Clinical impact of inflammatory and nutrition index based on metabolic tumor activity in non­small cell lung cancer treated with immunotherapy.

The aim of the present study was to explore the relationship between tumor metabolic glycolysis and inflammatory or nutritional status in patients with advanced non-small cell lung cancer (NSCLC) who received programmed death-1 (PD-1) blockade. A total of 186 patients were registered in the present study. All of patients underwent 18F-FDG PET imaging before initial PD-1 blockade, and maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were assessed as indicators of 18F-FDG uptake. As inflammatory and nutritional index, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ration (PLR), systemic immune inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI) and Glasgow prognostic score (GPS) were evaluated based on previous assessment. 18F-FDG uptake by MTV and TLG significantly correlated with the scores of NLR, PLR, SII, PNI and ALI, in addition to the level of albumin, lactate dehydrogenase, C-reactive protein, white blood cells, neutrophils, lymphocytes and body mass index. The count of NLR, PLR and SII was significantly higher in patients with <1 year overall survival (OS) compared with in those with ≥1 year OS, and that of PNI and ALI was significantly lower in those with <1 year OS compared with those with ≥1 year OS. High MTV under the high PLR, SII and low ALI were identified as significant factors for predicting the decreased PFS and OS after PD-1 blockade in a first-line setting. In second or more lines, high MTV was identified as a significant prognostic predictor regardless of the levels of PLR, SII, ALI and GPS. In conclusion, metabolic tumor glycolysis determined by MTV was identified as a predictor for the outcome of PD-1 blockade under the high inflammatory and low nutritional conditions, in particular, when treated with a first-line PD-1 blockade. A high MTV under high PLR and SII and low ALI in the first-line setting could be more predictive of ICI treatment than other combinations.

[A Long-Term Survival Case of Gastric Cancer with Pyloric Stenosis and Peritoneum Dissemination That Received Intravenous and Intraperitoneal Paclitaxel Combined with S-1 Therapy after Bypass Surgery].

Although a 74-year-old man with gastric cancer with pyloric stenosis(cT4aN[+]M0, Stage Ⅲ)had undergone surgery, he was diagnosed with peritoneum dissemination. He received bypass surgery, and an intraperitoneal access port was implanted in his subcutaneous space. Postoperatively, he received 4 courses of SOX therapy. In treatment effect, the primary tumor showed no change, and ascites developed. Therefore, we changed the chemotherapy regimen in intravenous and intraperitoneal paclitaxel combined with S-1 therapy. After starting this regimen, the primary tumor decreased in size, and the pyloric stenosis improved. Currently, the patient is alive without recurrence for 5 years and 8 months after intravenous and intraperitoneal paclitaxel combined with S-1 therapy and receiving this treatment regularly.

Prognostic significance of tumor infiltrating lymphocytes on first-line pembrolizumab efficacy in advanced non-small cell lung cancer.

AIM: Tumor-infiltrating lymphocytes (TILs) in the tumor and stroma are expected to accurately predict the efficacy of programmed death-1 (PD-1) blockade therapy. However, little is known about the prognostic significance of TILs in first-line PD-1 therapy. We assessed TILs in patients with advanced or metastatic non-small cell lung cancer (NSCLC) treated with pembrolizumab in the palliative setting. METHODS: Multiplex immunohistochemistry staining of TILs (CD4, CD8, Foxp3, and PD-1) and immunohistochemical staining of CK and PD-L1 in the tumor and stroma was performed in tumor specimens of 107 NSCLC patients and correlated with clinical outcomes, as a single-center retrospective study. TILs and programmed death ligand-1 (PD-L1) were assessed on biopsies (N = 93) or surgical resections (N = 14) before first-line pembrolizumab. RESULTS: A low number of stromal CD4 TILs were significantly associated with bone metastasis and poor performance status (PS). The median progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with a high number of stromal CD4 TILs (336 days and 731 days, respectively) than in those with low infiltration (204 days and 333 days, respectively). Patients with a high number of intratumoral CD8 TILs (731 days) yielded significantly better OS than those with low infiltration (333 days), but not for PFS. Multivariate analysis confirmed that stromal CD4 TILs were independent predictors of PFS, but not OS. Furthermore, intratumoral CD8 TILs were independent predictors of better OS. In the survival analysis of key subgroups, stromal CD4 TILs were identified as significant predictors of survival in patients with non-adenocarcinomatous histology and PD-L1 ≥ 50%. CONCLUSION: Stromal CD4 TILs were identified as a significant marker for predicting the PFS after pembrolizumab therapy, especially in patients with non-adenocarcinoma and high PD-L1 expression. In addition, intratumoral CD8 TILs were identified as significant predictors of OS.

