Implications of Prolonged Time to Pancreaticoduodenectomy After Neoadjuvant Chemoradiation.

BACKGROUND: For patients with pancreatic adenocarcinoma (PA), the optimal time interval between neoadjuvant chemoradiation (CR) to surgical resection has not been well established. METHODS: The National Cancer Database from 2006 to 2014 was queried for patients ≥18 y old diagnosed with PA who received neoadjuvant CR. Survival and short-term outcomes were compared between patients who had pancreaticoduodenectomy ≤12 wk and >12 wk after completion of CR. RESULTS: 1610 patients met selection criteria. Average radiation to surgery (RS) interval was 58.2 ± 39.5 d. 1419 patients had RS interval ≤12 wk (mean 47.4 d) and 191 had RS interval >12 wk (mean 138.8 d). Demographics, CA 19-9 levels, types of chemotherapy and radiation dosage were similar between the two groups. There were more patients with clinical stage III cancers in the >12 wk group than in the ≤12 wk group (33.5% versus 14%). Short-term outcomes were similar between the two groups. However, a long-term survival benefit was observed in the >12 wk group (median 25.8 versus 30.2 mo P = 0.049). An interval >12 wk was associated with significantly prolonged survival on multivariate analysis (HR: 0.80, 95% CI: 0.65-0.99; P = 0.042). Higher clinical stage and positive surgical margins were independently associated with worse survival. CONCLUSIONS: Surgical resection beyond 12 wk after CR for PA did not worsen short-term outcomes. Waiting may contribute to better patient selection, especially those with locally advanced tumors. In the absence of progressive disease, patients need to be continuously evaluated for surgical resection after CR.

Colon cancer as a subsequent malignant neoplasm in young adults.

BACKGROUND: The incidence of colon cancer (CC) is rising in younger adults and can occur de novo or in patients previously treated for another cancer. To the authors' knowledge, the impact on survival of CC occurring as a subsequent malignant neoplasm (SMN) has not been described for younger patients, which the authors anticipate to be lower with SMNs than that of primary CC. METHODS: Patients aged <50 years with CC in the 2004 through 2014 National Cancer Data Base were identified. Patients were stratified by primary or subsequent occurrence. The impact of SMN status on overall survival (OS) was evaluated. RESULTS: Of 41,915 patients, 2852 (6.8%) had colon SMNs. More patients with colon SMNs were aged 40 to 49 years compared with patients with primary CC (83% vs 77%; P < .001). Patients with colon SMNs presented with earlier clinical and pathological T, N, and M classifications (all P < .001). Colon SMNs more commonly occurred in the right colon, whereas primary CC was found to have a higher prevalence in the sigmoid colon (P < .001). Patients with colon SMNs more frequently underwent total colectomy (17% vs 5%; P < .001), but received less chemotherapy (53% vs 65%; P < .001). When adjusted for demographic, tumor, and treatment characteristics, SMN status was associated with a 23% decreased OS compared with primary CC (95% CI, 1.14-1.31; P < .001). Chemotherapy offered a 33% improvement in OS (95% CI, 0.56-0.8; P < .001). CONCLUSIONS: Colon SMNs in younger patients present at an earlier stage and are treated more aggressively surgically compared with primary CCs. Patients with SMNs of the colon have decreased survival, although chemotherapy offers a survival advantage. Further investigation is warranted to determine whether these disparities are due to the effects of cancer treatment or differences in tumor biology.

Racial and Socioeconomic Treatment Disparities in Adolescents and Young Adults with Stage II-III Rectal Cancer.

