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Introduction: This study aimed to evaluate the clinical impact of skeletal muscle mass and nutritional status in gastric cancer patients treated with nivolumab monotherapy as late-line treatment., Methods: We conducted a multi-institutional retrospective study of 90 gastric cancer patients who previously received anti-PD-1 therapy (nivolumab). On computed tomography images captured before nivolumab induction, the skeletal muscle index (SMI, cm2/m2) was defined as the erector muscle area (cm2) divided by the height (m) squared. Patients were divided into two groups: those with SMI-high (n = 45) and those with SMI-low (n = 45). Prognostic nutritional index (PNI) was also calculated before nivolumab induction. The associations of SMI and PNI with response rate (RR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety were analyzed., Results: The cutoff values for SMI were determined as 13.45 for males and 10.41 for females. SMI-high was significantly associated with a higher RR (odds ratio = 12.36, p = 0.02) and DCR (odds ratio = 2.97, p = 0.02). Although not significant, PNI-high also tended to be associated with a higher RR. Multivariate analysis showed that SMI-high was independently associated with a higher RR and higher DCR in gastric cancer. Moreover, prognostic analyses revealed that SMI-high (log-rank test p = 0.008) and PNI-high (log-rank test p = 0.0008) were significantly associated with longer OS since nivolumab induction. SMI-high was also associated with longer PFS (log-rank test p = 0.03). There were no significant differences in immune-related adverse event between SMI-low and SMI-high., Conclusion: SMI and PNI were associated with nivolumab efficacy in gastric cancer patients. Management of skeletal muscle loss and nutritional status in gastric cancer patients who will receive nivolumab would be beneficial to enhance survival outcomes., (© 2024 S. Karger AG, Basel.)

Introduction: DNA microarrays, such as the consensus molecular subtype (CMS) classification using >600 genes, are used to predict cancer patient prognosis. We recently constructed a simple 55-gene classifier (55GC) system to risk stratify colon cancer (CC)., Objective: Here, we validate the 55GC specifically for stage II CC and compare it with CMS categories., Methods: Tissue sections from 232 stage II CC patients who underwent curative surgery without adjuvant chemotherapy between 2009 and 2012 were subjected to DNA microarray analysis., Results: Based on the 55GC, patients were classified into microsatellite instability-like (27%), chromosomal instability-like (41%), and stromal (32%) subtypes with 5-year relapse-free survival (RFS) rates of 88.5, 83.3, and 71.2%, respectively (stromal vs. others: p = 0.0049). Multivariate analysis by Cox's proportional hazard model revealed that the stromal subtype, pT4, and the number of lymph nodes examined (<12) were independent poor prognostic factors. The overall concordance rate between 55GC and CMS was 72%, and 5-year RFS rates of patients with CMS1, CMS2, CMS3, and CMS4 cancers were 100, 85.5, 92.3, and 73.0%, respectively (p = 0.0113)., Conclusions: We conclude that the 55GC is a useful and reproducible grading system for stage II CC recurrence risk stratification., (© 2020 S. Karger AG, Basel.)

Background: Molecular targeted drugs having angiogenesis-inhibiting properties allow the induction of necrosis inside tumors. We retrospectively investigated the relationship between changes on imaging associated with regorafenib (REGO) and treatment outcomes using real-world data., Patients and Methods: The eligibility criteria included an ECOG PS of 0-1, a starting dose of 120 or 160 mg/day of REGO, and a duration of treatment of at least 35 days. Regarding changes on imaging, cavitation in lung lesions (CLL), morphologic response of liver lesions (MRL), and change of liver metastasis density (CLD) were evaluated., Results: We finally screened 671 cases, and 226 cases were eligible. In total, 172 and 145 patients had lung and liver metastases, respectively. Among the patients with lung metastasis, CLL was found in 69 patients (40.0%). The median progression-free survival (PFS) of the patients with and those without CLL was 3.2 and 2.4 months, respectively (hazard ratio [HR] = 0.758; 95% confidence interval [CI]: 0.529-1.087), and the median overall survival (OS) of these groups was 10.5 and 8.9 months, respectively (HR = 0.862; 95% CI: 0.579-1.285). MRL and CLD of liver metastasis were analyzed in 145 and 90 patients, respectively. The median OS with and without MRL was 8.9 and 8.2 months, respectively, whereas the median OS with and without CLD was 11.6 and 7.7 months, respectively (HR = 0.523; 95% CI: 0.275-0.992)., Conclusion: CLL may predict PFS but not OS among patients with lung metastasis. CLD was predictive of favorable outcomes for REGO in patients with liver metastasis., (© 2020 S. Karger AG, Basel.)

