0.030) were independently associated with worse overall survival. Patients with gallbladder NETs had improved survival relative to those with gallbladder adenocarcinoma (p = 0.001), but significantly worse survival than patients with NETs from other gastrointestinal sites (p < 0.001). CONCLUSIONS: Primary gallbladder NETs are aggressive lesions that carry a worse prognosis than NETs of other gastrointestinal sites. Older age, positive margins, and large cell histology are associated with abbreviated survival after resection.

Identification of nonalcoholic fatty liver disease following pancreatectomy for noninvasive intraductal papillary mucinous neoplasm.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) following pancreatectomy is a potential cause of long term morbidity in patients undergoing pancreatic resection with curative intent. Prior studies have reported an incidence of NAFLD up to 30% following pancreatectomy but the investigated cohorts were typically a mix of benign and malignant disease. Here we examined the incidence of NAFLD in a homogenous cohort of patients following pancreatectomy for benign intraductal papillary mucinous neoplasm (IPMN). METHODS: A retrospective review of patients who underwent pancreatic resection for IPMN from 2000 to 2016 was performed. Post pancreatectomy CT/MRI scans were obtained as standard surveillance. We investigated changes in the liver parenchymal density on post surgical imaging to estimate the frequency with which NAFLD occurred. Radiographic criteria for NAFLD included Hounsfield units less than 40 on CT or liver:spleen ratio <0.9 on CT or MRI. Fischer's exact test, Kruskal-Wallis test, and logistic regression were performed. RESULTS: Our study cohort included 109 patients who underwent pancreatectomy for nonmalignant intraductal papillary mucinous neoplasm with no evidence of NAFLD preoperatively and at least 6 months follow-up. Mean follow-up was 52 months (range 8-130/months). The incidence of postoperative NAFLD was 17/109 (15.6%). Most cases occurred within 12 months of pancreatectomy. On multivariate analysis, proximal pancreatectomy (pancreaticoduodenectomy) and development of atrophy of the pancreas remnant were significant risk factors for development of hepatic steatosis (p < 0.05). CONCLUSION: Patients undergoing pancreatectomy for benign disease have a significant risk of developing NAFLD but the frequency is lower than previously reported in cohorts that included individuals with malignant disease. Highest risk was observed in individuals who underwent pancreaticoduodenectomy or developed pancreatic atrophy. Further investigations to define the mechanisms that promote steatosis and interventions to prevent subsequent morbidity from NAFLD are warranted.

Does histology really influence gastric cancer prognosis?

BACKGROUND: Gastric cancer (GC) is associated with poor survival despite curative-intent surgical resection and systemic therapy. Our objective is to examine the impact of histology on prognosis as well as the impact of linitis plastica (LP) on survival. METHODS: The GC database at a single institution was evaluated for patients who underwent resection from 2000 to 2015. Clinicopathologic characteristics were examined and descriptive statistics was used to analyze four groups of patients based on Lauren classification: intestinal (n=93), diffuse (n=20), diffuse with signet-ring cell features (n=57), and LP (n=40). LP patients had diffuse GC but also presented with circumferential infiltration of the gastric wall for at least a third of the stomach length on endoscopy or imaging. Fisher's exact test was used to compare groups; Cox regression was used for multivariate analysis and Kaplan-Meier method for survival. RESULTS: Of 210 patients who underwent gastric resection, 112 (53%) were male with mean age 65.3 years (SD ±14.6 years). Intestinal GC patients were older at diagnosis but other patient demographics were similar between all groups. LP patients had a higher rate of R1 resection despite higher rates of total gastrectomy (P<0.01). Rates of perineural invasion (PNI) and nodal metastasis were higher in LP (P<0.001). The majority of intestinal GC patients (79%) had stage I/II disease compared to 70% of LP patients with stage III disease. Median overall survival (OS) was 13.7 months for LP, 79 months for intestinal, 97 months for signet-ring cell, and not reached for diffuse GC (P<0.001). When stratified by stage, there were no significant differences in survival by histology for stage II and stage III patients. However, by Cox regression analysis, factors associated with worse survival included lymphovascular invasion (LVI), nodal disease, and presence of LP. Neutrophil-lymphocyte ratio (NLR), neoadjuvant and adjuvant therapy, and tumor regression grade did not influence survival on multivariate analysis. CONCLUSIONS: Intestinal GC is thought to have a better prognosis. Interestingly, this study demonstrates similar outcomes in patients with intestinal, diffuse, and signet-ring cell GC. However, a subset of diffuse GC-LP was associated with an infiltrative pattern of disease characterized by PNI and LVI. Despite controlling for poor prognostic markers, LP was independently associated with a worse prognosis. More research is needed to identify methods of earlier diagnosis and effective systemic therapy to treat this aggressive disease.

