BRAF V600E-mutated Colorectal Neuroendocrine Carcinoma Effectively Treated with a Chemotherapy Protocol for BRAF-mutated Metastatic Colorectal Cancer: A Case Report.

Metastatic colorectal neuroendocrine carcinoma (NEC) is often treated using a chemotherapy protocol for small-cell lung cancer; however, the prognosis is extremely poor. A 55-year-old woman with BRAF V600E-mutated transverse colon NEC and liver metastases underwent colectomy followed by FOLFOXIRI plus bevacizumab. Consequently, the liver metastases markedly shrank. Owing to later worsening of the liver metastases, she received encorafenib and binimetinib plus cetuximab. Despite discontinuing binimetinib due to myalgia, she had a long-term response with a progression-free survival of 14 months and an overall survival of more than 27 months. A chemotherapy protocol for BRAF-mutated metastatic colorectal cancer may be a treatment option for BRAF V600E-mutated colorectal NEC.

Trajectory analyses to identify persistently low responders to COVID-19 vaccination in patients with inflammatory bowel disease: a prospective multicentre controlled study, J-COMBAT.

BACKGROUND: The degree of immune response to COVID-19 vaccination in inflammatory bowel disease (IBD) patients based on actual changes in anti-SARS-CoV-2 antibody titres over time is unknown. METHODS: Data were prospectively acquired at four predetermined time points before and after two vaccine doses in a multicentre observational controlled study. The primary outcome was humoral immune response and vaccination safety in IBD patients. We performed trajectory analysis to identify the degree of immune response and associated factors in IBD patients compared with controls. RESULTS: Overall, 645 IBD patients and 199 control participants were analysed. At 3 months after the second vaccination, the seronegative proportions were 20.3% (combination of anti-tumour necrosis factor [TNF]α and thiopurine) and 70.0% (triple combination including steroids), despite that 80.0% receiving the triple combination therapy were seropositive at 4 weeks after the second vaccination. Trajectory analyses indicated three degrees of change in immune response over time in IBD patients: high (57.7%), medium (35.6%), and persistently low (6.7%). In the control group, there was only one degree, which corresponded with IBD high responders. Older age, combined anti-TNFα and thiopurine (odds ratio [OR], 37.68; 95% confidence interval [CI], 5.64-251.54), steroids (OR, 21.47; 95%CI, 5.47-84.26), and tofacitinib (OR, 10.66; 95%CI, 1.49-76.31) were factors associated with persistently low response. Allergy history (OR, 0.17; 95%CI, 0.04-0.68) was a negatively associated factor. Adverse reactions after the second vaccination were significantly fewer in IBD than controls (31.0% vs 59.8%; p < 0.001). CONCLUSIONS: Most IBD patients showed a sufficient immune response to COVID-19 vaccination regardless of clinical factors. Assessment of changes over time is essential to optimize COVID-19 vaccination, especially in persistently low responders.

Efficacy of minocycline hydrochloride aspiration sclerotherapy with additional monoethanolamine oleate aspiration sclerotherapy for symptomatic hepatic cysts.

AIM: Minocycline hydrochloride (MINO) aspiration sclerotherapy (AS) has been widely used for treating hepatic cysts (HC). However, cyst recurrence remains problematic. Information on monoethanolamine oleate (EO) AS, another effective HC treatment, is currently limited. We investigated the efficacy of EO on ineffective MINO treatments, and the relationship between MINO AS and cyst fluid pH. METHODS: A total of 22 cases with symptomatic HC underwent AS with 500 mg of MINO from January 2016 to June 2021. Cyst fluid pH was measured before and after MINO injection. Cyst volume ratio (CVR, %) after 2 weeks was calculated as follows:cyst volume 2 weeks after MINO injection / pre-treatment cyst volume × 100. Treatment was completed if CVR after 2 weeks was ≤35% (MINO-group). For patients with CVR >35%, 2 g of EO was added (MINO/EO-group). Cyst volume ratio was measured every 12 months thereafter. RESULTS: There were no recurrence symptoms in any of the patients during follow-up. Of the 22 cases, 21 had CVR ≤20% after 12 months. The MINO/EO-group (n = 8) tended to have smaller CVRs after 12 months than the MINO-group (n = 14). Cyst volume ratio after 2 weeks was correlated to pH change (p = 0.012) and was larger in patients whose pH decreased by <1.5 (p = 0.015). All adverse events were mild, including in elderly patients. CONCLUSION: Adding EO is an effective and safe treatment for symptomatic HC when MINO AS alone is insufficient. Patients with pH decreases of <1.5 should be considered for additional EO treatment.