The combined effects of flavone acetic acid (FAA), hydralazine (HYD) and hyperthermia on B16 melanoma cells and solid tumor were examined in vitro and in vivo. In vitro, hyperthermia did not enhance the cytotoxicity of the combined use of FAA and HYD. In vivo, growth inhibition of B16 melanoma solid tumor by FAA (150 mg/kg) combined with HYD (5.0 mg/kg) could not be differentiated from that by FAA or HYD alone. Increased antitumor effect was recognized when FAA combined with HYD was used under conditions of hyperthermia. FAA combined with HYD significantly reduced tumor blood flow compared to FAA alone or HYD alone. We thus conclude that the significant reduction in tumor blood flow may play an important role in the enhanced antitumor effects of the combined treatment with FAA, HYD, and hyperthermia.

The interaction of cis-1,1-cyclobutanedicarboxylato(2R)-2-methyl-1,4- butanediammineplatinum(II) (NK121) and cis-diammine(glycolato)platinum(II) (254-S), analogues of cis-diamminedichloroplatinum(II) (CDDP), with hyperthermia was examined in vivo. Antitumor activity of the platinum complexes at the maximum tolerated dose (MTD) with or without hyperthermia was evaluated by the tumor growth delay assay using B16F10 melanoma growing in the legs of C57BL/6J mice. MTD of CDDP, NK121 or 254-S at the single intraperitoneal injection with hyperthermia was 8, 50 or 30 mg/kg, respectively. Treatment of the tumor-bearing limb at 43 degrees C for 30 min resulted in a tumor growth delay of 1.1 days. A single dose of CDDP produced a 3.3-day tumor growth delay. When CDDP was injected just before hyperthermia (43 degrees C, 30 min), the growth delay increased to 5.5 days (1.7-fold increase). With NK121, there was a 1.5-day growth delay. In combination with hyperthermia, the tumor growth delay by NK121 was 3.2 days (2.1-fold increase). Injection of 254-S led to a growth delay of 3.5 days, and this delay was extended to 5.7 days (1.6-fold increase) when combined with hyperthermia. Changes in serum blood urea nitrogen (BUN) were determined 5 days after intraperitoneal drug administration with or without hyperthermia. A single administration of CDDP 8 mg/kg resulted in an elevated BUN level, and this was enhanced in combination with hyperthermia (66.3 mg/dl, 2.7-fold over control). NK121 50 mg/kg at 37 degrees C did not result in elevation of BUN, but mild nephrotoxicity was noted in combination with hyperthermia (40.3 mg/dl, 1.6-fold increase over control). The administration of 254-S 30 mg/kg resulted in an elevated BUN level, and this elevation was enhanced in combination with hyperthermia (48.6 mg/dl, 2.0-fold increase over control). Our data showed that NK121 and 254-S as well as CDDP produced greater tumor growth delay together with hyperthermia than did the drug alone. Though these new compounds were designed with reduced nephrotoxicity, attention should be paid to increased nephrotoxicity when combined with hyperthermia.

The effect of the new hypoxic cell sensitizer, 1-[2-hydroxy-1-(hydroxymethyl)-ethoxy]methyl-2-nitroimidazole (RP-170), combined with heat against EMT6/KU cells, was determined under conditions of in vitro hypoxia. Heat-induced cytotoxicity for the EMT6/KU cells was increased to a greater extent under conditions of hypoxia and a normal pH of the medium. Hypoxia also reduced the surviving fraction of the cells treated either with RP-170 alone or with RP-170 plus heat. The concomitant treatment of RP-170 and heat inhibited the clonogenic activity of the EMT6/KU cells under conditions of in vitro hypoxia in all experimental groups, with a significant difference (p < 0.05). Therefore, RP-170 combined with exposure to heat may be an effective treatment for hypoxic cells in a solid tumor, as these cells are resistant to radiation and/or to many chemotherapeutic agents.

Carboquone (CQ) and hyperthermia (HT) are capable of preferentially killing oxygen-deficient cells, both in vitro and in vivo. We examined effects of the combination of CQ and HT on an in vitro hypoxic system and on murine solid tumors using hydralazine (HYD), a vasoactive agent. Under in vitro hypoxic conditions, the combined cytotoxicity of CQ and HT (43 degrees C, for 1 h) was enhanced and the enhancement ratio (ER) for the IC90 of CQ was 21.4-, 9.4-, and 2.6-fold compared to that for CQ alone, CQ under hypoxic condition, and CQ plus HT under aerated cells, respectively. Five mg/kg i.p. HYD reduced the level of tumor blood flow in mice to about 20% of constant level and this reduction persisted for 1 h. In mice bearing B16 melanoma tumors, HYD enhanced tumor susceptibility of the combined therapy of CQ and HT. The ER which was a comparison of tumor growth time in the control group, was 2.3, 3.6 for the two combination groups of 1, 2 mg/kg i.p. CQ, HT (43 degrees C for 20 min), and 5 mg/kg i.p. HYD, respectively. Thus, hyperthermochemotherapy using CQ combined with HYD, seems to selectively attack a solid tumor.

