Simple predictors for the completion of scheduled gemcitabine­cisplatin regimens based on real­world urothelial cancer data.

Gemcitabine plus cisplatin (GC) is the standard first line of chemotherapy for urothelial carcinoma. However, it is often difficult to complete scheduled GC therapy because of real-world adverse events. Therefore, the reasons behind delays, scheduled cancelations and determined predictive factors for completing scheduled GC therapy were retrospectively analyzed. Patients diagnosed with locally advanced or metastatic urothelial carcinoma from 2009 to 2020 received a 4-week GC therapy schedule in Oita University Hospital. Information was retrospectively extracted from medical records and all cycles were divided into two groups: One wherein all treatments were administered and completed on schedule and the other wherein treatment was either delayed or canceled in during the treatment schedule. Predictive factors were then statistically extracted between the two groups. In total, 70 patients received 201 cycles of a 4-week scheduled GC therapy. Of the 201 cycles, a total of 68 (33.8%) completed all scheduled treatments, while 133 (66.1%) did not complete the treatment as scheduled. In the group where administration was not completed on schedule, the factors of male, ureteral cancer, lower stage, <90% of gemcitabine and cisplatin dosage, solitary kidney, high creatinine level, low estimated glomerular filtration rate level, low platelet count and high alkaline phosphatase level at the initiation of each cycle were more significant. Additionally, the lowest anticancer drug percentage administration was on day 15. From these results, predictive factors for patients with various backgrounds who completed the scheduled 4-week GC therapy based on real-world data were identified. This information can be useful for clinical physicians when deciding the course of treatment.

Impact of Fish Intake Frequency on Cardiovascular Disease-Specific Survival in Hemodialysis Patients.

Introduction: Cardiovascular disease (CVD) is the leading cause of death in hemodialysis patients (HPs). As a food source, fish contains both CVD-preventive and CVD-promoting fatty acids; however, there is no consensus on fish consumption as a preventive measure for CVD in HPs. This single-center longitudinal cohort study aims to assess the impact of fish intake frequency (FIF) per week on CVD in Japanese HPs. Methods: Upon the initiation of the study, 148 HPs were evaluated to determine the FIF, and blood samples were analyzed. These patients were then monitored for 6 years.The relationships between each FIF and blood sampling data, CVD-specific survival (CSS), and new CVD-free survival (nCFS) were statistically calculated using Kaplan-Meier survival curves. Results: During the observation period, 65 deaths were reported, 16 of which were attributed to CVD. Further, 53 patients developed new CVD onset, and no association was found between the FIF and blood sampling data. Based on the Kaplan-Meier survival curves, there was a significant difference in the CSS probability rates at 72 months between patients with an FIF of ≥4 (0.719, 95% confidence interval (CI): 0.530-0.842) and those with an FIF of ≤3 (0.930, 95% CI: 0.851-0.968) (p < 0.01). However, the nCFS probability at 72 months did not significantly differ between patients with an FIF of ≥4 and those with an FIF of ≤3. Multivariate Cox proportional hazards regression showed that an FIF of ≥4 (hazard ratio: 3.64, 95% CI: 1.22-10.9, p = 0.02) was an independent predictor of CSS, but not of nCFS. Conclusions: It was suggested that a higher FIF in HPs might be one of the risks for developing CVD with increased mortality.

IL-6-Producing Pheochromocytoma Associated With Von Hippel Lindau Disease: A Case Report With Literature Review.

We present a first case report of an IL-6-producing pheochromocytoma associated with von Hippel Lindau (vHL) disease. Pheochromocytomas are rare tumors that produce catecholamines, leading to various symptoms. In this case, a 28-year-old woman with a family history of vHL disease presented with a prolonged fever. Laboratory examinations revealed elevated C-reactive protein levels, and notably, a significantly increased serum IL-6 level. Imaging studies confirmed bilateral adrenal tumors with increased uptake on fluorodeoxyglucose-positron emission tomography and 123I-metaiodobenzylguanidine scintigraphy in the right adrenal gland. Despite partial relief with nonsteroidal anti-inflammatory drugs and alpha-blockers, her fever persisted until prednisolone administration, which promoted a complete resolution. A histopathological analysis following a right laparoscopic adrenalectomy revealed a typical pheochromocytoma. We conducted further analyses, including an enzyme-linked immunosorbent assay (ELISA), a quantitative real-time polymerase chain reaction (PCR) test, and immunoblot assays from the resected tumor tissues. We compared the current case with other cases of pheochromocytoma that presented neither elevated serum IL-6 nor high fever. Using ELISA, we found that this patient exhibited more IL-6 secretion than that seen in other cases. Additionally, quantitative real-time PCR and immunoblot found that both the phosphorylated signal transducer and activator of transcription 3 (STAT3) messenger RNA (mRNA) and protein expression levels exceeded those of the other cases. Thus, we surmised that IL-6 was produced directly from the tumor tissue and IL-6 expression was potentiated through the IL-6/STAT3 signaling pathway. Our findings contribute to the understanding of IL-6-producing pheochromocytomas and their distinct clinical characteristics.

