Gastric cancer with microsatellite instability displays increased thymidylate synthase expression.

BACKGROUND: Gastric cancer (GC) with microsatellite instability (MSI) is a less aggressive disease and associated with resistance to 5-fluorouracil (5-FU)-based chemotherapy (CMT). Thymidylate synthase (TS) is inhibited by 5-FU, and another potential mediator of therapeutic resistance to 5-FU. Therefore, we aimed to analyze the association between MSI and TS expression in GC, and its impact on disease outcomes. METHODS: We retrospectively evaluated GC who underwent D2-gastrectomy. MSI and TS were analyzed by immunohistochemistry. We also investigated p53 expression, PD-L1 status, and tumor-infiltrating lymphocytes (CD4 and CD8). RESULTS: Out of 284 GC, 60 (21.1%) were MSI. Median TS-score for all cases was 16.5. TS expression was significantly higher in MSI compared to microsatellite-stable (MSS; p < 0.001). Considering both status, GC were classified in four groups: 167 (58.8%) MSS + TS-low; 57 (20.1%) MSS + TS-High; 24 (8.5%) MSI + TS-low; and 36 (12.7%) MSI + TS-high. MSI + TS-high group had less advanced pTNM stage, higher CD8+T cells levels (p < 0.001) and PD-L1 positivity (p < 0.001). Normal p53 expression was related to MSI GC (p < 0.001). Improved survival was observed in MSI + TS-high, but no survival benefit was seen with CMT. CONCLUSION: MSI GC was associated with high TS levels, which may explain therapeutic resistance to 5-FU. Additionally, MSI + TS-high showed better survival, but without improvement with CMT.

Preoperative chemotherapy is a better strategy than upfront surgery in cT4 gastric cancer.

BACKGROUND: Chemotherapy (CMT) followed by surgery is recommended by Western countries for advanced gastric cancer (GC). However, cT4 GC usually undergoes upfront surgery, due to symptoms. This study aimed to evaluate if preoperative CMT is a better strategy than upfront surgery in cT4 GC. METHODS: All cT4 GCs who underwent curative gastrectomy were included. Patients were divided according to their initial treatment: upfront surgery (SURG) or CMT + SURG. RESULTS: Among the 226 GC initially staged as cT4, 150 underwent SURG and 76 CMT + SURG. Groups were similar concerning age, comorbidities, American Society of Anesthesiologists, gastrectomy performed, and postoperative complications. The CMT + SURG group had less advanced pTNM. Median overall survival (OS) was 32 and 58.5 months for SURG and CMT + SURG, respectively (p = 0.04). Patients who received perioperative or adjuvant CMT had better OS compared to surgery alone (49.4 vs. 15.9 months, p < 0.001). OS was similar for those receiving preoperative and adjuvant CMT. Non-CMT, pN+, and R1 resection were independent risk factors for worse OS. CONCLUSION: Multimodal treatment associating CMT with surgery, regardless of whether the approach is pre- or postoperative, is essential to improve the survival of cT4 GC. As tolerance to adjuvant treatment is reduced, preoperative CMT is a better strategy than upfront surgery in these patients.

Gastrectomy for elderly gastric cancer patients: A propensity score-matching analysis.

BACKGROUND: Although D2-gastrectomy is the most effective treatment for resectable gastric cancer (GC), it is unclear whether elderly patients have increased risk of morbidity and worse survival. This study aimed to compare the short- and long-term outcomes of older age (OA) patients with those of less advanced age (LAA). METHODS: GC patients undergoing curative gastrectomy were retrospectively analyzed and divided into two groups: OA (>75 years) and LAA (<75 years). Propensity score-matching (PSM) analysis using seven variables was conducted to reduce selection bias. RESULTS: Among 586 patients, 494 (84.3%) were classified as LAA and 92 (15.7%) as OA. OA patients had worse clinical status, higher rates of D1-lymphadenectomy, subtotal gastrectomy, and Lauren type; higher mortality and worse survival. No difference in pathological tumor-node-metastasis (pTNM) stage was observed between groups. Preoperative chemotherapy was performed more frequently in the LAA group. After PSM (92 OA: 92 LAA), all variables included in PSM were matched, and mortality rates and survival became similar between groups. In multivariate analysis, American Society of Anaesthesiologists score III/IV was an independent factor associated with a 90-day mortality after PSM. CONCLUSION: Gastrectomy in elderly GC patients has similar outcomes compared with younger ones. Clinical status and disease stage are more important than the patient's age.