[A case of gastric cancer showing a durable response after the discontinuation of nivolumab due to the early onset of immune-related adverse events].

The Japanese guidelines for the treatment of gastric cancer recommend nivolumab as third-line chemotherapy for metastatic gastric cancer. We report a case of gastric cancer exhibiting a durable response after the discontinuation of nivolumab due to the early onset of immune-related adverse event (irAE). A 64-year-old man with advanced HER2-positive gastric cancer and distant lymph node metastasis received nivolumab as fourth-line therapy. After two courses of nivolumab, the lymph nodes showed progression. However, the treatment was discontinued because of interstitial pneumonia as an irAE. Disease regression was sustained for approximately 11 months without the readministration of nivolumab.

Prognostic factors for mortality in middle-aged and older hemodialysis patients: a 5-year observational study.

Clinical guidelines for hemodialysis therapy have been described in an evidence-based manner with most evidence from randomized control trials or retrospective studies in which all generations of the hemodialysis patients were enrolled. Therefore, the question still remains whether these guidelines can be applied to increasing older patients. This study is an observational study, including 735 patients who received maintenance hemodialysis in April 2006. At baseline, the participants' age was 62.1 ± 12.8 years (mean ± SD). Hemodialysis duration was 103.7 ± 89.3 months. In a 5-year observation period (actual follow-up period: 1551 ± 499 days), 175 patients died. Prognostic factors were investigated by multivariate analysis with Cox proportional hazard model. Next, we stratified the patients according to their age. 363 patients were included in the middle-aged patient's category between 40 and 64 years, and 314 were involved in the older patient's category between 65 and 84 years old. As a subanalysis, significant predictors of 5-year survival were examined in the age-stratified cohort. Then, Kt/V, serum ß2-microglobulin and calcium concentration were significant predictors in our entire cohort, as well as body mass index, neutrophil count, and serum sodium concentration even after adjustment for age, gender, diabetic status and hemodialysis duration. However, Kt/V, serum ß2-microglobulin and calcium concentration controlled by hemodialysis prescriptions were independent risk factors especially in older patients, not in middle-aged patients. In conclusion, hemodialysis prescriptions for lowering uremic toxins and managing mineral-bone disorder are important to decrease the risk of death even in older hemodialysis patients.

Implications of Albumin Leakage for Survival in Maintenance Hemodialysis Patients: A 7-year Observational Study.

Albumin leakage during hemodialysis (HD) presents a clinical dilemma. However, protein-binding uremic toxins are suggested to be responsible for increased mortality. No one has investigated the relationship between albumin leakage and mortality. Therefore, the purpose of this observational study was to analyze the association of albumin leakage with mortality in 690 HD patients who survived one year after enrollment. They were divided to three groups who received HD with large (3 g or more per HD session), middle (1 to 3 g) or small (less than 1 g) amount of albumin leakage, respectively. A propensity score analysis minimizing indication bias was performed. Consequently, in a 7-year observation period, 212 patients died. Albumin leakage 3 g or more per HD session provided better prognosis than albumin leakage less than 3 g per HD session. In conclusion, clinically acceptable large albumin leakage provides beneficial effects on mortality in maintenance HD patients.

Evidence for Targeting Low-Molecular-Weight Proteins in Hemodialysis and Hemodiafiltration.

