Pathologic Complete Response Despite Nodal Yield Has Best Survival in Locally Advanced Rectal Cancer.

BACKGROUND: Controversy exists regarding the ability of neoadjuvant chemoradiation (nCR) to diminish lymph node yield (LNY) and how that relationship is influenced by tumor response in patients undergoing proctectomy for locally advanced rectal cancer. MATERIALS AND METHODS: The National Cancer Database was used to identify patients with rectal adenocarcinomas from 2004 to 2014. Patients that received nCR were compared with those that underwent surgery alone. LNY was stratified into <12 and ≥12 groups to determine their differences in stage specific overall survival. RESULTS: Of 56,812 patients 46.5% underwent surgery alone and 53.5% were administered nCR. There were more patients with LNY<12 in the nCR group compared to surgery alone, across all stages (44.1% versus 36.5%, P < 0.001). nCR improved OS regardless of LNY (P < 0.001). Although patients with LNY≥12 had improved overall survival, patients who had a pathologic complete response (pCR) achieved the greatest survival. In patients that did not achieve a pCR, LNY≥12 was a marker of improved OS but LNY did not impact OS in patients that attained pCR (P < 0.001). CONCLUSIONS: Although nCR diminished LNY, LNY≥12 improved OS demonstrating the importance of quality total mesorectal excision. However, LNY did not impact patients that achieved pCR. These patients, who achieved the best OS, demonstrated that tumors' biologic response to nCR had the greatest impact on patient outcomes.

High Expression of microRNA-143 is Associated with Favorable Tumor Immune Microenvironment and Better Survival in Estrogen Receptor Positive Breast Cancer.

microRNA-143(miR-143) is a well-known tumor suppressive microRNA that exhibits anti-tumoral function by targeting KRAS signaling pathways in various malignancies. We hypothesized that miR-143 suppresses breast cancer progression by targeting KRAS and its effector molecules. We further hypothesized that high expression of miR-143 is associated with a favorable tumor immune microenvironment of estrogen receptor (ER)-positive breast cancer patients which result in improved survival. Two major publicly available breast cancer cohorts; The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. The miR-143 high expression group was associated with increased infiltration of anti-cancer immune cells and decreased pro-cancer immune cells, as well as enrichment of the genes relating to T helper (Th1) cells resulting in improved overall survival (OS) in ER-positive breast cancer patients. To the best of our knowledge, this is the first study to demonstrate that high expression of miR-143 in cancer cells associates with a favorable tumor immune microenvironment, upregulation of anti-cancer immune cells, and suppression of the pro-cancer immune cells, associating with better survival of the breast cancer patients.

Cytolytic Activity Score to Assess Anticancer Immunity in Colorectal Cancer.

BACKGROUND: Elevated tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment is a known positive prognostic factor in colorectal cancer (CRC). We hypothesized that since cytotoxic T cells release cytolytic proteins such as perforin (PRF1) and pro-apoptotic granzymes (GZMA) to attack cancer cells, a cytolytic activity score (CYT) would be a useful tool to assess anticancer immunity. METHODS: Genomic expression data were obtained from 456 patients from The Cancer Genome Atlas (TCGA). CYT was defined by GZMA and PRF1 expression, and CIBERSORT was used to evaluate intratumoral immune cell composition. RESULTS: High CYT was associated with high microsatellite instability (MSI-H), as well as high levels of activated memory CD4+T cells, gamma-delta T cells, and M1 macrophages. CYT-high CRC patients had improved overall survival (p = 0.019) and disease-free survival (p = 0.016) compared with CYT-low CRC patients, especially in TIL-positive tumors. Multivariate analysis demonstrated that CYT- high associates with improved survival independently after controlling for age, lymphovascular invasion, colonic location, microsatellite instability, and TIL positivity. The levels of immune checkpoint molecules (ICMs)-programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin domain 3 (TIM3), and indoleamine 2,3-dioxygenase 1 (IDO1)-correlated significantly with CYT (p < 0.0001); with improved survival in CYT-high and ICM-low patients, and poorer survival in ICM-high patients. CONCLUSIONS: High CYT within CRC is associated with improved survival, likely due to increased immunity and cytolytic activity of T cells and M1 macrophages. High CYT is also associated with high expression of ICMs; thus, further studies to elucidate the role of CYT as a predictive biomarker of the efficacy of immune checkpoint blockade are warranted.

