Inflammatory prognostic factors in advanced or recurrent esophageal squamous cell carcinoma treated with nivolumab.

BACKGROUND: In Japan, nivolumab administration is the standard treatment for patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) who are refractory or intolerant to fluoropyrimidines and platinum-based chemotherapy. We determined if inflammatory prognostic factors are useful in patients with ESCC treated with nivolumab monotherapy. METHODS: The clinical data of patients with ESCC treated with nivolumab monotherapy as the second- or later-line treatment were retrospectively analyzed. Neutrophil/lymphocyte, platelet/lymphocyte, and C-reactive protein/albumin ratios (CAR); prognostic index; and prognostic nutritional index were investigated. Cut-off values for each factor were determined according to overall survival using time-dependent receiver operating characteristic curves. RESULTS: During January 2017-June 2021, 93 consecutive patients with ESCC were enrolled from five institutions (median age, 70 years; male, 77%). With a median follow-up period of 9.1 (range, 1.0-34.7) months, the median overall and progression-free survival were 12.8 (95% confidence interval [CI], 9.0-16.6) and 4.0 (95% CI, 2.6-5.4) months, respectively. Of five inflammatory prognostic factors, the cut-off value for CAR was 0.62; prognosis was significantly longer in those with CAR < 0.62 (hazard ratio, 0.39; 95% CI, 0.22-0.67; p = 0.001). CONCLUSIONS: Inflammatory prognostic factors were useful in predicting prognosis for ESCC patients pretreated with nivolumab, especially for those with CAR < 0.62, suggesting that CAR adequately reflects prognosis.

Oxaliplatin-induced liver injury mimicking metastatic tumor on images: a case report.

Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.

[Efficacy of chemotherapy combined with bevacizumab for unresectable advanced or recurrent colorectal cancer].

Systemic treatment for metastatic or advanced colorectal cancer(mCRC)has remarkably progressed during recent years. All previously untreated mCRC patients at our institution between November, 2007 and June, 2010 were retrospectively evaluated. Of 72 patients, 39 were treated with chemotherapy alone, and 33 were treated with chemotherapy plus bevacizumab(BV). The median progression-free survival(mPFS)was 329 days in the group given chemotherapy plus BV, compared with 209 days in the group given chemotherapy alone(p=0. 0189). In sub-group analysis of those treated with chemotherapy plus BV, mPFS between 70 y/o

[A case of advanced hepatocellular carcinoma with portal vein invasion successfully treated by sorafenib].

A 73-year-old man was followed up for HCV-associated chronic hepatitis and hepatocellular carcinoma (HCC), developed in segment 8 of the liver. Radiofrequency ablation (P-RFA) was used to treat the tumor in June 2004. Afterwards, the patient underwent repetitive transcatheter arterial chemoembolization (TACE) against recurrent tumors 5 times. An abdominal computed tomogram (CT) showed an infiltrative mass in the left liver with tumor thrombus invading into the umbilical portion. Transarterial infusion (TAI) therapy of cisplatin (CDDP) was performed 2 times, in January and June of 2010. The size of the main tumor was decreased according to CT, and tumor marker levels such as AFP and PIVKA-II also decreased, but tumor thrombus of the portal vein developed into the main trunk (Vp4). We started therapy with sorafenib in July, 2010. Two months later, an abdominal CT revelaed further reduction of the main tumor and a shrunken tumor thrombus of the portal vein back to the left lobe. The therapeutic effect of sorafenib against HCC with tumor thrombus of the portal vein continued for 9 months.

[Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma accompanied with cystic change].

A 64-year-old male with throat discomfort visited our hospital, and a chest computed tomography (CT) scan revealed a cystic lesion with a central solid component in the right lung (in the lower lobe, 4.1 x 3.9 cm in diameter). Transbronchial lung biopsy was performed and the lesion was diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma of the lung. No other lymphoma lesion was detected and it was diagnosed as the stage I-E, and a right lower lobectomy was performed. The cystic lesion derived from alveolus and bronchus destroyed by lymphoma infiltration and it might be caused by air retention due to check-valve mechanism.

Localization of FAK is related with colorectal carcinogenesis.

