Motile sperm domain containing 1 is upregulated by the Wnt/ß-catenin signaling pathway in colorectal cancer.

Aberrant activation of the Wnt/ß-catenin signaling pathway plays a crucial role in the development and progression of colorectal cancer. Previously, we identified a set of candidate genes that were regulated by this signaling pathway, and the present study focused on motile sperm domain containing 1 (MOSPD1). Immunohistochemical staining revealed that the expression of MOSPD1 was elevated in tumor cells from colorectal cancer tissues compared with in non-tumor cells. Using ChIP-seq data and the JASPAR database, the regulatory region(s) in the MOSPD1 gene as a target of the Wnt/ß-catenin signaling pathway were searched, and a region containing three putative TCF-binding motifs in the 3'-flanking region was identified. Additional analyses using reporter assay and ChIP-quantitative PCR suggested that this region harbors enhancer activity through an interaction with transcription factor 7 like 2 (TCF7L2) and ß-catenin. In addition, chromatin conformation capture assay revealed that the 3'-flanking region interacts with the MOSPD1 promoter. These data suggested that MOSPD1 was regulated by the ß-catenin/TCF7L2 complex through the enhancer element located in the 3'-flanking region. These findings may be helpful for future studies regarding the precise regulatory mechanisms of MOSPD1.

Altered mucosal immunity in HIV-positive colon adenoma: decreased CD4+ T cell infiltration is correlated with nadir but not current CD4+ T cell blood counts.

BACKGROUND: People living with HIV (PLWH) face greater risks of developing non-AIDS-defining cancers (NADCs) than the general population; however, the underlying mechanisms remain elusive. The tumor microenvironment plays a significant role in the carcinogenesis of colorectal cancer (CRC), an NADC. We studied this carcinogenesis in PLWH by determining inflammatory phenotypes and assessing PD-1/PD-L1 expression in premalignant CRC stages of colon adenomas in HIV-positive and HIV-negative patients. METHODS: We obtained polyp specimens from 22 HIV-positive and 61 HIV-negative participants treated with colonoscopy and polyp excision. We analyzed adenomas from 33 HIV-positive and 99 HIV-negative patients by immunohistochemistry using anti-CD4, anti-CD8, anti-FoxP3, and anti-CD163 antibodies. Additionally, we analyzed the expression levels of immune checkpoint proteins. We also evaluated the correlation between cell infiltration and blood cell counts. RESULTS: HIV-positive participants had fewer infiltrating CD4+ T cells than HIV-negative participants (p = 0.0016). However, no statistical differences were observed in infiltrating CD8+ and FoxP3+ T cells and CD163+ macrophages. Moreover, epithelial cells did not express PD-1 or PD-L1. Notably, CD4+ T cell infiltration correlated with nadir blood CD4+ T cell counts (p <  0.05) but not with current blood CD4+ T cell counts. CONCLUSION: Immune surveillance dysfunction owing to decreased CD4+ T cell infiltration in colon adenomas might be involved in colon carcinogenesis in HIV-positive individuals. Collectively, since the nadir blood CD4+ T cell count is strongly correlated with CD4+ T cell infiltration, it could facilitate efficient follow-up and enable treatment strategies for HIV-positive patients with colon adenomas.

Severe thrombocytopenia induced by chemotherapy after total gastrectomy: A report of three cases.

Pancytopenia associated with vitamin B12 and folic acid deficiency has been reported in patients who have undergone total gastrectomy. Therefore, myelosuppression due to chemotherapy following total gastrectomy is considered to be more serious. We encountered three cases of severe thrombocytopenia in patients who received chemotherapy after total gastrectomy. The lowest platelet levels in these patients were 1.7 × 104/mm3, 2.3 × 104/mm3, and 0.9 × 104/mm3, respectively. None of the patients presented with vitamin B12 deficiency, and one patient presented with folic acid deficiency. The association between serum vitamin levels and chemotherapy-related adverse events is controversial. Since folic acid has a shorter half-life (6 hours) and cannot accumulate in the body, unlike vitamin B12 that is stored for a long time in the liver, folic acid deficiency is suspected to be associated with thrombocytopenia induced by post-total gastrectomy chemotherapy. However, serum folic acid levels fluctuate depending on the timing of evaluation and require a few days to evaluate. In conclusion, patients who undergo chemotherapy after total gastrectomy should be monitored for severe thrombocytopenia but serum vitamin B12 levels are not necessarily clinically important. By measuring serum folic acid levels at appropriate times, folic acid deficiency may prove to be a reference for predicting severe thrombocytopenia.