Does neoadjuvant/perioperative chemotherapy improve overall survival for T2N0 gastric adenocarcinoma?

BACKGROUND: The purpose of this study was to determine whether neoadjuvant and/or perioperative chemotherapy (NAC) has an overall survival (OS) benefit for patients with T2N0 gastric adenocarcinoma. STUDY DESIGN: We performed retrospective analyses using the National Cancer Data Base, 2004-2013. Patients with T2N0 gastric adenocarcinoma were divided into two treatment groups: (1) NAC plus surgery (NA + S) and (2) surgery alone (S). RESULTS: Of 1,704 patients included, 277 (16.3%) received NAC, and 1,427 (83.7%) were treated with surgery alone. Patients in the NA + S group were more likely to be younger, have fewer comorbidities, and have larger tumors located in the proximal stomach. Although in an unadjusted analysis of OS, the NA + S group had improved survival compared to the S group (HR = 0.81, 95% CI 0.67-0.99, P < 0.0001), this was not maintained in a propensity adjusted analysis (HR = 0.89, 95% CI 0.68-1.18, P = 0.42). Similarly, propensity adjusted analyses accounting for potential bias from clinical misstaging or treatment effect from NAC did not show any OS benefit from NAC. CONCLUSION: Based on the largest cohort of clinically staged T2N0 gastric adenocarcinoma, there was no OS benefit derived from NAC compared to surgery alone. For select patients with reliable preoperative staging, NAC may be omitted.

Genomic characterization of colitis-associated colorectal cancer.

BACKGROUND: Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, idiopathic, repeated inflammatory disease. Colorectal cancer (CRC) that develops in patients with IBD is known as colitis-associated colorectal cancer (CAC), but the underlying carcinogenic mechanism remains unclear. Genomic analysis of sporadic CRC has been well described based on next-generation sequencing (NGS) data. Using NGS, we compared all exons of 415 cancer-associated genes in patients in Japan and the USA who had CRC and found similar genomic alteration patterns among the two populations. However, genomic analysis of CAC has not been thoroughly investigated. MAIN BODY: The molecular pathogenesis of CAC shares many features with sporadic CRC, but there are distinct variations in the time and frequency of some alterations. Gene alterations in CAC are gradually being elucidated using genomic sequencing analyses. Some studies have shown that gene alteration patterns differ between UC and CD. The carcinogenesis of CAC depends on unique environmental, genetic, and immunological factors. CONCLUSIONS: In this review, we have discussed the differences in genomic alterations between sporadic CRC and CAC. NGS in patients with IBD has the potential to detect early CAC and to suggest therapeutic targets.

Peritoneal pocket hernia: A distinct cause of early postoperative small bowel obstruction and strangulation: A report of two cases following robotic herniorrhaphy.

Laparoscopic and robotic hernia surgery offers advantages over open herniorrhaphy including faster recover and lower wound infection but is associated with rare but serious complications such as visceral injury and intestinal obstruction. We describe two cases of small bowel obstruction with strangulation that occurred shortly after routine robotic hernia surgery. We define this rare type of strangulating internal hernia as a peritoneal pocket hernia and call attention to its diagnosis and management.

An Evaluation of Postoperative Complications and Cost After Short-Stay Thyroid Operations.

BACKGROUND: Concern for postoperative complications causing airway compromise has limited widespread acceptance of ambulatory thyroid surgery. We evaluated differences in outcomes and hospital costs in those monitored for a short stay of 6 h (SS), inpatient observation of 6-23 h (IO), or inpatient admission of >23 h (IA). METHODS: We retrospectively reviewed all patients undergoing thyroidectomy from 2006 to 2012. The incidence of postoperative hemorrhage, nerve dysfunction, and hypocalcemia were evaluated, as well as cost data comparing the SS and IO groups. RESULTS: Of 1447 thyroidectomies, 880 (60.8 %) were performed as SS, 401 (27.7 %) as IO, and 166 (11.5 %) as IA. Fewer patients in the SS group (59 %) underwent total thyroidectomy than IO (73 %) and IA (71 %; p < 0.01), and SS patients had smaller thyroid weights (27.9 g) compared with IO and IA (47.2 and 98.9 g, respectively; p < 0.01). Ten (0.69 %) patients developed hematomas requiring reoperation, five of the ten patients received antiplatelet or anticoagulant therapy perioperatively. Only one patient in the IA group bled within the 6- to 23-h period, and no patients with bleeding who were discharged at 6 h would have benefitted from 23-h observation. Twenty-four (1.66 %) recurrent laryngeal nerve injuries were identified, 16 with temporary neuropraxias. In addition, 24 (1.66 %) patients had symptomatic hypocalcemia, which was transient in 17 individuals. Financial data showed higher payments and lower costs associated with SS compared with IO. CONCLUSIONS: Selective SS thyroidectomy can be safe and cost effective, with few overall complications in patients undergoing more complex operations involving larger thyroids who were admitted to hospital.