BACKGROUND: With the identification of ß2-microglobulin (ß2MG) as an active participant in dialysis-related amyloid fibril formation, low-molecular-weight proteins (LMWPs) are now recognized as a distinct class of uremic toxins, and numerous compounds in this category have been identified. The class of LMWPs, although not precisely defined, has a molecular weight range of approximately 1,000-50,000 Da. With this in mind, dialysis prescriptions have been modified to increase the efficiency of uremic solute removal. Many studies have characterized the dialytic removal of ß2MG and it is therefore regarded as a surrogate for LMWPs. SUMMARY: In Japan, dialysis membranes that can efficiently remove ß2MG are recommended. Recently, researchers have reported that ß2MG is not only a uremic toxin that should be removed, but also a predictor of the prognosis of dialysis patients. In Japan, hemodiafiltration (HDF), especially on-line HDF, and protein-permeable hemodialysis (HD) is being actively carried out, and it is often reported that prognosis is improved by decreasing the concentrations of substances larger than ß2MG. It is important, then, that dialysis prescriptions achieve effective clearance of such substances. Key Messages: Over 2,000 uremic substances have been identified that form or accumulate because of renal failure and cause various symptoms and complications. Focusing on these facts, HD or HDF therapy, which is associated with albumin loss, was implemented targeting the LMWPs. Here, we report the effects of albumin-losing blood purification (HD/HDF) for the purpose of removing LMWPs.

Persistent reflux symptoms cause anxiety, depression, and mental health and sleep disorders in gastroesophageal reflux disease patients.

Some patients with gastroesophageal reflux disease experience persistent reflux symptoms despite proton pump inhibitor therapy. These symptoms reduce their health-related quality of life. Our aims were to evaluate the relationship between proton pump inhibitor efficacy and health-related quality of life and to evaluate predictive factors affecting treatment response in Japanese patients. Using the gastroesophageal reflux disease questionnaire, 145 gastroesophageal reflux disease patients undergoing proton pump inhibitor therapy were evaluated and classified as responders or partial-responders. Their health-related quality of life was then evaluated using the 8-item Short Form Health Survey, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale questionnaires. Sixty-nine patients (47.6%) were partial responders. These patients had significantly lower scores than responders in 5/8 subscales and in the mental health component summary of the 8-item Short Form Health Survey. Partial responders had significantly higher Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale scores, including anxiety and depression scores, than those of responders. Non-erosive reflux disease and double proton pump inhibitor doses were predictive factors of partial responders. Persistent reflux symptoms, despite proton pump inhibitor therapy, caused mental health disorders, sleep disorders, and psychological distress in Japanese gastroesophageal reflux disease patients.

The effect of albumin leakage in hemodialysis patients on redox status of serum albumin.

Human mercaptoalbumin (HMA) is a reduced form of albumin that is associated with cardiovascular disease in dialysis patients. Albumin-leaky hemodialysis (HD) is increasingly recognized as a gold standard therapy because it is correlated with better prognosis compared to conventional HD. However, albumin-leaky HD induces low serum albumin concentration because of albumin leakage, which is a classical risk factor for mortality. The aim of this study was to explain the preferable prognosis in patients undergoing albumin-leaky HD with low serum albumin concentration. Ten HD patients were enrolled. They were preconditioned with albumin-non-leaky HD (mean albumin leakage: 1.0 g) for 2 months. Subsequently, albumin-leaky HD (9.1 g) was performed for 6 months, followed by relatively non-leaky HD (within 3.0 g). The ratio and level of HMA were evaluated. The amount of albumin leakage was related to the ratio of HMA, and inversely correlated with serum albumin concentration. The level of HMA was maintained regardless of albumin leakage. Regarding HMA level, a moderate amount of albumin leakage was acceptable. A stably maintained HMA level in albumin-leaky HD patients can contribute to preferable prognosis even if they have low serum albumin concentration.

Impact of Lanthanum Carbonate on Prognosis of Chronic Hemodialysis Patients: A Retrospective Cohort Study (Kawashima Study).