INTRODUCTION: Stage II-III rectal cancer requires multidisciplinary cancer care, and adolescents and young adults (AYA, ages 15-39 years) often do not receive optimal cancer therapy. METHODS: Overall, 3295 AYAs with clinical stage II-III rectal cancer were identified in the National Cancer Database. Factors associated with the receipt of adjuvant and surgical therapies, as well as overall survival (OS), were examined. RESULTS: The majority of patients were non-Hispanic White (72.0 %), male (57.5 %), and without comorbidities (93.8 %). A greater proportion of Black and Hispanic patients did not receive radiation (24.5 and 27.1 %, respectively, vs. 16.5 % for non-Hispanic White patients), surgery (22.4 % and 21.6 vs. 12.3 %), or chemotherapy (21.5 % and 24.1 vs. 14.7 %) compared with non-Hispanic White patients (all p < 0.05). After controlling for competing factors, Black (odds ratio [OR] 0.7, 95 % confidence interval [CI] 0.5-0.9) and Hispanic patients (OR 0.6, 95 % CI 0.4-0.9) were less likely to receive neoadjuvant chemoradiation compared with non-Hispanic White patients. Females, the uninsured, and those treated at a community cancer center were also less likely to receive neoadjuvant therapy. Having government insurance (OR 0.22, 95 % CI 010-0.49) was a predictor for not receiving surgery. Although 5-year OS was lower (p < 0.05) in Black (59.8 %) and Hispanic patients (65.9 %) compared with non-Hispanic White patients (74.9 %), on multivariate analysis race did not impact mortality. Not having surgery (hazard ratio [HR] 7.1, 95 % CI 2.8-18.2) had the greatest influence on mortality, followed by poorly differentiated histology (HR 3.0, 95 % CI 1.3-6.5), nodal positivity (HR 2.6, 95 % CI 1.9-3.6), no chemotherapy (HR 1.9, 95 % CI 1.03-3.6), no insurance (HR 1.7, 95 % CI 1.1-2.7), and male sex (HR 1.5, 95 % CI 1.1-2.0). CONCLUSION: There are racial and socioeconomic disparities in the treatment of stage II-III rectal cancer in AYAs, many of which impact OS. Interventions that can address and mitigate these differences may lead to improvements in OS for some patients.

Outcomes of octogenarians undergoing gastrectomy performed for malignancy.

BACKGROUND: Studies on perioperative outcomes of octogenarians with gastric cancer are limited by small sample size. Our aim was to determine the outcomes of gastrectomy and the variation of treatments associated with advanced age (≥80 y). METHODS: The National Surgical Quality Improvement Program database was queried from 2005 to 2011. Patients who underwent gastrectomy for malignancy were identified using International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes. RESULTS: Of 2591 cases, 487 patients were octogenarians (≥80) and 2104 were nonoctogenarians (<80). Overall, 4.9% of patients had disseminated cancer. Octogenarians had higher 30-d mortality (7.2% versus 2.5%, P < 0.01) and more major complications (31.4% versus 25.5%, P < 0.01), though fewer octogenarians underwent total gastrectomy (24.0% versus 43.2%, P < 0.01) and extended lymphadenectomy (10.1% versus 17.4%, P < 0.01) than the nonoctogenarian cohort. On multivariate analysis, age ≥80 y was associated with major complications (OR, 1.3; 95% CI, 1.03-1.6; P = 0.03) and increased mortality (OR, 3.0; 95% CI, 1.9-4.9; P < 0.01). CONCLUSIONS: Advanced age (≥80 y) was associated with worse outcomes in patients undergoing gastrectomy for malignancy. Therefore, careful staging is necessary to reduce unnecessary operations in this population. Furthermore, surgeons must place greater attention on optimizing the octogenarian population before surgery.

Predictors and Survival Impact of False-Negative Sentinel Nodes in Melanoma.

BACKGROUND: The status of the sentinel lymph node in melanoma is an important prognostic factor. The clinical predictors and implications of false-negative (FN) biopsy remain debatable. METHODS: We compared patients with positive sentinel lymph node biopsy (SNB) [true positive (TP)] and negative SNB with and without regional recurrence [FN, true negative (TN)] from our prospective institutional database. RESULTS: Among 2986 patients (84 FN, 494 TP, and 2408 TN; median follow-up 93 months), the incidence of FN-SNB was 2.8%. While calculated FN rate was 14.5% [84 FN/(494 TP + 84 FN) × 100], when we accounted for local/in-transit recurrence (LITR) this rate was 8.5% [46 FN/(494 TP + 46 FN) × 100 %]. On multivariate analysis, male gender (OR 2.0, 95% CI 1.1-3.6, p = 0.018), head/neck primaries (OR 2.5, 95% CI 1.3-4.8, p < 0.006), and LITR (OR 3.5, 95% CI 2.1-5.8, p < 0.001) were associated with FN-SNB. Melanoma-specific survival (MSS) for the FN group was similar to the TP group at 5 years (68 vs. 73%, p = 0.539). However, MSS declined more for the FN group with a longer follow up and was significantly worse at 10 years (44 vs. 64%, p < 0.001). On multivariate analysis, FN-SNB was a significant predictor of worse MSS in melanomas <4 mm in Breslow thickness (HR 1.6; 95% CI 1.1-2.5, p = 0.021). CONCLUSIONS: Male gender, LITR, and head and neck tumors were associated with FN-SNB. FN-SNB was an independent predictor of worse MSS in melanomas <4 mm in thickness, but this survival difference did not become apparent until after 5 years of follow-up.