Potential of VEGFR2 expression as a predictive marker of PD­1 blockade in patients with advanced NSCLC.

Angiogenesis serves a crucial role in cancer progression. Vascular endothelial growth factor (VEGF) exhibits an immunosuppressive function in patients with cancer. However, it remains unclear whether expression of VEGF in tumor tissue can predict the outcome of programmed death­1 blockade in patients with advanced non­small cell lung cancer (NSCLC). A training (n=32) and validation (n=76) cohort of patients with advanced NSCLC who received first­line pembrolizumab were enrolled. Immunohistochemical staining for VEGF receptor 2 (VEGFR2) and tumor­infiltrating lymphocytes (TILs; CD4, CD8 and FOXP3) was performed in tumor specimens of both cohorts and association with clinical outcomes was assessed. The percentages of high VEGFR2 expression were 34.3% (11/32) in training cohort and 25.0% (19/76) in validation cohort. No statistically significant difference in objective response between high and low VEGFR2 expression was observed for training (27.2 vs. 45.0%) and validation (31.2 vs. 35.7%) cohorts. The positive rate of intratumoral FOXP3 was significantly associated with high VEGFR2 expression for validation cohort, but not training cohort. In validation cohort, high VEGFR2 expression in patients with non­adenocarcinoma (non­AC) was significantly correlated with positive FOXP3 TILs in intratumoral and stromal sites, but not CD4 and CD8. High VEGFR2 expression in both cohorts indicated a significantly worse overall survival (OS) than low VEGFR2 expression. VEGFR2 was identified as an independent prognostic marker associated with worse OS. High VEGFR2 expression was a significant marker for predicting worse OS in patients treated with first­line pembrolizumab, particularly in those with non­AC.

Effect of Systemic Steroid Use for Immune-Related Adverse Events in Patients with Non-Small Cell Lung Cancer Receiving PD-1 Blockade Drugs.

OBJECTIVES: Programmed death-1(PD-1)/programmed death ligand-1 (PD-L1) antibodies have clinical benefits for cancer patients facing immune-related adverse events (irAEs). However, the effect of steroid use on the prognosis of patients with non-small cell lung cancer (NSCLC) receiving PD-1 blockade remains unclear. METHODS: NSCLC patients with complete response (CR)/partial response (PR) or stable disease (SD)/not evaluable (NE) status plus progression-free survival (PFS) of 180 days after PD-1 blockade from December 2015 to December 2018 were retrospectively registered in our study and were divided into two groups: those with and without systemic steroid use for irAEs. RESULTS: In total, 126 patients who had benefitted from PD-1 blockade were enrolled in our study; among them, 44 received systemic steroids for irAEs, and 82 had no adverse events or, if they did, did not receive systemic steroids. Among the 44 patients requiring steroids, interstitial lung disease (ILD), adrenal insufficiency, diarrhea, and liver dysfunction were observed in 19, 9, 4, and 4 patients, respectively. More side effects were observed in the group treated by steroids. The median PFS and overall survival (OS) in patients with and without systemic steroid use were 11.7 and 16.0 months (p < 0.037) and 35.0 and 41.0 months (p < 0.28), respectively. In univariate and multivariate analyses of survival, systemic steroid treatment for irAEs was significantly associated with PFS. The occurrence of ILD, adrenal insufficiency, and fever was significant in patients who used systemic steroids for irAEs. CONCLUSIONS: Patients administered systemic steroids for irAEs due to PD-1 blockade treatment exhibited shorter PFS than those who were not. Systemic steroids might affect survival after PD-1 blockade even for patients who once acquired its clinical benefit.

