Naldemedine-induced opioid withdrawal with restlessness as the predominant symptom in a palliative care setting.

OBJECTIVES: Opioid analgesics play a central role in cancer pain treatment; however, it has been reported that opioid-induced constipation (OIC) develops in 80% of patients using opioid analgesics and leads to a decrease in quality of life. Naldemedine improves constipation without affecting the analgesic action of opioid analgesics via peripheral µ-opioid receptors. METHODS: We report a terminally ill cancer patient who was diagnosed with opioid withdrawal syndrome (OWS) based on symptoms centered around restlessness and sweating that developed 43 days after administration of naldemedine for OIC. RESULTS: The patient was a 78-year-old woman who was diagnosed with stage IVB uterine sarcoma in October, 1 year prior to her visit to our clinic,  and underwent chemotherapy after surgery, but the disease became progressive. Thereafter, metastasis to the fourth thoracic vertebrae (Th4) was identified, and loxoprofen and acetaminophen were started for pain at the metastatic site. Oxycodone hydrochloride hydrate 10 mg/day was additionally administered on postoperative day 11, followed by naldemedine 0.2 mg/day for OIC. On the 43rd day after administration, the patient began to wander the hospital ward in a wheelchair and became noticeably restless. OWS due to naldemedine administration was suspected, and naldemedine was discontinued. The symptoms improved 7 days later, and no similar symptoms were observed thereafter. SIGNIFICANCE OF RESULTS: Patients receiving palliative care often exhibit psychiatric symptoms such as anxiety and depression, but OWS due to naldemedine should also be considered as a potential cause.

Point Prevalence Surveys of Antimicrobial Prescribing in a Non-Acute Care Hospital in Saitama Prefecture, Japan.

Background: The global point prevalence survey (Global-PPS) is the standard for the surveillance of prescribed antimicrobials among inpatients and provides data for the development of hospital antimicrobial stewardship programs. Aim: To evaluate the prevalence and quality of antimicrobial prescriptions using the universally standardized Global-PPS protocol in a non-acute care hospital in Saitama Prefecture, Japan. Methods: Antimicrobial prescriptions for inpatients, staying at the hospital overnight, were surveyed on three separate week days in November 2018, January 2019, and May 2019. Information on the prescribed antimicrobials on the survey target day was obtained from the in-hospital pharmacy. Survey data were collected by physicians, based on the extracted information. Patient information was anonymized and entered in the Global-PPS Web application by physicians. We report the antimicrobial use prevalence, the indication for prescription, diagnosis, the most prescribed antimicrobials, and a set of quality indicators related to antimicrobial prescribing. Results: In total, 6.7% of the surveyed inpatients (120/1796) were prescribed antimicrobials on the survey day. Sulfamethoxazole/trimethoprim was the most commonly prescribed, with 20.0% of systemic antibiotic prescriptions (ATC J01). Of all antibiotics for systemic use, up to 58.4% were Watch antibiotics, as defined by the World Health Organization AWaRe classification. The most prescribed group of systemic antibiotics was non-penicillin beta-lactam antibiotics (34.4%), followed by penicillin antibiotics in combination with beta-lactamase inhibitors (25.6%), and sulfonamides with trimethoprim (20.8%). Healthcare-associated infections and medical prophylaxis were the most common indications reported in 69.3% and 26.3% of prescriptions, respectively. The most common diagnosis for systemic antibiotic prescriptions was pneumonia (49.6%). Reasons for antimicrobial prescriptions were indicated in the medical records for 67.1% of prescriptions, and the stop/review date was documented to be 50.3%. Compliance with local guidelines reached 66.7%. Conclusions: This study highlights important challenges related to antimicrobial prescription in a highly specific, non-acute care patient population.

Clinically applicable cases of anti-programmed cell death protein 1 immunotherapy for colorectal cancer patients.