Chemotherapy-related dysphonia: Similar and differentiating features of six cases.

Dysphonia has been reported with anti-angiogenic chemotherapy agents. Dysphonia in patients with cancer receiving chemotherapy tends to be overlooked in clinical practice since it is non-life-threatening. However, it reduces quality of life. Although inhibition of vascular endothelial growth factor receptor is the reported mechanism of dysphonia, it has not been elucidated. We report 6 cases of patients with dysphonia suspected to be due to panitumumab and nivolumab that have not been reported previously. Peripheral edema, a factor in dysphonia, can be seen with aflibercept, bevacizumab, panitumumab, and nivolumab. Therefore, chemotherapy drugs with peripheral edema may be related to dysphonia.

Association between thiamine decrease and neuropsychiatric symptoms in gastrointestinal and hematological cancer patients receiving chemotherapy.

BACKGROUND: Clinical evidence of thiamine-related neuropsychiatric symptoms, including the initial stage, is limited because serum thiamine levels tend to be evaluated only for patients who develop severe neuropsychiatric symptoms suspected to be related to severe thiamine deficiency. This study aimed to evaluate the relationship between thiamine decline and neuropsychiatric symptoms, including initial symptoms, and the effect of chemotherapy on serum thiamine levels in gastrointestinal and hematological cancer patients receiving chemotherapy. METHOD: We retrospectively identified 87 patients who were diagnosed with gastrointestinal and hematological cancers at our hospital. We evaluated the risk factors associated with neuropsychiatric symptoms, including initial symptoms (neuropsychiatric symptoms), the relationship between the presence of neuropsychiatric symptoms and serum thiamine levels, and changes in serum thiamine levels after chemotherapy. RESULTS: Logistic regression analysis identified thiamine decline as a significant factor associated with neuropsychiatric symptoms (p < 0.001, odds ratio = 0.040, 95% confidence interval [CI]: 0.010-0.163). The Mann-Whitney U test showed that patients with neuropsychiatric symptoms had significantly lower serum thiamine levels (19.5 ± 5.4 ng/mL, n = 39) than patients without neuropsychiatric symptoms (31.9 ± 14.2 ng/mL, n = 48) (p = 0.001). In hematological cancer patients, serum thiamine levels gradually declined after chemotherapy, with the lowest levels at 5-8 weeks (23.5 ± 7.6 ng/mL, P = 0.035 vs. 0 weeks, Wilcoxon rank sum test). CONCLUSION: Our study showed that a decrease in serum thiamine levels can be a risk factor for neuropsychiatric symptoms, and chemotherapy can lead to a decrease in serum thiamine levels.

Endoscopically unobservable appendiceal adenoma treated using laparoscopically assisted surgery.

INTRODUCTION: Primary benign adenomas of the appendix occur rarely. According to appendectomy and autopsy reports, benign adenomas of the appendix are sporadically reported, accounting for ~0.02-0.08% cases. PRESENTATION OF CASE: We report the case of a 58-year-old woman with a segmental polyp protruding into the appendiceal orifice. The polyp was spotted during lower gastrointestinal endoscopy; however, treatment was postponed at the patient's request. During a confirmatory lower gastrointestinal endoscopy for treatment, the polyp was no longer found protruding from the appendiceal orifice and had disappeared. An appendicectomy was performed for diagnostic and therapeutic purposes. Pathological examination showed a low-degree atypical tubular adenoma with no malignant findings. DISCUSSION: Despite the risk of perforation, surgical resection remains the gold standard for treating appendiceal adenoma. Resection can be performed endoscopically if the stem and base of the adenoma can be identified. In the present case, laparoscopy was a good indication from the safety standpoint, and it was radically curative. Furthermore, upon performing an appendectomy, the patient was informed of the risks of cancer-related complications or the need for additional resection. CONCLUSION: This suggestive case proves that appendiceal tumors can disappear endoscopically depending on the timing of examination and treatment.

Hyperammonemia-induced impaired consciousness following mFOLFOX6 therapy in a patient with recurrent rectal cancer.