Multivisceral resection vs standard gastrectomy for gastric adenocarcinoma.

INTRODUCTION: Multivisceral resection (MVR) is potentially curative for selected gastric cancer patients, supposedly at the cost of increased complications. However, current data comparing MVR to standard gastrectomy (SG) is lacking. OBJECTIVES: Compare complications and survival after MVR and SG. METHODS: In a retrospective cohort of 1015 patients with gastric adenocarcinoma, 58 underwent MVR and 466 SG. Groups were compared concerning their characteristics, complications, and survival. RESULTS: One hundred seventy-six patients had postoperative complications. Major complications were more frequent after MVR (P = .002). Surgical mortality was 8.6% and 4.9% for MVR and SG (P = .221). Older age, higher morbidities, and MVR were independent risk factors for major complications. The odds ratio for major complications was 5.89 for MVR with one or two organs and 38.01 for MVR with three or more organs. The pancreas was the most commonly removed organ and pT4b disease were confirmed in 34 (58.6%) of the MVR cases. Disease-free survival (DFS) was lower in MVR patients (51% vs 77.8%; P < .001), being worse according to the number of organs resected. In pN+ patients, DFS was worse after MVR. DFS was equivalent to pT4b and non-pT4b in the MVR group. CONCLUSIONS: Increased morbidity and lower survival are expected for gastric cancer patients undergoing MVR.

Acute effects of moderate-intensity and high-intensity exercise on hemodynamic and autonomic reactivity to the cold pressor test in young adults with excess body weight.

OBJECTIVE: To investigate the effects of a single session of moderate-intensity and high-intensity interval exercise in cardiovascular reactivity to the cold pressor test in young adults with excess body weight. METHODS: Twenty-two subjects with excess body weight (23 ± 2 years; 30.0 ± 3.4 kg·m) performed three sessions: (1) moderate-intensity exercise (30-minute cycling at 50%-60% of heart rate reserve); (2) high-intensity exercise (four series of 3-minute cycling at 80%-90% of heart rate reserve, interspersed by 2-minute recovery) and (3) control (i.e. 30-minute seated). Before and 30 minutes after the interventions, subjects undertook assessments of SBP/DBP and heart rate in response to the cold pressor test (1-minute rest + 1-minute hand immersed in 4°C water). Reactivity was calculated as the absolute response of SBP, DBP and heart rate to cold pressor test and compared between interventions using a two-way analysis of variance (P < 0.05). RESULTS: Neither moderate-intensity exercise or high-intensity interval exercise attenuated SBP/DBP reactivity to cold pressor test compared with control. On the other hand, heart rate reactivity was reduced after moderate-intensity exercise compared with control (1.36 ± 8.35 bpm vs. 5.18 ± 9.45 bpm). Furthermore, moderate-intensity exercise reduced absolute levels of SBP/DBP from pre- to post-intervention. CONCLUSION: A single session of moderate-intensity exercise or high-intensity interval exercise did not reduce the SBP/DBP reactivity to cold pressor test. However, absolute levels of SBP/DBP were lower after moderate-intensity exercise, indicating a hypotensive effect promoted by a single session of moderate-intensity exercise in young adults with excess body weight.

Isolated Obesity Is Not Enough to Impair Cardiac Autonomic Modulation in Metabolically Healthy Men.