We investigated the prevalence and characteristics of defective mismatch repair (dMMR) in colorectal cancer (CRC) patients who would potentially benefit from anti-programmed cell death protein 1 (PD-1) immunotherapy. Medical records were obtained and reviewed for 1147 patients who underwent surgical resection of stage I-IV CRC, in whom universal screening for Lynch syndrome using immunohistochemistry for MMR proteins had been undertaken. The molecular characteristics of dMMR CRCs were also investigated. Defective MMR accounted for 5.2% of stage I-IV CRC patients, including 12 (1.0% of all CRC patients) who had stage IV disease or recurrence after curative resection (n = 6 each). These 12 patients included patients with LS (n = 3) and Lynch-like syndrome (n = 1). Defective MMR tumors were predominantly located in the right-sided colon (P < 0.01). Approximately 1% of stage I-IV CRC patients could potentially benefit from anti-PD-1 immunotherapy, while one-third would require genetic counseling and/or MMR gene testing.

[A Family with Lynch Syndrome Diagnosed after a Proband of Elderly Multiple Colorectal Cancers].

The proband was a 77-year-old man who had been admitted to a local hospital for fecal occult blood. He was diagnosed with descending colon carcinoma, T4a, N1, M0, Stage Ⅲb, and rectal adenoma. He had undergone surgeries for rectal cancer at 52 years of age and cecum colon cancer at 57 years of age. Regarding his family history, 5 first-degree and 3 second- degree relatives had a history of gastrointestinal and gynecological cancers, thus meeting 2 of the 5 criteria of the revised Bethesda guidelines. The microsatellite-instability(MSI)test performed using preoperative biopsy tissues demonstrated high-frequency MSI(MSI-H). Hartmann's procedure was performed for MSI-H colon cancer under a strong suspicion of Lynch syndrome. Pathological findings were consistent with descending colon carcinoma, tub2, pT3, pN0, M0, pStage Ⅱa. He was then referred to our hospital. We performed the immunohistochemistry(IHC)analysis of the mismatch repair protein using surgical specimens. The IHC analysis revealed defective expression of the MSH2/MSH6 protein. We found a pathogenic variant in the mismatch repair gene, MSH2(c.1510+2T>G), through genetic testing and finally diagnosed the patient with Lynch syndrome. After disclosure of the results to the proband, 7 relatives underwent genetic testing for the MSH2 variant. Four relatives had the same variant and were also diagnosed with Lynch syndrome. They subsequently underwent surveillance for Lynch syndrome-associated cancers. In 2 variant carriers with a history of early colorectal cancer, an early colon cancer was identified and successfully resected endoscopically. Surveillance for Lynch syndrome-associated cancer is ongoing for the proband and variant carriers.

Prevalence and clinicopathologic/molecular characteristics of mismatch repair-deficient colorectal cancer in the under-50-year-old Japanese population.

PURPOSE: To clarify the prevalence and clinicopathologic/molecular characteristics of mismatch repair (MMR)-deficient colorectal cancer in the young Japanese population. METHODS: Immunohistochemical analyses for MMR proteins (MLH1, MSH2, MSH6, and PMS2) were performed in formalin-fixed paraffin-embedded sections prepared from the resected CRC specimens of 119 consecutive patients aged <50 years old, who underwent resection of the primary tumor at our institution between 1996 and 2015. Analyses for somatic BRAF V600E mutation, somatic hypermethylation of the MLH1 promoter, and germline MMR gene mutations were undertaken where indicated. RESULTS: MMR protein loss was found in 10 patients (8.4%), 7 (5.9%) of whom were subsequently identified to have Lynch syndrome (LS). The remaining 3 patients were categorized as having sporadic MMR-deficient CRC (n = 2) or "possible LS (n = 1)". In multivariate logistic regression analysis, the presence of tumor-infiltrating lymphocytes (P < 0.01), right-sided location of the tumor (P = 0.01), and a history of LS-associated tumors in the first-degree relatives (P < 0.01) were identified as independent factors predictive of MMR-deficient CRC. CONCLUSION: These results are of value in the clinical management of patients with the early onset CRC under circumstances where universal tumor screening approaches for LS are still not available, like in Japan.