Focal adhesion kinase (FAK) is an important mediator functioning between cells and the extracellular matrix and is closely related with the integrin-signaling pathway. FAK has been reported to be involved in the proliferation, differentiation and apoptosis of cells. To date, no report has demonstrated the involvement of FAK in the carcinogenesis of the digestive tract. Therefore, we examined colorectal, esophageal, pancreatic and mammary cancers for expression of FAK and Phospho (P)-FAK by immunohistochemistry. Strong expression of FAK in the cytoplasm was detected in all 4 tumor types and expressions of FAK and P-FAK increased as the degree of cell differentiation became higher in colorectal and esophageal carcinomas. Interestingly P-FAK expression was confined to the nuclei, which was an unexpected result. No previous report of such a finding has been published for gastrointestinal cancer. All four of the organs investigated in the present study showed P-FAK expression in the nuclei, suggesting an association between FAK activation and abnormal cell proliferation. We also performed immunostaining of P-FAK in cell lines to examine the significance of its experience in the nuclei. However, unlike clinical specimens, the cell lines did not show P-FAK expression in the nuclei. Moreover, the injection of cancer cells into the peritoneal cavity of mice also failed to demonstrate P-FAK expression in the nuclei. These results may be related with the function of carrier proteins of FAK such as Hic-5 and Zyxin, which are found only in humans. Taken together, FAK and P-FAK are involved in the carcinogenesis of digestive organs.

[A case of dihydropyrimidine dehydrogenase (DPD) deficiency with severe side effects from UFT/Uzel administration].

5-FU is among the drugs most frequently used in the treatment of gastrointestinal malignancies. Also, it has been reported to reveal severe side effects in the case of a dihydropyrimidine dehydrogenase (DPD) deficiency. A 75-year-old man showed severe nausea and vomiting after administration of UFT/Uzel as adjuvant chemotherapy. Because of severe thrombocytopenia and grade 4 neutropenia, platelet transfusion and G-CSF administration were performed. With time, the leukocyte, neutrophil and platelet count recovered to normal level. We strongly suspected a DPD deficiency from the result of urinary pyrimidine analysis.

[A case of advanced breast cancer leading to DIC after chemotherapy].

We reported a case of DIC who was administered FEC90 (5-FU 1,000 mg/body, epirubicin 170 mg/body, cyclophosphamide 1,000 mg/body) for advanced breast cancer. A 55-year-old woman was referred to our hospital with lumbago. There was a huge tumor in her left breast (10x10 cm) and bone scintigraphy showed multiple bone metastasis, so she was treated with FEC90. Before the third course, DIC occurred. The patient was then treated with FOY and heparin, and the DIC was resolved. We think the DIC of this case was related with tumor lysis syndrome. Febrile neutropenia has been occasionally emphasized during chemotherapy, but due care must be taken for lymphocyte depletion during treatment.

Translocation of heparanase into nucleus results in cell differentiation.

We recently reported that heparanase, one of the extracellular matrix-degrading enzymes, which plays a critical role in cancer progression, is located not only in the cytoplasm but also in the nucleus. Here we identified nuclear translocation of heparanase as a key step in cell differentiation. We applied an in vitro differentiation model of HL-60 cells with 12-0-tetradecanoylphorbol-13-acetate (TPA), in which nuclear translocation of heparanase was observed using immunohistochemical analysis. In this system, nuclear translocation of heparanase was abolished by inhibitors of heat shock protein 90 (HSP90), suggesting the involvement of HSP90 in translocation of heparanase. We further confirmed that overexpression of active form of heparanase induced differentiation of HL-60 cells, although the catalytic negative form of heparanase did not. Therefore we speculate that nuclear translocation of enzymatically active heparanase may be involved in cellular differentiation. Our results suggest that a novel function of heparanase upon cell differentiation would raise a potential new strategy for cancer therapy of promyeloid leukemia and other types of cancer.

Heparanase promotes angiogenesis through Cox-2 and HIF1alpha.