[Utility of the Filter Extraction Method for Detecting Anticancer Drug Contamination in Air].

The filter extraction method is a new, simple method for evaluating anticancer drug contamination in air. The method involves installing a filter in the exhaust port of an exhaust duct on a facility's air conditioner, then collecting and measuring fine particles of the antineoplastic agents adsorbed onto the filter. In this study, we analyzed the utility of maintaining continuous filter extraction for measuring cyclophosphamide and 5-fluorouracil contamination. The filters were installed in 3 areas of an outpatient chemotherapy room and then left in place for approximately 5 months. Results revealed the presence of cyclophosphamide and 5-fluorouracil in all 3 areas. However, the amounts and ratios of detected drugs differed among survey sites; this may have been caused by factors such as drug preparation, administration, and excretion. We conclude that the filter extraction method can be used continuously for monitoring anticancer drug contamination in air; thus, it can be utilized to monitor healthcare workers' occupational exposure to inhaled anticancer drugs. Indeed, the filter extraction method may be useful as a novel environmental monitoring technique.

A Phosphonium Ylide as a Ligand for [3 + 2] Coupling Reactions of Epoxides with Heterocumulenes under Mild Conditions.

The potential of carbonyl-stabilized phosphonium ylides as ligands for novel catalysis was explored. We found that the combination of phosphonium ylides and metal halide salts efficiently catalyzed the reaction of epoxides with carbon dioxide under mild conditions. Five-membered cyclic carbonates, including disubstituted cyclic carbonates, were obtained in good yields with the use of 1 atm of carbon dioxide at 35 °C. Terminal epoxides could be converted to N-aryl oxazolidinones in the reaction with isocyanates under a similar catalytic system.

A Patient with Advanced Gastric Cancer and Situs Inversus Totalis: Report of a Case.

Situs inversus totalis (SIT) is a rare congenital anomaly in which the positions of the abdominal and thoracic cavity structures are reversed. The reported incidence of SIT is one in 10,000 to 50,000 live births. There are few reports of gastric cancer in individuals with SIT or of the potential complications of surgical intervention in such cases. We report the case of a 79-year-old woman with SIT who underwent surgical treatment for advanced gastric cancer at our hospital and review the pertinent literature. Prior to surgery, abdominal computed topography angiography with 3-dimensional reconstruction was performed to uncover any variations and to verify the exact structures and locations of vessels. Total gastrectomy with D2 lymphadenectomy and cholecystectomy were performed safely and with careful consideration of the mirror-image anatomy.

Characteristics and prognosis of mucinous gastric carcinoma.

Mucinous gastric carcinoma (MGC) is a rare histological subtype of undifferentiated gastric carcinoma, accounting for ~2.6-6.6% of all gastric cancer cases. The clinicopathological characteristics and prognosis of MGC are controversial. The present study aimed to determine the clinicopathological characteristics and prognosis of patients with MGC. We retrospectively compared the characteristics and postoperative survival of 70 patients with MGC and 2,492 non-MGC (NMGC) cases who underwent surgical resection between 1990 and 2010. MGC was characterised by larger tumor size, macroscopic Borrmann type 2 and 3, T4 invasion of the gastric wall, positive N2 and N3 lymph node metastasis, positive lymphatic vessel invasion, positive venous invasion, peritoneal metastasis and advanced tumor stage III and IV. The prognosis of MGC patients was worse compared to that of NMGC patients, as the former group consisted of more advanced-stage cases. When patients with similar disease stages were compared, the incidence of peritoneal metastasis was significantly higher among MGC patients. However, hepatic metastasis was found significantly more often in NMGC patients. Otherwise, the prognosis of MGC and NMGC patients with similar disease stages was not significantly different. Therefore, our findings indicated that, although MGC is more rare and mostly detected at an advanced stage, the diagnosis of the mucinous histological subtype was not an independent prognostic factor.

Molecular targeting to treat gastric cancer.