[Evaluation of BRAF V600E Mutations in High-Level Microsatellite Instability(MSI-H)Colon Cancer - Comparison Between Genetic Testing and Immunohistochemical Staining].

BRAF V600E mutation plays an important role in the serrated neoplasia pathway of colorectal tumorigenesis and is a negative predictive factor for chemotherapy response as well as a prognostic factor in patients with colorectal cancer. To evaluate BRAF V600E mutations, a conventional polymerase chain reaction(PCR)is performed but recently immunohistochemistry (IHC)with a BRAF antibody has been used. Although similarities between the PCR and IHC methods have been reported, some investigators have doubts about the usefulness of IHC for BRAF mutation analysis. The subjects were 38 colorectal cancer patients with tumors demonstrating loss of both MLH1 and PMS2, and high-level microsatellite instability. Of the original 39 patients, 1 was excluded due to Lynch syndrome, which was identified using germline mutation testing. The mutation rate of BRAF V600E was 57.9% using both methods, but the concordance rate was 68.4%, with a kappa-value of 0.33. We should consider the usefulness of the IHC method in the evaluation of BRAF mutations in colorectal cancer patients.

[Significant prognostic factors in stage IV gastric cancer].

The aim of this study was to evaluate clinicopathological variables, including the granulocyte-to-lymphocyte ratio(G/L ratio), as prognostic factors for Stage IV gastric cancer patients. A total of 70 patients treated for Stage IV gastric cancer were enrolled in this study. Univariate analysis indicated that age ≥70 years, performance status >2, resection not being performed, chemotherapy not being administered, high C-reactive protein(CRP)levels, and carbohydrate antigen 19-9 levels were significantly associated with poor survival. Multivariate analysis of these factors identified resection not being performed, chemotherapy not being administered, and high CRP levels as independent unfavorable factors of survival. Although the G/L ratio was not a prognostic factor for Stage IV gastric cancer patients in this study, further studies with greater number of patients are required to determine whether the G/L ratio is a significant biomarker associated with survival.

A Model for Predicting DNA Mismatch Repair-deficient Colorectal Cancer.

BACKGROUND/AIM: Identifying patients with DNA mismatch repair-deficient (dMMR) colorectal cancer (CRC) is vital to improve treatment and identify patients with Lynch syndrome (LS). We developed a prediction model for dMMR CRC using clinicopathologic features. PATIENTS AND METHODS: We reviewed the medical records of 1,147 patients who underwent resection of stage I-IV CRC in whom universal screening for LS using immunohistochemistry for MMR proteins had performed. Univariate and multivariate logistic regression analyses were used to build a prediction model of dMMR CRC. RESULTS: The prevalence of dMMR CRC was 5.2%. Age (≥75 years), tumor location (right-sided colon), main histologic features (poor differentiation), maximum tumor size (≥65 mm), and stage (I/II) were independent significant variables related to dMMR. We created a formula for predicting the likelihood of dMMR, and the probability ranged from 0.2% to 83%. CONCLUSION: dMMR CRC can be identified efficiently using clinicopathologic features obtained in daily clinical practice.

[Is it possible to predict lateral lymph node metastasis by their sizes in patients with lower rectal cancer?--analysis of paraffin-embedded sections].