OBJECTIVES: FOLFOX is a standard chemotherapy regimen used to treat colorectal cancer. Adverse events associated with FOLFOX treatment include peripheral neuropathy and myelosuppression. This report discusses the case of a 64-year-old man with rectal cancer who developed hyperammonemia and impaired consciousness following initiation of mFOLFOX6 as a postoperative adjuvant therapy. METHODS: This case study reports on the clinical disease progression of the aforementioned patient. RESULTS: Following preoperative chemoradiotherapy, the patient underwent low anterior resection for rectal cancer. mFOLFOX6 was then initiated as postoperative adjuvant therapy. During the 5th cycle of mFOLFOX6 treatment, the patient presented with impaired consciousness and upper extremity convulsions. Blood testing revealed marked hyperammonemia (349 µg/dL (normal range: 12 - 66 µg/dL)). Imaging did not reveal any intracranial lesions that could cause impaired consciousness. The patient recovered within a day after rehydration and BCAA substitution. CONCLUSION: Although impaired consciousness is a rare adverse reaction of FOLFOX, it has a major psychological impact on the patient and his/her family. Hyperammonemia should therefore be considered a potential cause of impaired consciousness during FOLFOX therapy and should be appropriately diagnosed and treated.

Elemental diet therapy plays a significant role in preventing surgical recurrence of Crohn's disease in the era of biologics.

PURPOSE: Most patients with Crohn's disease (CD) experience surgical recurrence. In this era of novel therapies, we conducted this study to clarify which treatments effectively decrease the risk of surgical recurrence in patients with CD. METHODS: The subjects of this retrospective study were 37 patients with CD. We created cumulative surgery rate curves and performed univariate and multivariate analyses. RESULTS: Univariate analysis revealed that patients who consumed an elemental diet (ED; ≥ 900 kcal/day), anti-tumor necrosis factor-alpha, and thiopurines had a significantly better prognosis than those who did not (p = 0.011, p = 0.025, and p = 0.0080, respectively). Multivariate analysis revealed that ED therapy and thiopurines were independent significant factors for controlling surgical recurrence (p = 0.046 and p = 0.032, respectively). Additional analyses showed that the most promising ED therapeutic dose was ≥ 1200 kcal/day, while an ED therapeutic dose of ≥ 900 kcal/day was acceptable. CONCLUSIONS: Although univariate analyses revealed that all three treatment strategies had significant effects on surgical recurrence in patients with CD, multivariate analysis revealed that only ED therapy was significantly associated with surgical recurrence rates. Thus, ED therapy plays an important role in the management of CD, even in the era of biological therapies.

Potential thiamine deficiency and neurological symptoms in patients receiving chemotherapy for gastrointestinal cancer.

OBJECTIVES: The aim of this retrospective study was to search for risk factors for neurological adverse events in gastrointestinal cancer patients receiving chemotherapy and analyze the relationship between thiamine serum levels and neurological adverse events. MATERIALS AND METHODS: This is a single-center retrospective observational study. We enrolled patients who were diagnosed with gastrointestinal cancer at our hospital, for whom we measured the thiamine serum levels. We then performed a multivariate analysis (logistic regression) to identify risk factors for the neurological symptoms in our cohort. We then divided the patients into two groups, with and without neurological symptoms, based on their electronic medical records. By using the Mann-Whitney U-test, we performed a comparative analysis of the thiamine serum levels between the two groups. We also used descriptive statistics to examine the presence/absence of neurological symptoms or other potentially related clinical features in patients with decreased thiamine serum levels. RESULTS: The logistic regression analysis detected the decrease in thiamine serum levels as a statistically significant risk factor for neurological symptoms. The analysis of the relationship between the presence/absence of neurological symptoms and thiamine serum levels showed that the thiamine serum levels were significantly lower in the group presenting neurological symptoms. Descriptive statistics showed that all the patients with decreased thiamine serum levels had either cognitive decline, attention decline, or depression symptoms, and most of them were receiving the 5-fluorouracil anticancer drug and showing decreased serum albumin levels. We also observed a slight decrease in serum sodium, vitamin B12, and folate levels. CONCLUSION: When neurological symptoms occur in patients receiving chemotherapy for gastrointestinal cancer, the measurement of thiamine serum levels may become a standard reference for treatment indication.

Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/ß-catenin signaling in colorectal cancer cells.

Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through activation of the ß-catenin/TCF7L2 complex. Although genes upregulated by Wnt/ß-catenin signaling have been intensively studied, the roles of downregulated genes are poorly understood. Previously, we reported that interferon-induced proteins with tetratricopeptide repeats 2 (IFIT2) was downregulated by the Wnt/ß-catenin signaling, and that the suppressed expression of IFIT2 conferred antiapoptotic property to colorectal cancer (CRC) cells. However, the mechanisms underlying how Wnt/ß-catenin signaling regulates IFIT2 remain to be elucidated. In this study, we have uncovered that the expression of IFIT2 is induced by IRF1, which is negatively regulated by the Wnt/ß-catenin signaling. In addition, we found that downregulation of IRF1 is mediated by its degradation through the ubiquitination-proteasome pathway, and that decreased activity of a deubiquitinase complex containing USP1 and UAF1 is involved in the degradation of IRF1 by Wnt/ß-catenin signaling. These data should provide better understanding of the Wnt signaling pathway and human carcinogenesis.

Immunohistological analysis of pancreatic carcinoma after vaccination with survivin 2B peptide: Analysis of an autopsy series.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer by providing new options in addition to existing therapies. However, peptide vaccination therapies still represent an attractive approach, because of the antigen specificity. We identified survivin 2B peptide (SVN-2B), a 9-mer antigenic peptide encoded by survivin, and an SVN-2B peptide vaccine-based phase II randomized clinical trial targeting unresectable and refractory pancreatic carcinoma was undertaken. The SVN-2B peptide vaccine did not have any statistically significant clinical benefits in that study. Therefore, we undertook an autopsy study to analyze the immune status of the pancreatic cancer lesions at the histological level. Autopsies were carried out in 13 patients who had died of pancreatic cancer, including 7 who had received SVN-2B peptide vaccination and 6 who had not, as negative controls. The expression of immune-related molecules was analyzed by immunohistochemical staining. Cytotoxic T lymphocytes were analyzed by tetramer staining and enzyme-linked immunospot assay. Histological analysis revealed dense infiltration of CD8+ T cells in some lesions in patients who had received the SVN-2B peptide vaccine. A high rate of programmed cell death ligand 1 expression in cancer cells was observed in these cases, indicating that CTLs were induced by SVN-2B peptide vaccination and had infiltrated the lesions. The lack of a significant antitumor effect was most likely attributable to the expression of immune checkpoint molecules. These findings suggest that the combination of a tumor-specific peptide vaccine and an ICI might be a promising approach to the treatment of pancreatic carcinoma in the future.

Thiamine deficiency as a possible cofactor causing cognitive dysfunction in a patient with end-stage gastric cancer
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We describe a case of a patient treated for cognitive dysfunction (CD) with suspected thiamine deficiency (TD). A 74-year-old man with gastric cancer presented with grade 3 diarrhea and grade 1 anorexia. He had been receiving trastuzumab plus tegafur (a chemotherapeutic fluorouracil prodrug), gimeracil, and oteracil (S-1) and oxaliplatin. On admission, cognitive function was assessed with the Hasegawa's Dementia Scale (HDS-R) because he had impaired short-term memory. His thiamine levels increased from 22 to 109 ng/mL after administration of 75 mg of thiamine. Furthermore, the patient's HDS-R score improved from 9 to 22, and cognitive and memory functions improved. TD should be considered in older CD patients receiving oral chemotherapy agents including fluorouracil.

Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma.

The prognosis of advanced pancreatic adenocarcinoma is still extremely poor. This study sought to determine the efficacy of, and immunological response to, peptide vaccination therapy in patients with this disease. In this multicenter randomized phase II study, patients with advanced pancreatic adenocarcinoma after gemcitabine and/or tegafur/gimeracil/oteracil were randomly assigned to 3 groups that each received a 2-step treatment course. In Step 1, the groups received treatments of: (i) survivin 2B peptide (SVN-2B) plus interferon-ß (IFNß); (ii) SVN-2B only; or (iii) placebo until the patients show progression. In Step 2, all patients who consented to participate received 4 treatments with SVN-2B plus IFNß. The primary endpoint was progression-free survival (PFS) after initiation of Step 1 treatment. Secondary endpoints included immunological effects assessed by analysis of PBMCs after Step 1. Eighty-three patients were randomly assigned to receive SVN-2B plus IFNß (n = 30), SVN-2B (n = 34), or placebo (n = 19). No significant improvement in PFS was observed. Survivin 2B-specific CTLs were found to be increased in the SVN-2B plus IFNß group by tetramer assay. Among patients who participated in Step 2, those who had received SVN-2B plus IFNß in Step 1 showed better overall survival compared with those who had received placebo in Step 1. Patients vaccinated with SVN-2B plus IFNß did not have improved PFS, but showed significant immunological reaction after vaccination. Subgroup analysis suggested that a longer SVN-2B plus IFNß vaccination protocol might confer survival benefit. (Clinical trial registration number: UMIN 000012146).