PURPOSE: To evaluate whether excess body mass influences the heart rate variability (HRV) indexes at rest, and to correlate adiposity indicators and the aerobic fitness with cardiac autonomic variables in metabolically healthy young adults. METHOD: In all, 41 untrained males (Mage = 21.80, SD = 2.14 years), 14 normal weight (MBMI = 22.28, SD = 1.86 kg∙m-2), 11 overweight (MBMI = 26.95, SD = 1.43 kg∙m-2), and 16 obese (MBMI = 33.58, SD = 3.06 kg∙m-2) metabolically healthy (normal values of blood pressure, fasting blood glucose, triglycerides, and total cholesterol), underwent evaluations of the HRV at rest and of the peak oxygen consumption (VO2 peak) during maximal exercise on a cycle ergometer. RESULTS: Blood pressure, heart rate, HRV indexes, casual blood glucose, oxidative stress, and antioxidant activity did not differ among the groups. The VO2 peak (mL∙kg-1∙min-1) was lower in the obese group compared with the normal weight and overweight groups. The body mass (r = -.40 to -.45) and abdominal circumference (r = -.39 to -.52) were slightly to moderately correlated with SD1, SD2, RMSSD, SDNN, pNN50, LF, and HF indexes and total power. The VO2 peak (mL∙kg-1∙min-1) was slightly to moderately correlated (r = .48 to .51) with SD2, SDNN, and LF indexes in the individuals with excess body mass. CONCLUSION: Cardiac autonomic modulation at rest was preserved in metabolically healthy obese young men. However, the indicators of adiposity, as well as the aerobic fitness were correlated with cardiac autonomic modulation in the individuals with excess body mass.

Uncommon cause of liver abscess.

Gastrointestinal perforation by fishbone causing a liver abscess is a rare entity, but should be included in the differential diagnosis to avoid delay in the treatment.

Lymph Node Yield After Neoadjuvant Chemoradiotherapy in Rectal Cancer Specimens: A Randomized Trial Comparing Two Fixatives.

BACKGROUND: It is widely reported that neoadjuvant chemoradiation reduces lymph node yield in rectal cancer specimens. Some have questioned the adequacy of finding ≥12 lymph nodes for accurate staging, and fewer nodes were correlated with good response. Others reported that low lymph node count raises the chance for understaging and correlates with worse survival. In addition, a few studies demonstrated that diligent specimen analysis increases lymph node count. OBJECTIVE: The aim of this study was to compare Carnoy's solution and formalin concerning lymph node yield in specimens of patients with rectal cancer after neoadjuvant chemoradiation. DESIGN: This is a prospective randomized trial that was conducted from 2012 to 2015. SETTINGS: This study was performed in a reference cancer center in Brazil. PATIENTS: Patients who underwent low anterior resection with total mesorectal excision after neoadjuvant chemoradiation for rectal adenocarcinoma were included. INTERVENTION: Rectosigmoid specimens were randomized for fixation with Carnoy's solution or formalin. MAIN OUTCOME MEASURES: A total of 130 specimens were randomized. After dissection, the residual fat from the formalin group was immersed in Carnoy's solution in search for missed lymph nodes (Revision). RESULTS: The Carnoy's solution group had superior lymph node count (24.0 vs 16.3, p < 0.01) and fewer cases with <12 lymph nodes (6 vs 22, p = 0.001). The Revision group found lymph nodes in all cases (mean, 11.1), retrieving metastatic lymph nodes in 6 patients. It reduced the formalin cases with <12 lymph nodes from 33.8% to 4.6% and upstaged 2 patients. Tumor response to neoadjuvant chemoradiotherapy was not associated with lymph node count. LIMITATIONS: This was a unicentric study. CONCLUSIONS: Compared with formalin, the Carnoy's solution increases lymph node count and reduces the cases with <12 lymph nodes. Harvested lymph nodes are missed following routine analysis and this is clinically relevant. Finding <12 lymph nodes is not a sign of good response to neoadjuvant chemoradiation (www.clinicaltrials.gov. Unique identifier: NCT02629315). See Video Abstract at http://links.lww.com/DCR/A694.

Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer.