Considering the advantages and disadvantages of lateral lymph node dissection in patients with lower rectal cancer, it would be ideal to select candidates for lateral lymph node dissection by preoperative imaging study. This preliminary study was performed to examine whether it would be possible to predict lateral lymph node metastasis by their sizes in patients with lower rectal cancer. In study-1, we measured the maximal and minimal diameter of 17 lateral lymph nodes from 2 patients on the paraffin-embedded slides and compared them to the diameters of the fresh specimen. In study-2, a relationship between the size of lateral lymph nodes and the presence of metastasis was examined in 259 lateral lymph nodes from 35 patients. The mean reduction rate after paraffin embedding was 56.8% (34.7-78.8) for the maximal diameter and 62.0% (36.7-80.5) for the minimal diameter. The maximal (p<0.01) and minimal diameters (p<0.01) were significantly greater in the nodes positive for metastasis than in the negative nodes. The area under the receiver operating curve was significantly greater for the minimal diameter than for the maximal diameter( p=0.07). The sensitivity, specificity, and accuracy for predicting metastasis was 78.6%, 83.7%, and 83.4%, respectively when the cut off of the minimal diameter was set at 3.41 mm, which corresponds to 5.50 mm in living bodies. In conclusion, determining the minimal diameter of the lateral lymph nodes by preoperative imaging studies may be useful for selecting candidates for lateral lymph nodes dissection.

[Current trends and problems in chemotherapy for elderly patients with advanced gastric cancer].

PURPOSE: To assess current trends and problems in chemotherapy for elderly patients with unresectable gastric cancer. PATIENTS AND METHODS: Patients with unresectable gastric cancer were divided into two groups: an elderly group aged 70 years or older (n=28), and a control group aged younger than 70 years (n=46). The feasibility, safety, and efficacy of chemotherapy were compared between the two groups. The induction rate for a first-line treatment did not differ between the groups (89% for the elderly group versus 93% for the control group). A regimen comprising S-1 and cisplatinum (CDDP) was selected most frequently as the first-line treatment in both groups. When an analysis was restricted to patients given S-1 and CDDP, the elderly group showed fewer cycles of CDDP administration, a higher rate of grade 3 or worse adverse events, a lower rate of switching to a second-line treatment, and a shorter overall survival than the control group, although the p values did not reach a significant level. Among patients aged 70 years or more, those given S-1 alone showed an overall survival equivalent to that for patients given S-1 and CDDP. In conclusion, in clinical practice, it seems appropriate to consider whether the S-1+CDDP regimen is the most optimal first-line treatment for elderly patients with gastric cancer.

[Analysis of 12 cases of brain metastasis from colorectal cancer].

This retrospective study was performed to evaluate the outcomes of 12 patients with brain metastasis from colorectal cancer treated between 1999 and 2008. The range of patients was 33-72 years old (median: 64 years old). The male to female ratio was 2:1. The primary site was the colon in 4 patients and rectum in 8 patients. The site of brain metastasis was the cerebrum in 8 and cerebellum in 4. All brain lesions were metachronously detected. Three patients had a single lesion each, while the remaining 9 had multiple lesions. The range of the period from the resection of the primary lesion to the detection of brain metastasis was 144-2,062 days (median: 868 days). The types of treatment included whole brain radiotherapy after cerebral metastatectomy in three patients with a single lesion, whole brain radiotherapy only in 7 patients with multiple lesions, and modified FOLFOX6 (mFOLFOX6) regimen combined with whole brain radiation in recently treated two patients with multiple brain and lung metastases. The median overall survival period was 107 days. The longest survivor was a patient who survived for 505 days after the start of mFOLFOX6 plus radiation therapy. It appears that how we control metastases has become more important in recent years. For example, using new drugs, extracranial metastases of controllable cancer have become better controllable over longer periods.

[Clinical significance of chemotherapy and chemo-radiotherapy in patients with metastatic esophageal cancer].

PURPOSE: We investigated the clinical significance of chemo-radiotherapy (CRT) and chemotherapy (CT) in patients with primary metastatic esophageal cancer. PATIENTS AND METHODS: Twenty-six patients with esophageal cancer received CRT (n =21) or CT alone (n=5) as a first treatment for para-aortic lymph node and/or hematogenous metastases. The therapeutic effect, duration of treatment, changes in performance status before and after treatment, and survival were analyzed retrospectively. RESULTS: The median duration of treatment was 2.9 months for CRT and 2.3 months for CT. The response rate was 76% in patients who underwent CRT and 20% in patients who underwent CT. In 18 patients (69%), the level of performance status showed no change after treatment in comparison with that before treatment. The median survival time was 5.6 months after CRT and 5.8 months after CT (p=0.91). CONCLUSION: These results suggest that the majority of patients with extremely advanced esophageal cancer can tolerate CRT or CT well without compromising their performance status within their limited life expectancy.