External iliac arterial dissection after robot-assisted radical cystectomy with an intracorporeal ileal conduit and extended pelvic lymph node dissection.

Introduction: External iliac arterial dissection after robot-assisted laparoscopic procedures is an extremely rare complication. It may cause severe adverse outcomes, such as lower limb necrosis. Case presentation: A 73-year-old man was diagnosed with cT2 ≤ N0M0 bladder cancer and underwent robot-assisted radical cystectomy. After surgery, he complained of severe left lower leg pain. Computed tomography showed external iliac arterial occlusion. Furthermore, the emergency operation revealed external iliac arterial dissection and occlusion. Conclusion: The robot arm does not have any sense of force or touch. Thus, it is necessary to pay sufficient attention to the traction of blood vessels and contact with major organs.

A Rare Case of Hernia Incarceration Under the Closed Port-Site Fascia After Robot-Assisted Laparoscopic Radical Cystectomy: Insights and Management Strategies.

Most cases of port-site hernia were due to inadequate fascial closure of the port site. We experienced a rare case of hernia incarceration under the closed port-site fascia despite adequate closure of the fascia after robot-assisted laparoscopic radical cystectomy. In this case, the small intestine was incarcerated between the transversus abdominis and oblique abdominal muscles from the 12-mm trocar site for the assistant. We inserted forceps to release the incarceration, and the fascia and peritoneum of the port site were closed using a trocar site closure device under laparoscopy. We considered that all-layer suturing, including peritoneum and inner and outer oblique fascia suturing, was necessary for port-site closure, especially in patients with obesity, because hernias can occur with fascial closure alone.

A case of retroperitoneal venous malformation resected by laparoscopic surgery.

Introduction: Among vascular malformations, venous malformations are the most common type. Among these, retroperitoneal venous malformations are extremely rare. Case presentation: A 60-year-old woman was diagnosed with a retroperitoneal tumor 4.5 cm in diameter by abdominal computed tomographic scan. We had difficulty judging whether the tumor was benign or malignant. We performed laparoscopic surgery in order to remove the tumor and make a precise diagnosis. The pathological diagnosis was a venous malformation. Conclusion: Venous malformation located in the retroperitoneum is very rare, and there were few cases that could be removed by laparoscopic surgery. Laparoscopic surgery may be beneficial both for treatment and diagnosis of patients with a small retroperitoneal venous malformation.

Sustained suppression of enterohepatic circulation of mycophenolic acid by antimicrobial-associated diarrhea in a kidney transplant recipient with Crohn's disease: A case report.

Mycophenolic acid (MPA) undergoes enterohepatic circulation. A kidney transplant patient on mycophenolate mofetil was treated with tazobactam/piperacillin for pyelonephritis, and developed antimicrobial-associated diarrhea. Consequently, the MPA trough level decreased by approximately 90%. Furthermore, it took approximately a month for the MPA level to normalize even after diarrhea had resolved.

Highly sensitive simultaneous quantification of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry.

Indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid are uremic toxins that accumulate in renal failure and have been reported to decrease the activities of the drug-metabolizing enzyme cytochrome P450 3A and the drug transporter organic anion transporting polypeptides 1B, respectively. In this study, we established and validated an assay for simultaneous quantification of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma. The samples were pretreated by solid-phase extraction, and measured by ultra-high-performance liquid chromatography-tandem mass spectrometry. The validation results for this assay were within the acceptable limits recommended by the US Food and Drug Administration, with a lower limit of quantitation of 0.05 µg/mL for both indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. Recovery rates of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 100.7-101.9 and 100.2-101.3%, respectively. Matrix effects of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 101.1-105.5 and 97.0-103.8%, respectively. The validated assay was used to analyze indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations in the plasma samples of healthy volunteers and patients with chronic kidney disease. All the measured plasma indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations were within the calibration ranges. This novel method may contribute to predicting the activities of drug-metabolizing enzymes and drug transporters in individual patients.