Trastuzumab that targets human epidermal growth factor receptor 2 (HER2) protein is the only approved molecular targeting agent for treating gastric cancer in Japan and the outcomes have been favorable. However, trastuzumab is effective for only 10% to 20% of the population with gastric cancer that expresses HER2 protein. Molecular targeting therapy with bevacizumab against vascular endothelial growth factors (VEGF) and with cetuximab and panitumumab against the epidermal growth factors pathway that have been approved for treating colorectal cancer are not considered effective for treating gastric cancer according to several clinical trials. However, ramucirumab that targets VEGF receptor-2 prolonged overall survival in a large phase III clinical trial and it might be an effective molecular targeting therapy for gastric cancer. The significance of molecular targeting therapy for gastric cancer remains controversial. A large-scale randomized clinical trial of novel molecular targeting agents with which to treat gastric cancer is needed.

Reconstruction methods and complications in proximal gastrectomy for gastric cancer, and a comparison with total gastrectomy.

Proximal gastrectomy (PG) is a widely accepted, efficient treatment for upper-third early gastric cancer. However, it is associated with reduced quality of life (QOL) following surgery, and cancer recurrence in the remaining stomach. Various reconstruction methods have been proposed, but the optimal method has yet to be determined. We investigated the clinicopathological characteristics, reconstruction methods, and postoperative complications in 101 cases of PG, and additionally compared 93 cases of early gastric cancer treated by PG, and 38 cases treated by total gastrectomy (TG). We found that esophagogastrostomy was superior in terms of operation time, intraoperative blood loss, and postoperative hospital stay, while no significant differences were observed in postoperative complications compared with jejunal interposition or jejunal pouch interposition. We found more cases of multiple gastric cancers and advanced-stage cancer in the TG group than in the PG group. The TG group also had a significantly higher proportion of cases with large tumor diameters, low degrees of differentiation, many lymph node metastases, and advanced-stage disease. There were no differences in the recurrence rate or survival rate between the PG and TG groups. The PG group also showed significantly better results in operating time, intraoperative blood loss, and postoperative complications, with a tendency toward shorter hospital stays. In conclusion, PG is a curative but less invasive treatment for upper-third early gastric cancer, and esophagogastrostomy can be considered the most satisfactory reconstruction method following PG.

Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer.

BACKGROUND: CD133 is one of the most important stem cell markers in solid cancers. Some recent reports have described a possible relationship between CD133 and hypoxia-inducing factor-1-alpha (HIF-1α). The aim of this study was to clarify the clinical role of CD133 expression in gastric cancer and to investigate the correlation between CD133 expression and HIF-1α expression. METHODS: We studied 189 gastric cancer patients who underwent gastrectomy at Kurume University Hospital. CD133 and HIF-1α expression was examined using immunohistochemical staining. Fifty-six cases were CD133 positive, and they were divided into two expression types: luminal expression of the gland and cytoplasmic expression. We investigated the relationship among CD133 expression types, clinicopathological variables, prognosis, and HIF-1α expression. RESULTS: When comparing clinicopathological variables, expression of CD133 in the cytoplasm was related to metastasis and tumor progression. However, this relationship was not observed with luminal expression of the gland type. The survival rate in patients with cytoplasmic CD133 expression was significantly worse than that in the CD133-negative group. This relationship was observed in the survival rate of the adjuvant chemotherapy group and the curative resection group. Multivariate analysis revealed that the expression of CD133 in the cytoplasm was an independent prognostic factor in gastric cancer. Regarding the correlation between CD133 expression and HIF-1α expression, the HIF-1α positive rate was lower in patients with CD133 luminal expression of the gland type and higher in patients with cytoplasmic expression of CD133. CONCLUSION: Gastric cancer cells with CD133 expression in the cytoplasm were cells with high potential for malignancy, and this phenotype was associated with cancer progression, chemotherapy resistance, recurrence, and poor prognosis. Cytoplasmic expression of CD133 may be a useful prognostic marker in gastric cancer. Significant correlation was observed between HIF-1α expression and the immunohistochemical staining pattern of CD133.

Characteristics and prognosis of synchronous multiple early gastric cancer.