Treatment of Diaphragmatic Hernia Occurring After Transhiatal Esophagectomy.

BACKGROUND: Postesophagectomy diaphragmatic hernia (DH) is an uncommon problem but an important one to recognize and treat because of the risk of significant complications such as incarceration and strangulation. Diaphragmatic hernia appears to occur more frequently following transhiatal esophagectomy (THE) than after transthoracic procedures, likely because of the enlargement of the diaphragmatic hiatus required to perform THE. METHODS: After 199 consecutive esophagectomies were performed at Rutgers Robert Wood Johnson University Hospital between January 2000 and June 2013, ten patients were identified with DH; all underwent diaphragmatic hernia repair (DHR). All patients who underwent esophagectomy during this time period were cataloged in a prospectively maintained database that was then retrospectively reviewed. All DH were repaired using a novel biologic plug mesh technique. RESULTS: Ten esophagectomy patients developed DH; nine post-THE and one post-McKeown esophagectomy. One patient was excluded from analysis because of atypical presentation. Demographic data were similar between esophagectomy patients who developed DH and those who did not. Administration of neoadjuvant chemoradiation correlated with development of DH, but did not reach statistical significance. Complications directly related to DHR were few and mostly infectious, including empyema and pneumonia, and were more likely to occur in those who presented with acute obstruction. One patient presented with dysphagia post repair. CONCLUSIONS: Diaphragmatic hernia development post esophagectomy is an uncommon complication, but can have devastating results when there is bowel compromise. Repair by plugging the diaphragmatic hiatus with a biologic mesh is a safe and effective method for closing the defect and results in few complications.

Outcomes of microwave ablation for colorectal cancer liver metastases: a single center experience.

BACKGROUND AND OBJECTIVES: Surgical management of colorectal cancer liver metastases continues to evolve to optimize oncologic outcomes while maximizing parenchymal preservation. Long-term data after intraoperative microwave ablation are limited. This study investigates outcomes and patterns of recurrence in patients who underwent intraoperative microwave ablation. METHODS: A retrospective analysis of 33 patients who underwent intraoperative microwave ablation of colorectal cancer liver metastases from 2009 to 2013 at our institution was performed. Perioperative and long-term data were reviewed to determine outcomes and patterns of recurrence. RESULTS: A total of 49 tumors were treated, ranging 0.5-5.5 cm in size. Median Clavien-Dindo classification was one. Median follow-up was 531 days, with 13 (39.4%) patients presenting with a recurrence. Median time to first recurrence was 364 days. In those patients, 1 (7.8%) presented with an isolated local recurrence in the liver. Only 1 of 7 ablated tumors greater than 3 cm recurred (14.3%). Overall survival was 35.2% at 4 years, with a 19.3% disease-free survival at 3.5 years. No perioperative variables predicted systemic or local recurrence. CONCLUSION: Intraoperative microwave ablation is a safe and effective modality for use in the treatment of colorectal cancer liver metastases in tumors as large as 5.5 cm in size.

Small molecule compounds targeting the p53 pathway: are we finally making progress?

Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful.

A Retrospective Analysis of the Trends in Acute Appendicitis During the COVID-19 Pandemic.