Patterns and outcomes of colorectal cancer in adolescents and young adults.

BACKGROUND: The incidence of colorectal cancer (CRC) in the adolescent and young adult (AYA) population (aged 15-39 y) is rising. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results Database to study CRC in the AYA population. We studied clinical and socioeconomic factors associated with survival. RESULTS: Of the 11,071 cases of CRC, the most common site of the primary tumor was the rectum (25%), whereas 66.6% of the diseases were left sided. Most of the patients (72%) presented with regional or metastatic disease. However, the disease-specific survival (DSS) and the overall survival of the AYA population were comparable to those of the general population (DSS; 5- and 10-y: 64.8%, 57.3%; overall survival; 5- and 10-y: 61.5% and 52.4%). On multivariate analysis, disease stage at the time of the diagnosis was the strongest predictor of mortality. After controlling for disease stage, male gender, black race, and higher grade tumors were associated with worse survival. CONCLUSIONS: The AYA population presents with advanced distal CRC but have similar survival compared with the general population.

The identification of risk factors for venous thromboembolism in gastrointestinal oncologic surgery.

BACKGROUND: The aim of this study was to examine the incidence and factors associated with occurrence of venous thromboembolism (VTE) in patients undergoing major gastrointestinal (GI) surgery for malignancy. METHODS: The American College of Surgeon's National Surgical Quality Improvement Program, Participant User File database was queried from 2005 to 2012 to study major GI operations performed for cancer. Predictors of VTE and their relation to survival were studied. RESULTS: In 79,300 patients, the incidence of deep venous thrombosis was 1.7%, and pulmonary embolism was 0.9% during the 30-d postoperative period. The highest rate of VTE occurred after esophagectomy (5.9%) followed by pancreatectomy (3.2%), hepatectomy (3.2%), gastrectomy (2.5%), enterectomy (2.3%), colectomy, and proctectomy (2.0%). On multivariate analysis, disseminated cancer, age ≥ 80 y, body mass index > 35 kg/m(2), functional status, post operative sepsis, pulmonary dysfunction, and longer operative time were associated with occurrence of VTE. Occurrence of VTE was associated with mortality on multivariate analysis (odds ratio 2.4, 95% confidence interval 2.0-3.0, P < 0.001). CONCLUSIONS: Absolute incidence of VTE after major GI surgery is low but is associated with significant mortality and postoperative complications. Disseminated cancer, post operative sepsis, longer operative time, and increased body mass index >35 kg/m(2) further increased the risk of VTE in patients undergoing surgery for malignancy. Surveillance strategies should be implemented for those cancer patients who have multiple risk factors for VTE.

Pulmonary complications after major abdominal surgery: National Surgical Quality Improvement Program analysis.

BACKGROUND: Postoperative pulmonary complications (PPCs) after major abdominal surgery are common and associated with significant morbidity and high cost of care. The objective of this study was to identify the risk factors for PPCs after major abdominal surgery. MATERIALS AND METHODS: The American College of Surgeons' National Surgical Quality Improvement Program database from 2005-2012 was queried for patients who underwent major abdominal surgery (esophagectomy, gastrectomy, pacnreatectomy, enterectomy, hepatectomy, colectomy, and proctectomy). Predictors of PPCs were identified using multivariate logistic regression. RESULTS: Of 165,196 patients who underwent major abdominal surgery 9595 (5.8%) suffered PPCs (pneumonia 3.2%, prolonged ventilator support ≥48 h 3.0%, and unplanned intubation 2.8%). On multivariate analysis, significant predictors of overall and individual PPCs include esophagectomy, advanced American Society of Anesthesiology Classification System, dependent functional status, prolonged operative time, age ≥80 y, severe chronic obstructive pulmonary disease, preoperative shock, ascites, and smoking. Obesity was not a risk factor. Female gender was overall protective for PPCs. CONCLUSIONS: PPCs after abdominal procedures are associated with a number of clinical variables. Esophageal operations and American Society of Anesthesiology Classification System were the strongest predictors. These results provide a framework for identifying patients at risk for developing pulmonary complications after major abdominal surgery.