Heparanase has been given attention for its role in the invasion and metastasis of various cancers for years. We have also investigated and reported the role of heparanase in several human cancers, including gastric, esophageal and colon carcinomas. Other than the critical role of heparanase in tumor invasion and metastasis, it is also believed that heparanase is involved in angiogenesis, another feature of tumor progression which is complicatedly mediated by many molecules, including cyclooxygenese-2 (Cox-2). Thus, our recent study elucidated a possible relationship of heparanase with Cox-2 upon tumor angiogenesis. Based upon our study, three major transcription factor binding sites containing NF-kappaB, NF-IL-6 and CRE sites seemed to have a compensative and cooperative role in heparanase-induced Cox-2 upregulation. On the other hand, tumor hypoxia often occurs in most tumors and Cox-2-induced HIF1alpha overexpression has recently been shown in various cancers. Here we believe that heparanase may also be involved in tumor hypoxia through the induction of HIFalpha either directly or indirectly through the Cox-2 pathway. This hypothesis indicates a possible novel function of heparanase and its link to HIF1alpha and Cox-2, and therefore this function would give us a clue about potential new strategies for cancer therapy.

Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning.

Ultraviolet-light (UV)-induced tanning is defective in numerous 'fair-skinned' individuals, many of whom contain functional disruption of the melanocortin 1 receptor (MC1R). Although this suggested a critical role for the MC1R ligand melanocyte stimulating hormone (MSH) in this response, a genetically controlled system has been lacking in which to determine the precise role of MSH-MC1R. Here we show that ultraviolet light potently induces expression of MSH in keratinocytes, but fails to stimulate pigmentation in the absence of functional MC1R in red/blonde-haired Mc1r(e/e) mice. However, pigmentation could be rescued by topical application of the cyclic AMP agonist forskolin, without the need for ultraviolet light, demonstrating that the pigmentation machinery is available despite the absence of functional MC1R. This chemically induced pigmentation was protective against ultraviolet-light-induced cutaneous DNA damage and tumorigenesis when tested in the cancer-prone, xeroderma-pigmentosum-complementation-group-C-deficient genetic background. These data emphasize the essential role of intercellular MSH signalling in the tanning response, and suggest a clinical strategy for topical small-molecule manipulation of pigmentation.

Heparanase regulates esophageal keratinocyte differentiation through nuclear translocation and heparan sulfate cleavage.

Heparanase is an endo-beta-glucuronidase that specifically cleaves heparan sulfate (HS) chains. Heparanase is involved in the process of metastasis and angiogenesis through the degradation of HS chains of the extracellular matrix and cell surface. Recently, we demonstrated that heparanase was localized in the cell nucleus of normal esophageal epithelium and esophageal cancer, and that its expression was correlated with cell differentiation. However, the nuclear function of heparanase remains unknown. To elucidate the role of heparanase in esophageal epithelial differentiation, primary human esophageal cells were grown in monolayer as well as organotypic cultures, and cell differentiation was induced. Expression of heparanase, HS, involucrin, and p27 was determined by immunostaining and Western blotting. SF4, a novel pharmacological inhibitor, was used to specifically inhibit heparanase activity. Upon esophageal cell differentiation, heparanase was translocated from the cytoplasm to the nucleus. Such translocation of heparanase appeared to be associated with the degradation of HS chains in the nucleus and changes in the expression of keratinocyte differentiation markers such as p27 and involucrin, whose induction was inhibited by SF4. Furthermore, these in vitro observations agreed with the expression pattern of heparanase, HS, involucrin, cytokeratin 13, and p27 in normal esophageal epithelium. Nuclear translocation of heparanase and its catalytic cleavage of HS may play a critical role in the differentiation of esophageal epithelial cells. Our study provides a novel insight into the role of heparanase in an essential differentiation process.

COX-2 induction by heparanase in the progression of breast cancer.

Breast cancer confined within the lactiferous duct or lobule, without invading the stroma, is called ductal carcinoma in situ (DCIS), whereas breast cancer that has invaded the stroma through the basal membrane is called invasive cancer. Heparanase, an endo-beta-D-glucuronidase that specifically degrades heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays an important role when breast cancer cells breach the basal membrane. Recently, we have reported that heparanase is involved in angiogenesis through direct induction of cyclo-oxygenase-2 (COX-2). COX-2 induces vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and is thus involved in neovascularization. The present study was undertaken to analyze surgically resected breast cancer specimens for heparanase and COX-2 expression, using specimens from 59 patients with invasive cancer and 85 patients with DCIS (including 41 cases of DCIS adjacent to invasive cancer). This study yielded the following results: a) the distribution of heparanase within tumor tissue was identical to that of COX-2; b) heparanase expression was more frequent in invasive cancer than in non-invasive cancer; c) a close positive correlation was noted between heparanase and COX-2 expression (this correlation was particularly strong in cases of invasive cancer); and d) COX-2 expression was always seen in cases positive for heparanase expression. Our results indicate that heparanase expression increases during the progression of breast cancer into invasive cancer, and that this change is accompanied by increased COX-2 expression. They also suggest that heparanase may play a novel role for COX-2 mediated tumor angiogenesis in breast-cancer progression.