[Modified FOLFOX6 treatment for obstructive jaundice caused by hepatic lymph-node metastasis from liver metastases of rectal cancer--a case report].

Chemotherapy is potentially hazardous for patients with liver dysfunction. Although FOLFOX regimen is one of the standard chemotherapies for nonresectable liver metastases of colorectal cancer, the safety of this regimen has not been established yet in patients with obstructive jaundice associated with multiple liver metastases. We report a case of nonresectable liver metastases of rectal cancer treated by modified FOLFOX6 regimen after percutaneous transhepatic biliary drainage for obstructive jaundice, which was caused by hepatic lymph-node metastasis. Five days after giving a birth, a 32-year-old woman underwent Hartmann's procedure for perforation of rectal cancer associated with multiple liver metastases. She was admitted again to receive chemotherapy 35 days after surgery, but the level of total bilirubin was elevated (3.9 mg/dL). Since the total bilirubin level was not rapidly decreased after PTBD, the modified FOLFOX6 regimen was started with a 70% dose. After an introduction of mFOLFOX6 treatment, a biliary-stenting was successfully performed, and the mFOLFOX6 continued with a full dose starting from the 5th cycle. Although the therapeutic efficacy after an additional 8-cycle was classified as stable disease (SD), she did not show any sign of adverse effects except for grade 1 neurotoxicity.

Spontaneous mesenteric hemorrhage associated with Ehlers-Danlos syndrome.

The vascular type of Ehlers-Danlos syndrome is a genetic disorder of connective tissue and is frequently associated with catastrophic arterial complications. Its surgical treatment is extremely difficult because of the fragility of vessels. This article describes three patients with vascular type of Ehlers-Danlos syndrome who developed mesenteric hemorrhage due to spontaneous arterial rupture. The clinical and molecular characteristics of the disease are briefly reviewed.

Para-Nonylphenol Induces Apoptosis of U937 Human Monocyte Leukemia Cells in vitro.

BACKGROUND: Human autoimmune diseases are caused by a variety of factors, such as environmental chemicals, including para-nonylphenol. Macrophages play many critical roles in the regulation of immunity and the progression of autoimmune diseases. However, little information is available regarding the effects of para-nonylphenol on cellular signaling pathways and the death of these cells in vitro. Here, we show that very high concentrations of para-nonylphenol (50-100 µM) induce apoptosis in U937 human monocyte leukemia cells in a dose-dependent manner. METHODS: Cell viability was judged using the trypan blue exclusion method. FACS analysis for DNA fragmentation was conducted, cellular signaling pathways were evaluated using western blot analysis, and caspase activity was measured by using substrates. U937 cells were differentiated by PMA. RESULTS: Treatment with > 50 µM para-nonylphenol induced apoptosis in U937 monocyte cells and MCF- 7 and MDA-MB231 human breast cancer cells. We found cytochrome c release from the mitochondria to the cytoplasm, DNA fragmentation, and decreased expression of anti-apoptotic protein Bcl-XL. Caspase 3 and 9 were induced, but caspase 1 and 3-inhibitor treatment suppressed apoptosis. Para-nonylphenol decreased the levels of activated AKT and increased the levels of activated JNK/SAPK at 15 min after treatment. Furthermore, with PMA treatment, U937 cells were differentiated into a macrophage-like phenotype and showed attenuated cell death against para-nonylphenol. CONCLUSION: As this assay system is simple and rapid, it may represent a useful artificial tool to clarify the signaling pathways of apoptotic cell death in human monocytes in vitro.