In hemodialysis patients, mineral and bone disorder is an important risk factor for cardiovascular disease and subsequent death through the progression of vascular calcification. Serum phosphorus plays a major role in this process. In the present study, we retrospectively analyzed the effects of oral phosphate binder, lanthanum carbonate (LC), on the mortality in hemodialysis patients. Among a total of 841 patients who underwent maintenance hemodialysis on 1 July 2010, patients who were treated with LC (LC group, N = 324) and those who were treated without LC (NLC group, N = 517) were compared with respect to their all-cause mortality for a long-term observation period of up to 36 months. The mortality rate was compared using the Cox proportional hazard model adjusted by the propensity score. The adjusted hazard ratio for mortality in the LC group versus NLC group was 0.515 (95% confidence interval, 0.328-0.807), suggesting that the use of LC is associated with an almost 50% reduction in the mortality rate. The present retrospective study including all hemodialysis patients demonstrated, for the first time, an association between the use of LC and improved prognosis in hemodialysis patients. Randomized controlled trials should be done in the future to validate our present findings.

A phase II prospective study of the trastuzumab combined with 5-weekly S-1 and CDDP therapy for HER2-positive advanced gastric cancer.

BACKGROUND: We evaluated the efficacy and safety of 5-weekly S-1 and cisplatin combined with trastuzumab, a monoclonal antibody against human epidermal growth factor receptor type 2 (HER2) for HER2-positive advanced gastric cancer (AGC). METHODS: This phase II study treatment consisted of S-1 (80-120 mg per day) orally on day 1-21, cisplatin (60 mg/m(2)) intravenously on day 8, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival, progression-free survival (PFS), response rate (RR), and safety. RESULTS: A total 22 patients from seven centers were enrolled. In the 20 patients evaluable for analysis, the 1-year survival rate was 70 % (95 % confidence interval (CI) 49.9-90.1 %), and median survival time, PFS, and RR were 15.3, 7.5 months and 41.2 %, respectively. Major grade 3/4 adverse events were neutropenia (30 %), anorexia (30 %), leukopenia (25 %), fatigue (20 %), and anemia (15 %). CONCLUSIONS: Five-weekly S-1 and cisplatin combined with trastuzumab showed effective with favorable safety profile in patients with HER2-positive AGC.

Treatment of renal anaemia with erythropoiesis-stimulating agents in predialysis chronic kidney disease patients: Haemoglobin profile during the 6 months before initiation of dialysis.

AIM: Erythropoiesis-stimulating agents (ESAs) are all effective for renal anaemia in patients with chronic kidney disease (CKD). However, it was reported that the haemoglobin (Hb) concentration decreases to 8.4 g/dL during the initial phase of dialysis despite treatment with recombinant human erythropoietin (rHuEPO). This study compared Hb at the initiation of dialysis among patients treated with three different ESAs (rHuEPO, darbepoetin alfa [DA], and a continuous erythropoietin receptor activator [CERA]). METHODS: The subjects were 82 CKD patients who started dialysis at Kawashima Hospital between 1 January 2009 and 28 February 2015 and who received only one kind of ESA for at least 6 months before initiation of dialysis. Baseline characteristics and laboratory data at initiation of dialysis were compared among the three groups. Then changes of the Hb, ESA dose, and erythropoiesis resistance index were assessed over time during the 6 months before initiation of dialysis. Differences of Hb at the initiation of dialysis were also assessed. RESULTS: Among the 82 patients, 36 received rHuEPO, 13 received DA, and 33 received CERA. Baseline characteristics and laboratory data of the patients showed no significant differences among the three groups. The monthly Hb decreased gradually during the 6-month period before initiation of dialysis in all three groups. Hb was significantly higher in the CERA group than the rHuEPO group at the initiation of dialysis. CONCLUSION: Long-acting ESAs may be more useful for predialysis patients with CKD because they do not attend hospital frequently, unlike haemodialysis patients.

Factors associated with pain during vascular access intervention therapy.