Endoscopic ultrasound staging for early esophageal cancer: Are we denying patients neoadjuvant chemo-radiation?

AIM: To evaluate the accuracy of endoscopic ultrasound (EUS) in early esophageal cancer (EC) performed in a high-volume tertiary cancer center. METHODS: A retrospective review of patients undergoing esophagectomy was performed and patients with cT1N0 and cT2N0 esophageal cancer by EUS were evaluated. Patient demographics, tumor characteristics, and treatment were reviewed. EUS staging was compared to surgical pathology to determine accuracy of EUS. Descriptive statistics was used to describe the cohort. Student's t test and Fisher's exact test or χ2 test was used to compare variables. Logistic regression analysis was used to determine if clinical variables such as tumor location and tumor histology were associated with EUS accuracy. RESULTS: Between 2000 and 2015, 139 patients with clinical stageIorIIA esophageal cancer undergoing esophagectomy were identified. There were 25 (18%) female and 114 (82%) male patients. The tumor location included the middle third of the esophagus in 11 (8%) and lower third and gastroesophageal junction in 128 (92%) patients. Ninety-three percent of patients had adenocarcinoma. Preoperative EUS matched the final surgical pathology in 73/139 patients for a concordance rate of 53%. Twenty-nine patients (21%) were under-staged by EUS; of those, 19 (14%) had unrecognized nodal disease. Positron emission tomography (PET) was used in addition to EUS for clinical staging in 62/139 patients. Occult nodal disease was only found in 4 of 62 patients (6%) in whom both EUS and PET were negative for nodal involvement. CONCLUSION: EUS is less accurate in early EC and endoscopic mucosal resection might be useful in certain settings. The addition of PET to EUS improves staging accuracy.

Intralesional and systemic immunotherapy for metastatic melanoma.

INTRODUCTION: Immunotherapy has revolutionized the treatment of metastatic melanoma and dramatically improved patient outcomes. Ipilimumab, an inhibitor of cytotoxic T-lymphocyte antigen-4 (CTLA-4), was the first immunotherapeutic agent to demonstrate improved survival in advanced melanoma. More recently, other immune checkpoint inhibitors, including the programmed death-1 (PD-1) inhibitors pembrolizumab and nivolumab, have demonstrated efficacy in locally advanced unresectable and metastatic melanoma. In addition to systemically delivered immunotherapies, intralesional therapies such as talimogene laherparepvec (TVEC) play an important role in the treatment of locoregionally advanced and metastatic melanoma. Areas covered: This review provides an overview of the mechanisms behind immune checkpoint inhibitors. Clinical evidence of their efficacy is presented and discussion of new patterns of response and associated immune related adverse events associated with immunotherapy are provided. Expert opinion: Treatment options for locally advanced and metastatic melanoma are expanding with new developments in immunotherapy and immune checkpoint inhibitors. The utility of these novel therapies in the adjuvant setting is currently being explored. The ideal treatment of metastatic melanoma continues to be multimodal, combining systemic treatments, intralesional and regional therapies, surgery and radiotherapy to achieve optimal outcomes.

Epidermal Growth Factor Receptor Signaling to the Mitogen Activated Protein Kinase Pathway Bypasses Ras in Pancreatic Cancer Cells.

OBJECTIVE: Epidermal growth factor (EGF) receptor (EGFR/HER1) is overexpressed in human pancreatic cancers. However, anti-EGFR therapy does not exhibit significant therapeutic activity with oncogenic K-ras mutation. We sought to assess the signaling relationship between EGFR and mutant K-ras, which is commonly detected in pancreatic cancer. METHODS: Pancreatic cancer cells harboring mutated K-ras were treated with EGF to assess signaling from EGFR to mitogen-activated protein kinase (MAPK) pathway. The role of Ras family of proteins in transducing EGFR signals was assessed using short interfering RNA. Other components of MAPK and PI3K (phosphoinositide 3-kinase) pathways were examined for their roles in EGFR signaling. RESULTS: First, EGF signaling in pancreatic cancer cells occurs selectively through HER1. Second, knockdown of all Ras isoforms failed to block EGF-mediated phosphorylation of extracellular signal-regulated kinase (ERK). Inhibition of Raf was observed to partially abrogate ERK phosphorylation, whereas MEK inhibition resulted in complete attenuation of EGF-mediated ERK phosphorylation. Finally, inhibition of phosphoinositide 3-kinase/AKT and CDC42/PAK pathways did not block EGFR signaling. CONCLUSIONS: Our study results demonstrate that EGFR-mediated signaling in mutant K-ras pancreatic cancer cells does not follow canonical MAPK signaling. Our novel findings suggest the existence of alternate signaling pathways to downstream MAPK in the presence of mutant K-ras.