The effects of neoadjuvant chemoradiation on pancreaticoduodenectomy­the American College of Surgeon's National Surgical Quality Improvement Program analysis.

BACKGROUND: The purpose of this study was to investigate the effects of preoperative chemoradiation therapy on postoperative outcomes of pancreaticoduodenectomy (PD). MATERIALS AND METHODS: The American College of Surgeon's National Surgical Quality Improvement Program Participant User File from 2005-2011 was used to analyze the outcomes of patients who underwent chemoradiation therapy before PD. Their outcomes were compared with those who underwent PD without neoadjuvant therapy. RESULTS: We identified 110 patients who received preoperative chemoradiation therapy before undergoing PD for pancreatic malignancies and compared them with 4915 patients who did not. The two groups were similar in their preoperative comorbidities and demographics. The neoadjuvant group experienced a significantly longer operative time with a higher rate of vascular reconstruction, transfusion requirement, and superficial wound infection compared with those who did not receive neoadjuvant therapy. However, mortality and the rate of major complications between the two groups were similar. CONCLUSIONS: Preoperative chemoradiation therapy is associated with an increase in transfusion requirement and superficial surgical site infection. However, it is not associated with an increase in 30-d mortality or major complications.

Production of both IL-27 and IFN-gamma after the treatment with a ligand for invariant NK T cells is responsible for the suppression of Th2 response and allergic inflammation in a mouse experimental asthma model.

Using an allergen-induced airway inflammation model, we show that an injection of alpha-galactosylceramide (alpha-GalCer), a ligand for invariant NK T (iNKT) cells, induced IL-27 and that this process is essential for the attenuation of the Th2 response. After the systemic administration of alpha-GalCer into the mice primed with OVA in alum, Th2 cytokine production of OVA-primed CD4(+) T cells in their lymph nodes, IgG1 and IgE Ab formation, and infiltration of eosinophils in bronchoalveolar lavage after the OVA challenge were suppressed. Systemic administration of rIFN-gamma into OVA-primed mice could not reproduce these effects of alpha-GalCer. IL-27p28 was detected both in the culture supernatant of alpha-GalCer-stimulated spleen cells and in the serum of the alpha-GalCer-treated mice, but not in the iNKT cell-deficient mice. Splenic iNKT cells produced IL-27p28 in the culture supernatant upon stimulation with PMA plus ionomycin, although the transcript of IL-27p28 in the iNKT cells was constitutively expressed regardless of the stimulation. By contrast, the transcript of IL-27EBI3 was induced in the iNKT cells upon stimulation with PMA plus ionomycin in vitro and with alpha-GalCer treatment in vivo, suggesting that IL-27 (p28/EBI3) could be produced by iNKT cells in an activation-dependent manner. Although repeated injections of rIL-27 did not substitute for the effects of a single injection of alpha-GalCer, administration of rIL-27 along with rIFN-gamma reproduced in vivo effects of the alpha-GalCer injection. These data indicate that production of both IL-27 and IFN-gamma by the alpha-GalCer treatment is responsible for suppression of the Th2 response and allergic inflammation.

Characterization of the immature dendritic cells and cytotoxic cells both expanded after activation of invariant NKT cells with alpha-galactosylceramide in vivo.