Colonic interposition and supercharge for esophageal reconstruction.

AIMS: We evaluated the techniques of colonic interposition and supercharge for esophageal reconstruction and discussed the main considerations related to these procedures. PATIENTS AND METHODS: In this study, we performed 51 esophageal reconstructions using colonic interposition. Twenty-eight of the 51 patients had synchronous or allochronic gastric malignancy. We selected colonic interposition for high anastomosis in 11 patients and also for esophageal bypass in 3 patients. This procedure was also selected to preserve gastric function in 5 patients. We recently performed the supercharge technique for colonic interposition in 41 patients. RESULTS: Despite the long duration and multistep nature of the operation procedure, no perioperative complications were noted. The patients returned to a good quality of life. The incidence of postoperative weight loss did not differ significantly between the colonic reconstruction group and the gastric reconstruction group. In terms of heartburn and dumping syndrome, the outcome was markedly better in the colonic reconstruction group (no cases of heartburn or dumping syndrome) than that in the gastric reconstruction group. CONCLUSION: For reconstruction of the esophagus, the colonic interposition and supercharge technique is advantageous and contributes to the patient's quality of life.

Heparanase is involved in angiogenesis in esophageal cancer through induction of cyclooxygenase-2.

PURPOSE: Both heparanase and cyclooxygenase-2 (COX-2) are thought to play critical roles for tumor malignancy, including angiogenesis, although it is unknown about their relationship with each other in cancer progression. We hypothesized that they may link to each other on tumor angiogenesis. EXPERIMENTAL DESIGN: The expressions of heparanase and COX-2 in 77 primary human esophageal cancer tissues were assessed by immunohistochemistry to do statistical analysis for the correlation between their clinicopathologic features, microvessel density, and survival of those clinical cases. Human esophageal cancer cells were transduced with heparanase cDNA and used for reverse transcription-PCR and Western blot to determine the expression of heparanase and COX-2. COX-2 promoter vector and its deletion/mutation constructs were also used along with transduction of heparanase cDNA for luciferase assay. RESULTS: Heparanase and COX-2 protein expression exhibited a similar pattern in esophageal tumor tissues, and their expression correlated with tumor malignancy and poor survival. Their expression also revealed a significant correlation with high intratumoral microvessel density. Up-regulation of COX-2 mRNA and protein was observed in esophageal cancer cells transfected with heparanase cDNA. COX-2 promoter was activated after heparanase cDNA was transduced and the deletion/mutation of three transcription factor (cyclic AMP response element, nuclear factor-kappaB, and nuclear factor-interleukin-6) binding elements in COX-2 promoter strongly suppressed its activity. CONCLUSION: Our results suggest that heparanase may play a novel role for COX-2-mediated tumor angiogenesis.

Effects of imatinib vary with the types of KIT-mutation in gastrointestinal stromal tumor cell lines.

Mutations of proto-oncogene c-kit in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. However, no study has been published concerning the effects of imatinib on GIST cells with various types of KIT mutation. To investigate the effects of imatinib on various c-kit mutations found in GISTs, cell proliferation and apoptosis assays were performed in two GIST cell lines with different KIT mutations. One of the cell lines, GIST-T1, revealed a heterozygous deletion of exon 11 in the c-kit, while the other cell line, GIST882, possessed a homozygous missense mutation of exon 13 in the c-kit gene. Imatinib inhibited proliferation and induced apoptosis in both cell lines. Imatinib potently suppressed proliferation of the GIST882 cell line at the concentration of 1.0 microM, whereas it inhibited the GIST-T1 at 0.1 microM. In two types of activating mutant KIT, imatinib could inhibit the constitutive activation of both types of KIT mutant, although the antiproliferative effect on GIST882 was weaker than on GIST-T1. Western blot analysis revealed that apoptosis related proteins were activated or suppressed by imatinib in both cell lines in the respective manner. Our results suggest that the apoptotic signal trans-duction caused by imatinib in GISTs is susceptible to various types of KIT mutation.