Serum carcinoembryonic antigen (CEA) levels were determined preoperatively in 221 patients with well-differentiated gastric cancer. The mean preoperative serum CEA level was 15.9 +/- 88.5 ng/ml (1.0-1,133.0 ng/ml) for all patients, and the incidence of an elevated CEA (> 5 ng/ml) was 11.8% (26/221). The CEA-positive patients had larger tumors, a more prominent serosal invasion, more frequent lymphatic and vascular involvement, less expansive tumor growth and higher rates of lymph node and hepatic metastases than did the CEA-negative patients. Thus, the CEA-positive patients had a more advanced stage of disease, and 61.5% underwent noncurative resection (vs. 11.3% in CEA-negative patients). The survival rate of the CEA-positive patients was lower than that of the CEA-negative ones (p < 0.01). As the multivariate analysis revealed the preoperative CEA level to be an independent prognostic factor for survival, an assay for this antigen prior to surgery is to be recommended.

The in vitro succinate dehydrogenase (SD) inhibition (SDI) test was used to determine the heat sensitivity of tumor cell lines and human tumor cells. The tumor cells were exposed to heat in vitro and the decrease in SD activity was assayed using a colorimetric assay, the SDI test. With respect to survival curves of HeLa cells, the SDI test correlated well with the clonogenic assay and the dye exclusion assay. Decrease in the SD activity of HeLa cells after the heat treatment (41-44 degrees C, 10 min to 5 h) depended on both the temperature and the duration of heat exposure. S- and G2/M-phase-rich HeLa cells were more sensitive to heat than were the G1-phase-rich cells. The SDI test exhibited a wide variation in the heat sensitivity among four cell lines (HeLa, B-16, V-79, and a human GT-1 squamous cell carcinoma). Variation in heat sensitivity was also detected among individual tumor tissues obtained from clinical specimens of gastric, esophageal, and colorectal cancers. Gastric cancer tissues were more sensitive to heat than were esophageal and colorectal tissues. We recommended that if the SDI test is used to assess the heat sensitivity of clinical tumor tissues in vitro, appropriate therapy for individual patients can be designed.

Using atomic absorption spectrophotometry, we determined the concentration of platinum in tissues obtained at autopsy of 4 patients with recurrent gastric cancer. Patients had been given intraperitoneal cis-diamminedichloroplatinum(II) (cisplatin, CDDP). There was no correlation between the concentration of platinum and the dose of CDDP. Platinum was distributed in all organs examined, the highest amount being in the liver. Thus, when CDDP is administered intraperitoneally for treatment of patients with malignant disease, the toxicity to various organs, including the liver and the kidney, needs to be considered.

Enhancement of the cytotoxicity of mitomycin C (MMC) and carboquone (CQ) by hypoxia at elevated temperature was examined using the SDI test of mouse Sarcoma 180 and Ehrlich cells and clonogenic assay of HeLa cells. When Sarcoma 180 and Ehrlich cells were incubated at 43 degrees C for 2-10 h, the hyperthermic effect was enhanced by hypoxia. The succinate dehydrogenase activity of the cells was reduced by hyperthermia to a greater extent in the presence of hypoxia (O2:5%) than under conditions of aeration (O2:20%). When the cells were exposed to various concentrations of MMC and CQ, under hypoxia, activity of the drugs was enhanced compared to the findings under conditions of aeration. The enhancement was prominent in case of drugs and hyperthermia combined. Clonogenicity of hypoxic HeLa cells was also reduced to a greater extent with this combination than in case of aerated cells. We tentatively speculate that hyperthermo-chemotherapy using MMC and CQ has a potential to attack selectively hypoxic cells present in a solid tumor.

The chemosensitivities of squamous cell carcinoma (SCC) tissues from the head and neck area were compared to findings of adenocarcinoma, mainly from digestive organs. The sensitivity of each tissue was determined using the in vitro succinate dehydrogenase (SD) inhibition test, which shares a common principle with the 3-(4,5-dimethyl-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Tumor tissues were obtained at surgery or biopsy. Anticancer drugs tested were carboquone, Adriamycin, mitomycin C, cisplatin (CDDP), aclacinomycin A, 5-fluorouracil and 1-hexylcarbamoyl-5-fluorouracil with 10 times the peak plasma concentration, respectively. The means +/- standard deviations of SD activities in SCC tissues were significantly lower than those in adenocarcinoma tissues (p less than 0.001), and the sensitivity rates of SD activity in SCC tissues had a higher value than those in adenocarcinoma tissues (p less than 0.05), against each drug. Our study showed that CDDP-based combination regimens might be effective for SCC tissues. The chemosensitivity of each excised tissue should be tested, in order to prescribe sensitive, effective drugs for each patient.