Impact of gastric cancer resection on body mass index.

Major gastric resection alters digestive function and may lead to profound weight loss. The objective of our study was to evaluate trends in body weight loss after curative gastrectomy for malignancy. A review of patients who underwent gastrectomy from 1999 to 2012 at two institutions was conducted. Patient demographics and treatment were assessed. Student's t test and analysis of variance were used to compare groups. Of 168 patients, two patients (1.2%) were Stage 0, 73 (43.5%) Stage I, 46 (27.4%) Stage II, 45 (26.8%) Stage III, and two (1.2%) stage unknown. Fifty-eight patients (34.5%) underwent total gastrectomy with Roux-en-Y esophagojejunostomy and 110 patients (65.5%) underwent subtotal gastrectomy. The average per cent decreases in body mass index (BMI) postgastrectomy at one month, six months, 12 months, and 24 months were 7.6, 11.7, 11.5, and 11.1 per cent, respectively (P = 0.003). The decreases in BMI were the same for all time periods whether patients had subtotal or total gastrectomy. Weight loss after gastric cancer resection is an important measure of quality of life. By understanding patterns of weight change after gastrectomy, we can better counsel and prepare our patients for the long-term effects of gastric cancer surgery.

Increasing age and survival after orthotopic liver transplantation for patients with hepatocellular cancer.

BACKGROUND: Orthotopic liver transplantation (OLT) is the gold standard treatment for patients with early hepatocellular carcinoma (HCC). There are concerns about the efficacy of OLT for HCC in older patients, who we hypothesized might have poorer outcomes. Therefore, we sought to examine advanced age and its impact on OLT outcomes. STUDY DESIGN: The United Network for Organ Sharing database was queried for patients who underwent OLT for HCC from 1987 to 2009. Patients were divided into 3 age groups: 35 to 49 years old, 50 to 64 years old, and 65 years or older, and patient characteristics were compared. Univariate and multivariate analyses were performed to assess the impact of age on OLT outcomes. RESULTS: Of 10,238 patients with OLT for HCC, 16.5% (n = 1,688) of patients were 35 to 49 years old, 67.8% (n = 6,937) were 35 to 49 years old, and 15.8% (n = 1,613) were 65 years and older. By Kaplan-Meier method, the 50- to 64-year-old age group had the highest overall survival, despite having one of the highest rates of hepatitis C positivity (70%), but this group also had the lowest rate of diabetes mellitus (8.7%). The lowest overall survival was observed in the 65-year or older age group (p < 0.001). Finally, there was no difference in disease-specific survival among the age groups (p = 0.858), and patients aged 65 years and older had the highest rate of death from nonhepatic causes (17.5%). CONCLUSIONS: Although OS was prolonged in younger patients who underwent OLT for HCC, there was no observed difference in disease-specific survival among the age groups. Our results suggest that carefully selected patients 65 years of age and older can derive equal benefit from OLT for HCC when compared with their younger counterparts.

Choledochoduodenostomy as the biliary-enteric bypass of choice for benign and malignant distal common bile duct strictures.

Choledochoduodenostomy (including hepaticoduodenostomy) for common bile duct (CBD) strictures has been underused because of concerns regarding postoperative duodenal fistula and cholangitis attending the so-called "sump syndrome." An institutional retrospective review of 55 consecutive choledochoduodenostomy procedures for CBD strictures from 1995 to 2011 was performed to examine its suitability as the biliary-enteric bypass procedure of choice. There were 30 male (55%) and 25 female (45%) patients with a mean age of 49 years (range, 13 to 73 years). Thirty-seven (67%) patients had benign CBD strictures and 18 (33%) had unresectable periampullary adenocarcinomas. Forty-nine (89%) underwent choledochoduodenostomy and six (11%) underwent hepaticoduodenostomy. There were no 30-day postoperative deaths, anastomotic leaks, or intra-abdominal abscesses. Five patients (9%) sustained Clavien Grade III or IV complications. Over a mean long-term follow-up of 29 months (range, 1 to 162 months), there was one anastomotic stricture successfully managed by endoscopic dilation and temporary stenting. Liver function tests in all other patients returned to and remained within normal limits. We conclude that choledochoduodenostomy is the preferred biliary-enteric bypass for both benign and malignant distal CBD strictures because of its ease, safety, and durability. Persistent fears of duodenal fistula and the "sump syndrome" are not warranted by the empiric data and should be abandoned.