Invariant natural killer T (iNKT) cells can perform multiple functions characteristic of both innate and acquired immunity. Activation of iNKT cells in vivo by repeated alpha-GalCer injections can induce immune tolerance, but the mechanisms responsible for such immunoregulation remain unclear. We prepared alpha-GalCer-liposomes, a single injection of which into mice resulted in the expansion of splenic CD11c(low)CD45RB(high) cells, which consists of two populations, CD180(+) and CD49b(+). Expansion of these cells was not observed in alpha-GalCer-liposome-treated mice deficient in IL-10 or iNKT cells. MHC and co-stimulatory molecules were down-regulated in CD11c(low)CD180(+) cells compared with conventional dendritic cells (cDCs), suggesting that the former possess characteristics of immature DCs. Meanwhile, the CD11c(low)CD49b(+) cells expressed IL-10 and Ctla4, and possessed greater lytic activity than resting NK cells. These observations suggest that both immature DCs (CD11c(low)CD180(+)) and cytotoxic cells (CD11c(low)CD49b(+)) might be expanded by alpha-GalCer-activated iNKT cells and could therefore be involved in immune tolerance.

Alpha-galactosylceramide-driven immunotherapy for allergy.

We report here that the delivery of both alpha-galactosylceramide (alphaGalCer), a representative ligand for invariant natural killer T (iNKT) cells, and an antigenic polypeptide to marginal zone B cells induces the differentiation of regulatory cells in vivo, and suppresses the secondary antibody responses in mice. Splenic CD21+ CD23- B cells of mice treated with alphaGalCer-liposomes produce IL-10 when co-cultured with iNKT cells, whereas the cells treated with aqueous alphaGalCer fail to do so. Adoptive transfer of the B cells into syngenic mice leads to the expansion of splenic CD11c(low) CD45RB(high) cells, which convert naive CD4+ T cells from RAG2-deficient DO11.10 mice to CD4+ CD25(high) Foxp3+ T cells in the presence of OVA323-339 peptide. Administration of alphaGalCer-OVA-liposomes into OVA-primed mice causes the development of CD4+ CD25(high) Foxp3+ T cells that produce both IL-10 and IFN-gamma, and induced the antigen-specific suppression of the secondary antibody responses when boosted with OVA alone. These results indicate that antigen-containing alphaGalCer-liposomes can facilitate the development of tolerogenic antigen-presenting cells and inducible regulatory T cells that are involved in the suppression of immune responses to antigens.

Construction of an open-access database that integrates cross-reference information from the transcriptome and proteome of immune cells.

MOTIVATION: Although a huge amount of mammalian genomic data does become publicly available, there are still hurdles for biologists to overcome before such data can be fully exploited. One of the challenges for gaining biological insight from genomic data has been the inability to cross-reference transcriptomic and proteomic data using a single informational platform. To address this, we constructed an open-access database that enabled us to cross-reference transcriptomic and proteomic data obtained from immune cells. RESULTS: The database, named RefDIC (Reference genomics Database of Immune Cells), currently contains: (i) quantitative mRNA profiles for human and mouse immune cells/tissues obtained using Affymetrix GeneChip technology; (ii) quantitative protein profiles for mouse immune cells obtained using two-dimensional gel electrophoresis (2-DE) followed by image analysis and mass spectrometry and (iii) various visualization tools to cross-reference the mRNA and protein profiles of immune cells. RefDIC is the first open-access database for immunogenomics and serves as an important information-sharing platform, enabling a focused genomic approach in immunology. AVAILABILITY: All raw data and information can be accessed from http://refdic.rcai.riken.jp/. The microarray data is also available at http://cibex.nig.ac.jp/ under CIBEX accession no. CBX19, and http://www.ebi.ac.uk/pride/ under PRIDE accession numbers 2354-2378 and 2414.

Differential MMP-2 activity of ligament cells under mechanical stretch injury: an in vitro study on human ACL and MCL fibroblasts.