We determined the correlation between DNA strand breaks and the toxicity of carboquone (CQ) in HeLa cells in vitro and in mouse sarcoma 180 (S-180) cells in vivo, using in situ nick translation. The break sites in the DNA were translated artificially in the presence of Escherichia coli DNA polymerase I and [3-H]-labelled dTTP, and sites in the DNA were visualized by autoradiographic observation of grains in the nuclei. These breaks appeared as early as 5 min in the CQ-treated HeLa cells and increased in a dose- and time-dependent manner compared to findings in the control cells, i.e., 10.2-fold at 3 x 10(-6) M in 60 min. Strand breaks in the S-180 cells appeared in a dose- and time-dependent manner, i.e., 6.1-fold after the mice had been exposed to CQ (3.6 mg/kg) for 2 h. This level correlated with the increase in host life span. Our findings show that the survival response of cells decreases, while the level of DNA strand breaks increases following exposure to CQ. The nick translation method is a rapid in situ assay for determining drug-induced DNA damage of tumor cells, under in vitro and in vivo conditions and in a semiquantitative manner.

We compared the colorimetric reactions between the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl 2H-tetrazolium bromide (MTT) assay and the succinate dehydrogenase inhibition (SDI) test, in order to evaluate the usefulness of the SDI test for in vitro chemosensitivity testing. The addition of sodium succinate enhanced the colorimetric absorbance at 565 nm in the MTT assay in a dose- and a time-dependent manner, in mouse sarcoma-180 (S-180) cells. At 10 microM of sodium succinate, a dose used in the SDI test, the absorbance of the MTT assay increased by about 2.5-fold in the S-180 cells and in 10 human tumor tissues. The absorbance in the SDI test correlated well with the viable cell number of S-180 cells (r = 0.9993). These results show that the SDI test, using MTT as a tetrazolium salt, has a higher sensitivity for predicting cell viability, compared to the MTT assay.

The chemosensitivity of 20 human neoplastic tissues including 13 gastric and 7 colorectal cancers was tested using 5-fluorouracil (5-FU) and its analogues: 1-(2-tetrahydrofuryl)-5-FU (FT), uracil/FT (UFT) and 1-hexylcarbamoyl-5-FU (HCFU), and the in vivo subrenal capsule (SRC) assay. The relative variation of tumor size (delta TS/TSo) was calculated as follows: delta TS/TS0 = (TS6-TS0/TS0) x 100%, where TS6 was the tumor size on day 6 and TS0 on day 0, and the chemosensitivity was considered to be sensitive when delta TS/TS0 in the treated group was decreased to below -10%. The mean tumor size was -10.9 +/- (SD) 10.9% for 5-FU, -12.3 +/- 17.1% for FT, -18.4 +/- 15.8% for UFT and -17.9 +/- 15.4% for HCFU. The decrease of tumor size was marked when exposed to UFT (p less than 0.01) or HCFU (p less than 0.02), compared with that to 5-FU. Positive correlations were noted between the tumor sizes of 5-FU and its analogues (5-FU vs. FT, r = 0.851; 5-FU vs. UFT, r = 0.746; 5-FU vs. HCFU, r = 0.685). In 9 tissues resistant to 5-FU, 2 (22%) were sensitive to FT, 4 (44%) to UFT, 5 (56%) to HCFU and 7 tissues (78%) to at least one of these analogues. These results suggest that the SRC assay is useful for predicting the effective drug among 5-FU and 5-FU analogues, for individual patients with cancer.

The effects of Vinca alkaloids, vinblastine, vincristine, and vindesine, on protein synthesis were determined using HeLa cells. Vinblastine at the concentration of 1 microgram/ml induced new proteins, isoelectric points 4.8 and 7.0-7.5 and molecular weights 48 and 92 kd, in the HeLa cells, identified using two-dimensional gel electrophoresis. The 48-kd and the clustered (4-components) 92-kd proteins were also noted in HeLa cells treated with vincristine or vindesine. As most of the 48- and 92-kd proteins were Triton insoluble, they can be considered components of the cytoskeletal structure. Syntheses of these proteins were blocked by actinomycin D, therefore, new messenger RNA synthesis is required for induction. These proteins were not induced by an alkylating agent, antitumor antibiotics, or an antimetabolite. Our findings show that the 48- and the clustered 92-kd proteins are Vinca alkaloid reactive components and can be considered candidates for the elucidation of the antineoplastic effect of Vinca alkaloids.