The role of heparanase in gastrointestinal cancer (Review).

Heparanase is endoglycosidase that degrades heparan sulfate, the main polysaccharide constituent of the extracellular matrix and basement membrane. Heparanase has been thought to have an important role in the process of cancer invasion and metastasis. Recent studies have revealed that heparanase has multifunctional modulatory effects in the progression of cancer cells and the cell-to-extracellular matrix interaction. Our recent research has shown the important roles of heparanase in the progression of esophagus, stomach and colon cancer, and heparanase expression was closely related to the prognosis of gastrointestinal cancer. Therapies targeting heparanase may result in promising tactics in cancer therapies. Heparanase gene silencing and inhibiton of enzymatic activities have potential use as targets for anticancer drug development. Here, we reviewed the role of heparanase in gastrointestinal tract tumors.

Emergence of nuclear heparanase induces differentiation of human mammary cancer cells.

The study of epithelial differentiation touches upon many modern aspects of biology. The epithelium is in constant dialogue with the underlying mesenchyme to control stem cell activity, proliferation in transit-amplifying compartments, lineage commitment, terminal differentiation and, ultimately, cell death. There are spatially distinct compartments dedicated to each of these events. Recently we reported that heparanase is expressed in nucleus as well as in the cytoplasm and that nuclear heparanase seems to be related to cell differentiation. In this study, we investigated the role of nuclear heparanase in differentiation by transducing human mammary epithelial cancer cells with heparanase which was delivered specifically into nucleus. We observed that expression of nuclear heparanase allowed the cells to differentiate with the appearance of lipid droplets. This finding supports the idea that heparanase plays a novel role in epithelial cell differentiation apart from its known enzymatic function.

Free jejunal graft for hypopharyngeal and esophageal reconstruction.

AIMS: This study assessed the techniques of the free jejunal graft for the reconstruction of hypopharynx or cervical esophagus and discussed the main aspects related to those procedures. METHODS AND RESULTS: By using free jejunal grafts, we reconstructed 54 hypopharyngeal and cervical esophageal cancers. In this study, 23 out of 54 patients had a malignant tumor located in the hypopharynx and 31 in the cervical esophagus (27 primary cases and four secondary cases). Despite the multi-step and time-consuming procedure, we did not incur any trans-operative complication. Furthermore, we undertook the larynx preserving cervical esophagectomy and free jejunal graft reconstruction in six patients with cervical esophageal cancer, and those patients acquired a good quality of life. CONCLUSION: For the reconstruction of hypopharynx or cervical esophagus, the free jejunal graft is a very useful technique and improves the patient's quality of life.

Stable long-term induction of perforin-positive CD8+ T cells in gut by oral administration of streptococcal preparation OK-432.

Perforin is known as a pore-forming cytotoxic granule released from cytotoxic T cells. Previous experiments in vitro revealed the presence of precursor cells that are capable of producing perforin in the immune system cells. The present study was undertaken to examine whether perforin-positive cells could be induced in the digestive tract and to characterize their precursor cells. Expression of perforin-positive cells in the intestine of Balb/c mice induced by OK-432 was analyzed by immunohistochemical staining and RT-PCR. Oral treatment of Balb/c mice with OK-432 resulted in the occurrence of perforin-positive cells in the inferior segment of small intestine, the superior segment of large intestine, mesenteric lymph nodes and spleen. In the small intestine, perforin-positive cells were found in the lamina propria mucosa. The presence of perforin-positive cells was also noted following long-term OK-432 treatment. Similar results were obtained following treatment with biological response modifiers such as lipopolysaccharide. In mice with GVHD (graft-versus-host disease), the presence of perforin-positive cells was noted in the small intestine and spleen. When the serial sections of the small intestinal mucosa from OK-432-treated mice were immunostained with anti-perforin, anti-CD8 and anti-asialo-GM1 antibodies, the perforin-positive cells were found to be CD8-positive. The results suggest that CD8(+) cells in lamina propria mucosa play a significant role as effectors in the mucosal immune system which is activated by various stimuli.