AIM: To assess the clinicopathologic characteristics, risk factors, and prognosis for synchronous multiple early gastric cancer (SMGC). METHODS: A total of 146 patients with SMGC and 1194 patients with single gastric cancer who had undergone gastrectomy between 1989 and 2008 were retrospectively analyzed to determine their clinicopathologic characteristics and postoperative survival. Tumors were classified into groups on the basis of location and histology. Smoking habits were evaluated using the Brinkman index. Clinical and pathological factors were compared using either Fisher's exact test or Pearson's χ(2) test. Logistic regression analysis was performed to identify independent risk factors. Survival rate was calculated using the Kaplan-Meier method. RESULTS: SMGCs accounted for 10.9% of gastric cancer cases and occurred predominantly in elderly male patients with a family history of gastric cancer who were both smokers and drinkers. These tumors were typically macroscopically elevated and histologically differentiated. There were no significant differences between SMGC and single gastric cancer patients with respect to tumor location, tumor size, lymph node metastasis, the number of metastatic lymph nodes, venous invasion, or tumor stage (P = 0.052, P = 0.347, P = 0.595, P = 0.805, P = 0.559, and P = 0.408, respectively). Further, there was no significant difference in postoperative survival between the patient groups (P = 0.200). Of the 146 SMGC patients, a single patient had remnant cancer. CONCLUSION: A careful preoperative endoscopy is necessary for patients who are at high risk of SMGC, and minimally invasive treatment may be indicated in some cases.

[Neoadjuvant chemotherapy with combined S-1 plus weekly low-dose cisplatin followed by surgical resection for advanced gastric cancer].

We retrospectively examined patients with advanced gastric cancer who underwent gastrectomy following neoadjuvant chemotherapy (NAC) with S-1 plus weekly low-dose cisplatin (CDDP). Between 2007 and 2009, 27 patients with advanced gastric cancer not amenable to curative surgery were enrolled. One course of NAC comprised S-1 (80 mg/m2/day) for 21 consecutive days and CDDP (20 mg/m2) on days 1, 8, and 15; this was followed by a 2-week rest after the end of S-1 administration. Grade 3 side effects were observed in 5 patients: 3 experienced neutropenia and 2 experienced digestive symptoms. The outpatient completion rate was 81.5% (22/27); there was no incidence of renal dysfunction. During pretherapy diagnosis, depth of invasion was classified as T4 in all cases. Postoperative pathologic results showed that the depth of invasion was T3 or lower in 4 patients. In addition, the number of patients with N0 and M0 classification increased and downstaging was observed in 12 patients (44.4%). A comprehensive assessment revealed that a partial response (PR) was observed in 13 patients and stable disease (SD) was observed in 12 patients, resulting in a response rate of 48.1%. The median survival time was 580 days, and the 1-year survival rate was 72%. NAC with S-1 plus weekly low-dose CDDP can also be administered on an outpatient basis, and it is a potential regimen for the treatment of advanced gastric cancer associated with a poor prognosis.

Cronkhite-Canada syndrome complicated with multiple gastric cancers and multiple colon adenomas.

BACKGROUND: We experienced a case in which Cronkhite-Canada Syndrome presented with complications of multiple gastric cancers and multiple colon adenomas. CASE REPORT: Our case is a 64-year-old male who visited a nearby hospital with diarrhea and weight loss. The patient was anemic and hypoproteinemic, with multiple polyps in the stomach, duodenum, and large intestine. He also presented with alopecia, onychatrophia, cutaneous pigmentation, and dysgeusia, and was diagnosed with Cronkhite-Canada Syndrome. Follow-up examinations found multiple gastric cancers and colon adenomas. We performed a total gastrectomy and a polypectomy of the large intestine lesions, revealing 4 well-differentiated adenocarcinomas in the resected stomach, and tubular adenomas in the large intestine lesions. Intraoperative findings included scattered melanoid pigmentation on the mesentery and the small intestinal wall. Tumor cells were positive for p53 and Ki67 and partially positive for MUC5AC and MUC2. Cronkhite-Canada Syndrome polyps are generally classified as juvenile type polyps, and these polyps rarely become cancerous. However, of the 383 cases of Cronkhite-Canada Syndrome reported in Japan, complications of gastric cancer were found in 39 cases (10.2%), and only 8 cases with multiple gastric cancer were reported in Japan. including the cases we have personally experienced. There were only two English literatures on Cronkhite-Canada Syndrome complicated with gastric cancer. So it is necessary to notify this information of Cronkhite-Canada Syndrome to the world. CONCLUSIONS: Close gastrointestinal examination and strict follow-up are believed to be essential for Cronkhite-Canada Syndrome patients.