A case of an elderly patient with high-grade colorectal cancer in poor general condition who showed near complete response to chemotherapy and achieved long-term survival.

INTRODUCTION: Chemotherapy is difficult to administer in patients with poor performance status (PS), advanced metastatic lesion, and unresectable colon cancer. We report herein our experience of a patient who showed complete response to chemotherapy and marked PS improvement. The patient presented with the following adverse factors poor PS, advanced progression of metastatic lesions, advanced unresectable colorectal cancer with severe stricture, and old age. PRESENTATION OF CASE: The patient was an 80-year-old male diagnosed with occlusive cancer of the descending colon with multiple metastases in the liver, Stage Ⅳb (National Comprehensive Cancer Network guidelines version 2. 2018). A 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) + panitumumab (Pmab) regimen was successfully administered and led to decreased tumor marker levels; oral intake also became possible. Additional examinations showed that the primary lesion and distant metastatic lesions had almost disappeared; the patient had achieved a near complete response (CR). Currently, 35 cycles of mFOLFOX6＋Pmab have been administered, and his near CR has been maintained for 32 months. DISCUSSION: Best supportive care (BSC) is the recommended option for elderly patients with advanced unresectable colon cancer. This is the first case in which an elderly patient with poor PS and advanced unresectable colorectal cancer was treated with combination chemotherapy of mFOLFOX6 + Pmab. CONCLUSION: Although the use of chemotherapy for elderly with advanced unresectable colorectal cancer or those with poor PS is limited, this case shows that systemic chemotherapy is now an option for such cases previously managed with BSC.

Abdominal CT-aided diagnosis of acute appendicitis in the presence of mobile cecum: A case report.

INTRODUCTION: A mobile cecum is a frequently encountered congenital anomaly. It is important to recognize this atypical position of the cecum as it may interfere with an accurate diagnosis of acute appendicitis. PRESENTATION OF CASE: A 48-year-old man presented with abdominal pain, anorexia, and fever. He had mild lower abdominal discomfort, and rebound tenderness in the suprapubic region, but no guarding or right lower quadrant findings. Laboratory tests identified an elevated white blood cell count (12350 cells/mL) and C-reactive protein level (4.56 mg/dL). In view of the clinical picture suggestive of localized peritonitis, an abdominal computed tomography (CT) was performed, which revealed a caudally located cecum, lying in the pelvis, along with evidence of an acutely inflamed appendix. An urgent surgical procedure was performed, which confirmed the diagnosis of acute appendicitis accompanying a mobile cecum. DISCUSSION: In the presence of a mobile cecum, the clinical findings of acute appendicitis may be atypical owing to the abnormal position of the appendix. In such cases, there is the possibility of a missed diagnosis. In our case, a CT examination that was performed in view of the clinical diagnosis of mild peritonitis aided in establishing the diagnosis of acute appendicitis and a mobile cecum. CONCLUSION: Anatomical variations of the cecum and the appendix may result in atypical presentation of acute appendicitis. A high index of suspicion, and a CT examination may be helpful in establishing the diagnosis in such cases.

Protein lysine methyltransferase SMYD3 is involved in tumorigenesis through regulation of HER2 homodimerization.

HER2 is a receptor tyrosine kinase, which is amplified and overexpressed in a subset of human cancers including breast and gastric cancers, and is indicated in its involvement in progression of cancer. Although its specific ligand(s) has not been detected, HER2 homodimerization, which is critical for its activation, is considered to be dependent on its expression levels. Here, we demonstrate a significant role of HER2 methylation by protein lysine methyltransferase SMYD3 in HER2 homodimerization. We found that SMYD3 trimethylates HER2 protein at lysine 175. HER2 homodimerization was enhanced in the presence of SMYD3, and substitution of lysine 175 of HER2 with alanine (HER2-K175A) reduced the formation of HER2 homodimers. Furthermore, HER2-K175A revealed lower level of autophosphorylation than wild-type HER2. We also identified that knockdown of SMYD3 attenuated this autophosphorylation in breast cancer cells. Our results imply that SMYD3-mediated methylation of HER2 at Lysine 175 may regulate the formation of HER2 homodimer and subsequent autophosphorylation and suggest that the SMYD3-mediated methylation pathway seems to be a good target for development of novel anti-cancer therapy.