Adrenal Vein Sampling With Gadolinium Contrast Medium in a Patient With Florid Primary Aldosteronism and Iodine Allergy.

We describe a 35-year-old woman who was allergic to iodine contrast medium and was diagnosed with primary aldosteronism (PA) based on functional confirmatory tests. She was suspected to have unilateral PA because of marked hypertension, spontaneous hypokalemia, high plasma aldosterone, reduced plasma renin activity, and a right hypodense adrenal tumor. She wanted to become pregnant and requested adrenalectomy instead of medical treatment with mineralocorticoid receptor antagonists. Localization of PA by adrenal vein sampling (AVS) was necessary, but angiography with iodine contrast medium was not possible because of her allergy. AVS was performed using gadolinium contrast agent (gadoterate meglumine) instead of iodine, in combination with computed tomography angiography (CTA). In AVS, before and after adrenocorticotropin (ACTH) loading, 12 blood samples were drawn from the right adrenal vein, left adrenal central vein, left adrenal common duct, left and right renal veins, and the lower inferior vena cava with only 5 mL of gadolinium medium. There were no complications during AVS. Examination revealed an elevated aldosterone/cortisol ratio on the right side, lateralized ratio of 7.4, and contralateral ratio of 0.76; the patient was diagnosed with right unilateral PA. She underwent right adrenalectomy and showed improvements in aldosterone level from 312.4 pg/mL to 83.0 pg/mL, potassium from 3.0 mEq/L to 3.9 mEq/L, and systolic blood pressure from 138 mm Hg to 117 mm Hg. In PA patients with iodine allergy, AVS can be performed safely and precisely using gadolinium contrast combined with CTA.

Sensitive UHPLC-MS/MS quantification method for 4ß- and 4α-hydroxycholesterol in plasma for accurate CYP3A phenotyping.

4ß-Hydroxycholesterol (4ß-OHC) is formed by Cytochrome P450 (CYP)3A and has drawn attention as an endogenous phenotyping probe for CYP3A activity. However, 4ß-OHC is also increased by cholesterol autooxidation occurring in vitro due to dysregulated storage and in vivo by oxidative stress or inflammation, independent of CYP3A activity. 4α-hydroxycholesterol (4α-OHC), a stereoisomer of 4ß-OHC, is also formed via autooxidation of cholesterol, not by CYP3A, and thus may have clinical potential in reflecting the state of cholesterol autooxidation. In this study, we establish a sensitive method for simultaneous quantification of 4ß-OHC and 4α-OHC in human plasma using ultra-high performance liquid chromatography coupled to tandem mass spectrometry. Plasma samples were prepared by saponification, two-step liquid-liquid extraction, and derivatization using picolinic acid. Intense [M+H]+ signals for 4ß-OHC and 4α-OHC di-picolinyl esters were monitored using electrospray ionization. The assay fulfilled the requirements of the US Food and Drug Administration guidance for bioanalytical method validation, with a lower limit of quantification of 0.5 ng/ml for both 4ß-OHC and 4α-OHC. Apparent recovery rates from human plasma ranged from 88.2% to 101.5% for 4ß-OHC, and 91.8% to 114.9% for 4α-OHC. Additionally, matrix effects varied between 86.2% and 117.6% for 4ß-OHC and between 89.5% and 116.9% for 4α-OHC. Plasma 4ß-OHC and 4α-OHC concentrations in healthy volunteers, stage 3-5 chronic kidney disease (CKD) patients, and stage 5D CKD patients as measured by the validated assay were within the calibration ranges in all samples. We propose this novel quantification method may contribute to accurate evaluation of in vivo CYP3A activity.

Vrk2 deficiency elicits aggressive behavior in female zebrafish.

Vaccinia-related kinase 2 (VRK2) is a serine/threonine kinase initially identified in highly proliferative cells such as thymocytes and fetal liver cells, and it is involved in cell proliferation and survival. VRK2 is also expressed in the brain; however, its molecular function in the central nervous system is mostly unknown. Many genome-wide association studies (GWASs) have reported that VRK2 is a potential candidate molecule for neuropsychiatric diseases such as schizophrenia in humans. However, the pathophysiological relationship between VRK2 and neuropsychiatric disorders has not been fully investigated. In this study, we evaluated vrk2-deficient (vrk2-/- ) zebrafish and found that vrk2-/- female zebrafish showed aggressive behavior and different social preference compared with control (vrk2+/+ ) zebrafish, with low gamma-aminobutyric acid (GABA) content in the brain and high density of neuronal dendrites when compared to vrk2+/+ zebrafish. These findings suggest that female vrk2-/- zebrafish were indeed a model of malbehavior characterized by aggression and social interaction, which can be attributed to the low levels of GABA content in their brain.