Background: The corona virus disease of 2019 (COVID-19) imposed new public health constraints that deterred people from coming to the hospital. The outcome of patients who developed appendicitis during mandated COVID-19 quarantine has yet to be examined. The main objective was to establish whether there was an increased rate of perforated appendicitis seen during COVID-19 quarantine. Secondary objectives included observing the type of procedure performed, length of stay, and associated complications. Materials and Methods: This retrospective analysis was designed to look at the rates of appendicitis and perforated appendicitis observed during mandatory "safer at home order" from March to May 2020. The same time period a year earlier was used for comparative analysis. The study utilized data gathered from a single health care system, which consisted of a large regional referral center with three emergency rooms (ERs). Patients were included in the study if they presented to any ER in our health care system with a chief complaint of acute appendicitis. Perforated appendicitis was determined either radiographically or intraoperatively. Interventions included surgery, percutaneous drainage, or medical management. Results: There were 107 patients who were included. During quarantine, a total of 48 patients presented with acute appendicitis, with 16 perforations, compared with the previous year where 59 patients presented with acute appendicitis, with 10 perforations (33% versus 17% P = .04). Most patients underwent laparoscopic appendectomy (91%, n = 98), six patients (6%) were managed with intravenous antibiotics and 3 patients (3%) with percutaneous drainage. Patients who perforated had a longer duration of symptoms (2 versus 1, P = .03), white blood cell count (13,190 versus 15,960 cells/mm3, P = .09), and longer operative time (72 versus 89 minutes, P = .01). Patients who perforated had an increased length of stay and rate of complication. Conclusion: There was an overall increased rate of perforated appendicitis seen during quarantine compared with the previous year. Patients with perforated appendicitis had an increased length of stay, longer operative time, and increased rate of complications. Thus, although people were staying home due to public health safety orders, it negatively impacted those who developed appendicitis who may have presented to the hospital otherwise sooner.

Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and with better clinical outcomes in triple negative breast cancer.

Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival.

An Unusual Case of Lower Extremity Clear Cell Hidradenocarcinoma.

Hidradenocarcinoma (HC) is a rare malignant sweat gland tumor with metastatic potential primarily located in the head, neck, and trunk. We present an unusual case of a large lower extremity Clear Cell HC managed with surgical resection and adjuvant locoregional radiation after excluding lymph node involvement.

Tumor Infiltrating Lymphocytes and Macrophages Improve Survival in Microsatellite Unstable Colorectal Cancer.

Due to the loss of DNA repair mechanisms in colorectal cancer (CRC) with microsatellite instability (MSI), somatic mutations accumulate within DNA; making them more prone to attack by tumor infiltrating lymphocytes (TIL) and macrophages. We hypothesize that MSI-High (MSI-H) patients have favorable survival due to increased tumor immunogenicity. The Cancer Genome Atlas (TCGA) was used to evaluate gene expression from 283 patients with CRC, comparing MSI-H and microsatellite stable (MSS) patients. CIBERSORT algorithm estimated the fraction of immune cell types. We found that low expression of DNA repair genes (MLH1, MLH3, PMS1, PMS2, ATR, PRKDC, ATM, BRCA2) associated with MSI-H. MSI-H was directly associated with Helper T-cells (p = 0.034) and M1 macrophages (p < 0.0001). MSI-H tumors associated with diminished intra-tumoral heterogeneity as well as higher expression of checkpoint molecules PD-1, PD-L1, CTLA4, LAG3 and TIM3 (p < 0.0001). Improved OS was seen in patients with low ATM, PMS2 and MLH3. In the TCGA CRC cohort, decreased expression of DNA repair genes associated with MSI-H. MSI-H patients had improved survival, likely due to higher TIL and M1 macrophage infiltration as well as lower intra-tumoral heterogeneity. MSI-H also associates with expression of immune checkpoint molecules with potential for development of therapeutic targets.

High expression of polo-like kinase 1 is associated with TP53 inactivation, DNA repair deficiency, and worse prognosis in ER positive Her2 negative breast cancer.