OBJECTIVE: The objective of this study is to investigate and compare factors associated with pain during vascular access intervention therapy. SUBJECTS AND METHODS: Fifty patients provided informed consent to participate in a survey of pain by questionnaire after receiving dialysis treatment at our hospital. Balloons for use during the procedure were chosen at random in this prospective randomized control study. A numeric rating scale (NRS) was used for pain assessment. RESULTS: A semi-compliant balloon caused significantly worse pain as compared with the other types of balloons (NRS, 7.67 ± 1.57 vs. 6.02 ± 1.89; p<0.05). There was no correlation between maximum inflation pressure and pain, or between age and pain, and no difference between diabetic and non-diabetic patients. A comparison among vascular dilation locations, as well as a comparison of AVF with AVG also revealed no significant differences. CONCLUSIONS: The reason for severe pain with use of the semi-compliant balloon as compared with the other types might have been due to its characteristics during inflation, as increased diameter leads to an increase in pressure. Mismatching of balloon diameter to vascular diameter may also increase pain.

Vascular access for long-term hemodialysis/hemodiafiltration patients.

PURPOSE: We investigated the characteristics of patients who received long-term hemodialysis/hemodiafiltration (HD/HDF) treatment for over 30 years at our group of hospitals and type of vascular access (VA) used. SUBJECTS AND METHODS: As of August 2014, 950 patients were receiving HD/HDF treatment at one of our hospitals. Of those, we investigated 41 (4.3%) undergoing long-term treatment in regard to their characteristics and VA type. The items subjected to analysis were sex, primary illness, age at time of dialysis initiation, present age, duration (years) of HD/HDF, type of arteriovenous fistula (AVF) and arteriovenous graft (AVG), history of surgery and AVF persistence rate. RESULTS: The subjects consisted of 22 men and 19 women, and their mean HD/HDF duration was 33.4 ± 2.8 years. For primary illness, the majority (n = 31) had chronic glomerulonephritis. The age at time of dialysis initiation was 31.7 ± 7.76 years and present age was 64.5 ± 7.65 years. They had received 3.8 VA surgeries. For present VA type, 23 patients (56.0%) had an AVF and 13 (31.7%) an AVG, while 4 AVF patients (9.7%) had a history of AVG use. One patient (2.4%) had a superficialized artery. The mean HD/HDF duration of the 13 AVG patients was 7 years and the longest was 18 years. AVF persistence rate estimated by the Kaplan-Meier method was 75% at 30 years after dialysis initiation. CONCLUSIONS: The present results suggest that the ratio of patients with AVG increased with prolonged HD/HDF treatment. AVG has a higher probability of complications and lower patency as compared to AVF, thus careful management is needed. On the other hand, AVG contributes more to a good long prognosis, as it offers efficient dialysis. In cases of vascular deterioration due to long-term hemodialysis, it is inevitable to change from AVF to AVG, thus the ratio of AVG patients is expected to increase in cases of long-term HD/HDF.

Evaluation of sterilization using the MEH200® (cotton pack) in vascular access puncture.

BACKGROUND: In recent years, chlorhexidine-alcohol has been attracting increasing attention for its role in skin antisepsis. There have been few reports on the infection frequency associated with vascular access and no reports on the infection frequency associated with antiseptics. AIMS: We investigated skin disinfection during vascular access puncture in patients on chronic hemodialysis (HD). METHODS: We analyzed patients on chronic HD with arteriovenous fistula (AVF) and arteriovenous graft (AVG) between January 2006 and December 2010. RESULTS: The MEH200® (cotton pack including alcohol and chlorhexidine gluconate) was used in 97% of patients. A total of 1130 patients were analyzed, including 911 with AVF and 219 with AVG. Of these, seven with AVF had an infection attributed to the insertion site, which represented a rate of 0.008% of patients per year. Twenty patients with AVG had an infection attributed to the insertion site, which represented a rate of 9.1% of patients per year. The frequency was not higher than that previously reported. CONCLUSIONS: In HD patients, the MEH200® may be effective for the prevention of bacteremia.

Simple surgical method for a native arteriovenous fistula of chronic hemodialysis patients and the patency rate.