Targeted therapies in colorectal cancer: surgical considerations.

Colorectal cancer (CRC) is a leading worldwide health concern that is responsible for thousands of deaths each year. The primary source of mortality for patients with CRC is the development and subsequent progression of metastatic disease. The most common site for distant metastatic disease is the liver. Although patients with metastatic disease to the liver have several effective treatment options, the only one for cure remains surgical resection of the liver metastases. Historically, most patients with liver metastases have had unresectable disease, and only a small percentage of patients have undergone complete curative resection. However, improved systemic therapies have led to an evolution in strategies to treat metastatic CRC to the liver. Under most conditions the management of these patients remains complex; and as chemotherapy options and new targeted therapies continue to improve outcomes, it is clear that a multidisciplinary approach must be the foundation on which advanced surgical and medical techniques are employed. Here, in this review, we highlight the role of targeted therapies in the surgical management of patients with metastatic CRC to the liver.

TP53 and let-7a micro-RNA regulate K-Ras activity in HCT116 colorectal cancer cells.

Recent reports have indicated that KRAS and TP53 mutations predict response to therapy in colorectal cancer. However, little is known about the relationship between these two common genetic alterations. Micro-RNAs (miRNAs), a class of noncoding RNA implicated in cellular processes, have been increasingly linked to KRAS and TP53. We hypothesized that lethal-7a (let-7a) miRNA regulates KRAS through TP53. To investigate the relationship between KRAS, TP53, and let-7a, we used HCT116 KRAS(mut) human colorectal cancer cells with four different genotypic modifications in TP53 (TP53(-/-), TP53(+/-), TP53(mut/+), and TP53(mut/-) ). Using these cells we observed that K-Ras activity was higher in cells with mutant or knocked out TP53 alleles, suggesting that wild-type TP53 may suppress K-Ras activity. Let-7a was present in HCT116 KRAS(mut) cells, though there was no correlation between let-7a level and TP53 genotype status. To explore how let-7a may regulate K-Ras in the different TP53 genotype cells we used let-7a inhibitor and demonstrated increased K-Ras activity across all TP53, thus corroborating prior reports that let-7a regulates K-Ras. To assess potential clinical implications of this regulatory network, we examined the influence of TP53 genotype and let-7a inhibition on colon cancer cell survival following chemoradiation therapy (CRT). We observed that cells with complete loss of wild-type TP53 alleles ((-/-) or (-/mut)) were resistant to CRT following treatment with 5-fluorouracil and radiation. Further increase in K-Ras activity with let-7a inhibition did not impact survival in these cells. In contrast, cells with single or double wild-type TP53 alleles were moderately responsive to CRT and exhibited resistance when let-7a was inhibited. In summary, our results show a complex regulatory system involving TP53, KRAS, and let-7a. Our results may provide clues to understand and target these interactions in colorectal cancer.

Trends in radiotherapy after breast-conserving surgery in elderly patients with early-stage breast cancer.

BACKGROUND: The benefit of adjuvant radiotherapy (RT) in elderly breast cancer patients is debatable. The purpose of this study was to evaluate trends in RT rates after breast-conserving surgery. METHODS: Breast cancer patients ≥70 years treated from 2000 to 2009 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Patients were estrogen receptor positive with negative or unknown lymph node status. Trends in RT recommendation over years were evaluated with the Jonckheere-Terpstra test. Multiple logistic regression and Cox proportional hazard tests were used to determine factors associated with radiation recommendation and survival. RESULTS: Of 46,581 patients, 31,989 (68.7 %) were recommended RT and 14,592 (31.3 %) were not. The recommendation for RT decreased from 70.3 % in 2000 to 67.4 % in 2009 (p < 0.0001). Seven of 18 registries exhibited decreased radiation recommendation rates, and 4 of 18 exhibited an increase. Recommendation of RT was associated with earlier year of diagnosis, younger age, Asian/Pacific Islander race, and negative lymph nodes. Predictors of worse survival were no radiation [hazard ratio (HR) 1.68, 95 % confidence interval (CI) 1.61-1.75], no nodes examined (HR 1.83, 95 % CI 1.75-1.91), large (>2-5 cm) tumor size (HR 2.02, 95 % CI 1.86-2.19), older age (80+, HR 2.38, 95 % CI 2.25-2.53), and black race (HR 1.13, 95 % CI1.03-1.23). CONCLUSIONS: Rates of radiation recommendation in the elderly have been steadily decreasing without appreciable acceleration in this decline. This trend was not consistent across all registries. Continued research is necessary to assess differences in clinical practice and its impact on patient outcomes.