Polo-like kinase 1 (PLK1), the most investigated member of the PLK family, plays a pivotal role both in the p53-mediated regulation of DNA damage repair and in mitosis, especially in the G2/M phase. However, the evidence on the clinical and prognostic relevance of PLK1 is limited to triple negative subtype among breast cancer (BC). We hypothesized that high expression of PLK1 is associated with TP53 inactivation, DNA repair deficiency, and worse prognosis in ER positive in BC in a large-scale cohort should clarify its clinical relevance for each BC subtype. Total of 3173 BC cases; 1025 from TCGA cohort, 1904 from METABRIC, and 244 from neoadjuvant chemotherapy (NAC) cohort from Gene Expression Omnibus dataset, GSE32603, were analyzed. PLK1 expressions were significantly higher in high Nottingham Grade and triple negative BC. High expression of PLK1 was significantly associated with TP53 mutation, high expression of TP53 mRNA as well as protein, and it significantly correlated with the homologous recombination deficiency score. High PLK1 expression significantly enriched cell cycle related gene sets (G2/M check point, E2F targets), MTORC1 signaling, and MYC target gene sets in the Gene Set Enrichment Analysis. High expression of PLK1 was significantly associated with tumor infiltrating lymphocytes and tumor associated macrophages (high levels of CD8+ T cells, M0 and M1 macrophage, and low levels of M2 macrophage), and high immune cytolytic activity. While high expression of PLK1 did not associate with pathological complete response after NAC, it was associated with poor prognosis in the whole cohort and in the ER-positive/HER2-negative subtype of TCGA. High expression of PLK1 is significantly associated with TP53 mutations, DNA repair deficiency and worse prognosis in BC particularly in HR+HER2- subtype. Using bioinformatics methods with large cohorts.

Association of Clinicopathologic and Molecular Markers on Stage-specific Survival of Right Versus Left Colon Cancer.

BACKGROUND: Previous studies have shown that variability in molecular markers correlates with poorer survival outcomes in patients with right-sided colon cancer (RCC) compared with left-sided colon cancer (LCC). However, several studies have shown conflicting results when examined stage for stage. We examined RCC and LCC to assess for differences in histopathologic features and overall survival (OS). MATERIALS AND METHODS: The National Cancer Database was used to identify patients with RCC and LCC from 2004 to 2013. A propensity-adjusted analysis evaluating the association between the primary site and OS was performed. RESULTS: Of the 422,443 patients identified, 54.7% had RCC and 45.3% had LCC. For all stages, the patients with RCC were older, had more poorly differentiated tumors, and had a greater degree of microsatellite instability compared with those with LCC. Patients with RCC also had more KRAS mutations than did those with LCC. RCC patients had poorer 3- and 5-year OS at all stages, especially stage 3 (62% vs. 73% and 50% vs. 62%, respectively; P < .001). The median OS was 77.5 months for LCC and 62.3 months for RCC (P < .001). CONCLUSION: The present study is one of the largest studies demonstrating that RCC and LCC are different biologic entities. Patients with RCC had significantly greater rates of microsatellite instability for all stages, which has been previously shown to be prognostically advantageous. However, the results of the present study showed poorer OS at every disease stage for RCC compared with LCC. These factors have important implications for the further use of targeted therapies in the treatment of advanced colon cancer.

Disparities in major surgery for esophagogastric cancer among hospitals by case volume.

BACKGROUND: The purpose of this study was to characterize disparities among centers performing major surgery for esophageal or gastric cancer stratified by case volume. METHODS: The National Cancer Data Base (NCDB) was queried for cases of esophagectomy or total gastrectomy. Centers were compared based on number of cases during 2004-2013: low volume [1-99], middle [100-200], and high [>200]. RESULTS: For esophagectomy, 17,547 patients were included; 73.5% were treated in low volume centers, 14.6% in middle, and 11.9% in high. For gastrectomy, 20,059 patients were included, with 87.5%, 8.3%, and 4.3%, respectively. Patients treated at low volume centers were more likely to be of racial/ethnic minorities, uninsured, and have lower socioeconomic status. Overall survival (OS) was superior for patients treated at high volume centers. On multivariable analysis for either procedure, a higher number of disparate factors was identified in the low and middle volume centers compared to the high volume centers, which were associated with poorer OS. CONCLUSIONS: This study identified higher numbers of disparate patient factors associated with low/middle volume centers compared to high volume centers, which were associated with worse OS, and further makes the case for performance of esophagectomy and total gastrectomy at high volume centers.

A Case of Crossed Left Renal Ectopia Identified during Colostomy Reversal.

Unilateral crossed renal ectopia without fusion is an uncommon anatomic anomaly, which often goes undiagnosed. We report a case of this renal variant discovered incidentally during colostomy reversal after Hartmann's procedure for diverticular stricture.