Characteristics and prognosis of gastric cancer in young patients.

The clinicopathological features of gastric cancer (GC) differ between younger and older patients, and it is thought that younger patients have a worse prognosis than older patients due to delayed diagnosis and more aggressive tumor behavior. These characteristics, however, remain controversial. A total of 3,818 patients with pathologically confirmed primary gastric adenocarcinoma were treated at our institution. We analyzed the difference in demographic and clinicopathological characteristics between 169 young [≤40 years of age, younger group (YG)] and 3,649 older [>40 years of age, older group (OG)] GC patients. There was a significantly higher proportion of females in the YG compared with the OG (53.3 and 31.0%, respectively; P<0.0001). The 5-year overall survival of the YG was significantly lower compared to that of the OG (59.7 and 65.9%, respectively; P=0.049). However, YG patients with curative resection had a similar 5-year survival rate to OG patients with curative resection (88.0 and 85.8%, respectively; P=0.547). Female patients in the YG showed a significantly lower survival rate than males in the YG (44.3 and 73.1%, respectively; P=0.0002). Multivariate analyses revealed that macroscopic type, depth of invasion, peritoneal metastasis, distant metastasis and curative resection were independent prognostic factors for the YG with GC. Young GC patients who undergo curative resection do not have a worse prognosis than older patients. Early diagnosis is important in successfully carrying out a curative resection and offering a better prognosis, particularly in females.

Molecular targeting therapy using bevacizumab for peritoneal metastasis from gastric cancer.

AIM: To clarify the significance of vascular endothelial growth factor (VEGF) in peritoneal metastasis from gastric cancer, using the gastric cancer cell line MKN-45 compared with the high potential peritoneal dissemination gastric cancer cell line MKN-45P. METHODS: The supernatant of culture medium of MKN-45 cells or MKN-45P cells was collected and the concentrations were measured of various cytokines, matrix metalloproteinases, growth factor and angiogenic factors, including VEGF. We performed an initial pilot study to explore whether bevacizumab, a humanized monoclonal antibody against VEGF, had any suppressive effect on the peritoneal dissemination from gastric cancer in an experimental nude mouse model of peritoneal metastasis. RESULTS: The concentrations of interleukin-6 (IL-6), IL-8, VEGF and matrix metalloproteinase-2 protein in the culture supernatant were each significantly higher than each of those for MKN-45. In the in vivo study, the volume of ascites and the mitotic index were significantly lower in the therapy group than in the non-therapy group. The survival curve of the therapy group was significantly higher than that of the non-therapy group. These results suggested that VEGF was correlated with peritoneal metastasis from gastric cancer. CONCLUSION: Findings suggested that bevacizumab for inhibiting VEGF could suppress peritoneal dissemination from gastric cancer.

Surgical procedures, complications, and prognosis for gastric cancer in the very elderly (>85): a retrospective study.

Many elderly individuals suffer from reduced functioning of major organs with cardiovascular and respiratory system comorbidity. Consequently, surgical stress and postoperative complications can be fatal. We investigated whether gastrectomy can safely improve the prognosis in very elderly (>85 years) patients with gastric cancer. We compared the clinical and pathological features of patients 85 years and older (Group A) with those 80- to 84-year-old (Group B) who underwent gastrectomy. We also compared the survival rates of Group A and Group B, and investigated the prognostic factors. Group A had a high incidence of patients with 3 or more comorbidities, but these did not influence postoperative complications or survival rate. Patients at stage I or II had a significantly higher survival rate than those who did not undergo surgery. However, there was no statistical difference in survival rate at stage III or IV. Our study results revealed that in the early stages (I and II) of well-differentiated gastric cancer with low risk of lymph node metastasis, surgery should consist of minimal lymphadenectomy and be minimally invasive. Further, treatments other than gastrectomy should be considered for patients in whom complete resection via reduction surgery is not possible.