BACKGROUND/AIM: The maintenance and control of vascular access in chronic hemodialysis patients are causing serious problems not only in the quality of life of patients but also in the medical economy. In this regard, we investigated the cumulative patency rate of native arteriovenous fistula (AVF) as a vascular access. METHODS: Simple surgical method for a native AVF is selected. The cumulative patency rate of AVF was compared for each parameter. More particularly, the patency rate in the AVF was investigated by primary disease, age at the time of operation, gender, condition, and site. Furthermore, the influence of factors, including primary disease, gender, age at the time of operation (1 year old), and dialysis period (1 year) on the patency rate, was investigated using Cox's proportional hazard model. RESULTS: The patency rate of AVF was 85.6, 75.0, 67.5, 52.2% for 12, 36, 60, 120 months, respectively. When the patency rate was investigated by factor, the rate was significantly higher in the males than females. When the influence of risk factors on the patency rate was investigated, the significant and independent risk factors in all the cases were 'female' sex. CONCLUSIONS: The AVF is considered as the vascular access with the highest patency rate in the chronic hemodialysis patients. However, the factor influencing this rate is gender. In conclusion, female has a higher risk than male.

Reduction or discontinuation of antibiotic prophylaxis in vascular access surgery, tendon sheath incision and PD catheter placement.

PURPOSE: Immune response in dialysis patients is suppressed and these patients are susceptible to bacterial infections. Therefore, minimal use of antibiotics in dialysis patients is recommended to avoid generating drug-resistant bacteria. However, minor surgeries including vascular access surgery, tendon sheath incision and peritoneal dialysis (PD) catheter placement are inevitable in dialysis patients and evidence-based recommendations on the judicious use of antibiotics are not currently available for these procedures. In this study, the optimal antibiotic prophylaxis for minor surgeries was evaluated. METHODS: This is a retrospective study. In dialysis patients at Kawashima Hospital, a three-step reduction of antibiotic use was performed in 651 cases of arteriovenous fistula (AVF) and tendon sheath incision surgeries from July 2009 through October 2012. Moreover, general surgical guidelines-recommended dose of preoperative antibiotics only were used in 532 cases of arteriovenous graft (AVG) and PD catheter placement from January 2010 through October 2012. The surgical site was observed for 2 weeks after the surgery. RESULTS: In only one case of AVF surgery, redness of the skin around the stitches was noticed 5 days after the surgery, which was healed with antibiotics taken orally for 3 days. Neither AVG nor PD catheter placement demonstrated any infection at the surgical site during the 2-week observation period. CONCLUSIONS: Even in dialysis patients, neither pre- nor postoperative antibiotics are necessary for AVF and tendon sheath incision surgeries. AVG and PD catheter placement surgeries require only a small amount of antibiotics preoperatively.

Vascular access for long-term hemodialysis/hemodiafiltration patients in Japan.

BACKGROUND: Many patients are receiving long-term hemodialysis (HD) or hemodiafiltration (HDF) treatment in Japan. Vascular access is a lifeline for patients on HD or HDF, and proper maintenance of vascular access is one of the key factors that make long-term HD and HDF possible. We investigated the conditions of vascular access in patients undergoing chronic HD or HDF in our hospital group in Japan to assess the relationship between the type of vascular access and long-term treatment. PATIENTS AND METHODS: We studied the conditions of vascular access in 899 patients who were on chronic HD or HDF, including patients who had been on dialysis for over 20 years as of December 2014. RESULTS: There were 125 patients who had been on dialysis treatment for over 20 years, with the longest dialysis vintage being 37 years, and they accounted for 13.9% of the total number of subjects. The primary disease was diabetes in two cases and chronic glomerulonephritis in the rest. There were 105 patients with an arteriovenous fistula and only 20 with an arteriovenous graft (AVG) (16.0%), whereas 91 had an AVG (11.7%) among the 774 patients who had been on dialysis treatment for less than 20 years, which indicated that the percentage of patients with an AVG increased with dialysis vintage. CONCLUSIONS: An arteriovenous fistula was the main type of vascular access used in patients who had been on dialysis treatment for over 20 years, which is very rare, even on the global scale. However, switching to an AVG is unavoidable in cases of vein deterioration due to long-term use. Access via an AVG is expected to increase further in long-term patients in the future.