Recent studies have revealed that following injuries, ligament tissues such as anterior cruciate ligaments (ACL), release large amounts of matrix metalloproteinases (MMPs). These enzymes have a devastating effect on the healing process of the injured ligaments. Although these enzymes are produced following ligament injuries, because of different healing capacities seen between the medial collateral ligament (MCL) and ACL, we were curious to find if the MMP activity was expressed and modulated differently in these tissues. For this purpose ACL and MCL fibroblasts were seeded on equi-biaxial stretch chambers and were stretched in different levels. The stretched cells were assayed using Zymography, Western Blot and global MMP activity assays. The results showed that within 72 h after injurious stretch, production of 72 kD pro-MMP-2 increased in both ACL and MCL. However, the ACL fibroblasts generated significantly more pro-MMP-2 than the MCL fibroblasts. Furthermore we found in ACL pro-MMP-2 was converted more into active form. With 4-aminophenyl mercuric acetate (APMA) treatment, large amounts of pro-MMP-2 were converted into active form in both. This indicates that there is no significant difference between ACL and MCL fibroblasts in post-translational modification of MMP-2. The fluorescent MMP activity assays revealed that the MMP family activities were higher in the injured ACL fibroblasts than the MCL. Since the MMPs are critically involved in extracellular matrix (ECM) turnover, these findings may explain one of the reasons why the injured ACL hardly repairs. The higher levels of active MMP-2 seen in the ACL injuries may disrupt the delicate balance of ECM remodeling process. These results suggest that the generation and modulation of MMP-2 may be directly involved in the different responses seen in ACL and MCL injuries.

Primary lymph node gastrinoma. A diagnosis of exclusion. A case for duodenotomy in the setting of a negative imaging for primary tumor: A case report and review of the literature.

INTRODUCTION: Zollinger-Ellison syndrome (ZES) is caused by uninhibited secretion of gastrin from a gastrinoma. Gastrinomas most commonly arise within the wall of the duodenum followed by the pancreas. Primary lymph node gastrinomas have also been reported in the literature. This is a case of ZES where preoperative localization revealed a gastrinoma in a solitary portacaval lymph node, presumed to be a primary lymph node gastrinoma. PRESENTATION OF CASE: The patient is a 57 year old female diagnosed with ZES, suspected of having a primary lymph node gastrinoma. The patient underwent an exploratory laparotomy and excision of a portacaval lymph node with a frozen section which was positive for gastrinoma. Intraoperative sonography of the pancreas, upper endoscopy with transillumination of the duodenum, and a duodenotomy with bimanual examination of the duodenal wall were also performed. The patient was found to have a 4mm duodenal mass near the pylorus, which was excised. DISCUSSION: Pathology showed that the duodenal mass was primary gastrinoma. Serum gastrin levels taken four months postoperatively were normal and the repeat octreotide scan did not show any evidence of recurrence. CONCLUSION: Primary lymph node gastrinoma is a diagnosis of exclusion. The duodenum and pancreas must be fully explored to rule out a primary gastrinoma that may be occult.

Identification of canine natural CD3-positive T cells expressing an invariant T-cell receptor alpha chain.

A representative T-cell subset exclusively using an invariant TCRalpha chain (iTCRalpha) is natural killer T (NKT) cells which are becoming an emerging topic for cancer and immune disorder in humans and mice. However, NKT cells in dogs have not yet been identified. In this study, CD3(+) T-lymphocyte population reactive to alpha-galactosylceramide-loaded mouse CD1d (alpha-GalCer/CD1d) were identified with flow cytometric analysis in mononuclear cells from spleen, liver, and peripheral blood of a dog with percentages of 0.028%, 0.045%, and 0.004%, respectively. Using cDNA library synthesized from mRNAs of the alpha-GalCer/CD1d reactive CD3(+) lymphocytes in the spleen cells, molecular analysis of canine iTCRalpha was carried out. Consequently, Variable (Valpha) and Joining (Jalpha) regions of iTCRalpha cDNA were found to be homogeneous to both mouse Valpha14-Jalpha281 and human Valpha24-JalphaQ. Characteristic features of iTCRalpha of NKT cells, such as the amino acid sequence of complementarity-determining region (CDR) 3 and extra cysteine residue, were well conserved among dogs, mice, and humans. In quantitative real-time PCR analysis, relative expression of the canine iTCRalpha mRNA in alpha-GalCer/CD1d reactive CD3(+) lymphocytes was 271-fold higher than that in CD3(+) lymphocytes unbound to alpha-GalCer/CD1d, indicating that the iTCRalpha mRNA was preferentially expressed in alpha-GalCer/CD1d-reactive CD3(+) lymphocytes in the dog. Together, the results strongly suggested that alpha-GalCer/CD1d-binding CD3(+) T lymphocytes identified in this study could be considered to be canine NKT cells.