BACKGROUND AND OBJECTIVES: Gastric cancer (GC) has recently been categorized in molecular subtypes, which include Epstein-Barr (EBV)-positive and microsatellite instability (MSI) tumors. This distinction may provide prognostic information and identifies therapeutic targets. The aim of this study was to evaluate EBV, MSI, and PD-L1 immunoexpression in GC and its relationship with clinicopathological characteristics and patient's prognosis. METHODS: We evaluated 287 GC patients who underwent D2-gastrectomy through immunohistochemistry for DNA mismatch repair proteins and PD-L1, and in situ hybridization for EBV detection utilizing tissue microarray. RESULTS: EBV-positive and MSI were identified in 10.5% and 27% of the GCs, respectively. EBV positivity was associated to male gender (P = 0.032), proximal location (P < 0.001), undetermined Lauren type (P < 0.001), poorly differentiated histology (P = 0.043) and severe inflammatory infiltrate (P < 0.001). MSI-tumors were associated to older age (P = 0.002), subtotal gastrectomy (P = 0.004), pN0 (P = 0.024) and earlier TNM stage (P = 0.020). PD-L1-positive was seen in 8.8% of cases, with predominant expression in EBV-positive GC (P < 0.001). MSI was associated to better survival outcomes. CONCLUSION: EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy.

Carnoy's solution is an adequate tissue fixative for routine surgical pathology, preserving cell morphology and molecular integrity.

AIMS: To compare Carnoy's solution (CS) and 10% neutral buffered formalin solution (NBF) as tissue fixatives in colorectal cancer specimens. METHODS AND RESULTS: Surgical specimens from patients with colorectal cancer were analysed. Three groups were studied, as follows: group 1 consisted of 16 paired samples fixed in CS and NBF; and groups 2 and 3 consisted of 14 prospective and 80 retrospective samples, respectively, both randomized for fixation in CS or NBF. Groups 1 and 2 were analysed for amount, quality and integrity of DNA. Morphological analysis, including some of the usual special stains and polymerase chain reaction (PCR), were also performed for group 1, and Sanger sequencing for group 2. Immunohistochemical (IHC) reactions for mismatch repair proteins were studied in groups 1 and 3. Fixative performances were similar for morphology, special stains, and IHC reactions, as well as for the amount, quality and integrity of extracted DNA. PCR amplification was not possible in two cases from CS group 1. Sanger sequencing gave conclusive results for the CS samples tested. CONCLUSIONS: Carnoy's solution and NBF are equivalent fixatives for colorectal cancer specimens and are adequate for routine utilization in surgical and molecular pathology.

Surgical management of gallbladder disease in the very elderly: are we operating them at the right time?

BACKGROUND: As life expectancy rises worldwide and the prevalence of gallstones increases with age, the number of very elderly patients requiring treatment for gallstone diseases is increasing. The aim of this study was to compare the results of cholecystectomy in patients 80 years or older according to different clinical presentations. METHODS: This is a retrospective study of 81 patients 80 years or older. Indications for surgery were stratified into three groups: outpatients (symptomatic chronic cholecystitis), inpatients (complicated gallstone diseases), and urgent patients (acute cholecystitis). Data analysis included age, sex, the American Society of Anesthesiologists score, indication for surgery, length of hospital stay, morbidity, and mortality. RESULTS: The mean age of the patients was 83.9 (range 80-94 years); there were 34 (42%) men. Thirty patients were operated on for acute cholecystitis. Patients in the urgency group significantly required the ICU more often, required a longer hospital stay, and had more complications, with 32% mortality. No differences were found between inpatients and outpatients, with both groups presenting low morbidity, no mortality, and the same postoperative length of stay. CONCLUSION: More than 80% of the patients were operated on because of complicated gallstone disease. Although the outcomes of patients undergoing semielective cholecystectomy were similar to those of patients treated as outpatients, patients operated with acute cholecystitis presented extremely high morbidity and mortality rates. Thus, we can only recommend that early elective cholecystectomy be performed in elderly patients as soon as they are found to have symptomatic gallstones. Also, further trials are required to elucidate the optimal management of acute cholecystitis in elderly patients.

Isolated splenic metastasis from lung squamous cell carcinoma.

Isolated splenic metastasis from lung cancer is a very rare occurrence with only a few reports available. Here, we report the case of a 82-year-old male who underwent a bilobectomy for a lung squamous cell carcinoma and 16 months later developed an isolated splenic metastasis. Additionally, previous reports are reviewed and discussed.