Current Status of Endoscopic Surgery in Japan: The 15th National Survey of Endoscopic Surgery by the Japan Society for Endoscopic Surgery.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, operative procedures have been standardized, and the safety and efficacy of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less invasive type of surgery, the number of endoscopic procedures performed has increased in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. Notably, a technical skills certification system for surgeons was established by the JSES to train instructors on how to teach safe endoscopic surgery. Furthermore, the JSES has conducted a national survey every 2 years. In 2019, 291,792 patients underwent endoscopic surgery in all surgical domains, such as abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The 15th National Survey of Endoscopic Surgery conducted by the JSES demonstrated the status of laparoscopic surgery in Japan in 2018-2019.

Dopamine-Secreting Pheochromocytoma and Paraganglioma.

Predominantly or exclusively dopamine-secreting pheochromocytoma and paraganglioma are very rare. We report a 64-year-old woman with an adrenal incidentaloma. She was normotensive and had no symptoms of catecholamine excess. The 24-hour urine catecholamine level showed normal norepinephrine (122.9 µg/day), normal epinephrine (24.3 µg/day), and markedly elevated dopamine (148 212.4 µg/day). 123I-metaiodobenzylguanidine (MIBG) scintigraphy revealed tumor uptake. After α-blockade as preoperative management, she successfully underwent laparoscopic left adrenalectomy and was finally diagnosed with an exclusively dopamine-secreting pheochromocytoma. The tumor was histologically comprised of small polygonal cells with high cellularity and was immunohistochemically positive for all 3 catecholamine-synthesizing enzymes: tyrosine hydroxylase (very weak), dopamine ß-hydroxylase (heterogeneous), and phenylethanolamine N-methyltransferase (very weak). Electron microscopy revealed very few catecholamine-containing small vesicles with a few organelles, which reflected immature cells. No biochemical or imaging evidence of recurrence or metastasis were evident 1 year after the surgery. We conducted a literature search in the PubMed database. A total of 33 cases were collected. Our case had the second-highest 24-hour urinary dopamine excretion and was the first in which immunostaining for catecholamine synthase and electron microscopy were performed together. Histological findings in our case give a possible hypothesis that the mechanism underlying a dopamine-secreting pheochromocytoma is associated with immature catecholamine vesicles in which dopamine ß-hydroxylase is localized, thus resulting in inhibited conversion from dopamine to norepinephrine. We also discuss the reasons for the lack of catecholamine excess symptoms, whether preoperative management of α-blockade is needed, and the association between the prognosis and genetic mutation, with an extensive literature review.

Association of CYP3A5 polymorphisms and parathyroid hormone with blood level of tacrolimus in patients with end-stage renal disease.

Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end-stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact-PTH (iPTH) level with blood tacrolimus concentration in patients with end-stage renal disease just before kidney transplantation. Forty-eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co-administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation.

Laparoscopic ileal ureteral replacement to preserve the natural anti-reflux system: An initial case report.

INTRODUCTION: Ileal ureteral replacement is one of the treatment options for long ureteral strictures. Most ileal ureteral replacements anastomose the distal side of the ileal segment directly to the bladder. We have reported here an initial case of laparoscopic ileal ureteral replacement for preserving the natural anti-reflux system. CASE PRESENTATION: A 29-year-old male presented with right flank pain, and his imaging results revealed multiple strictures of the right upper-middle ureter. Hence, we performed a laparoscopic ileal ureteral replacement surgery. The normal distal ureter was preserved, and the distal side of the ileal segment was anastomosed to it. As such, the natural anti-reflux system could be completely preserved. Following this, the renal function was maintained, and no urinary tract infection was recorded. CONCLUSION: Laparoscopic ileal ureteral replacement, which preserves the natural anti-reflux system, can be considered as a treatment option for refractory upper-middle ureteral strictures.

Only three cycles of nivolumab showed remarkable durable response and reversible myeloradiculoneuropathy in a patient with metastatic papillary renal cell carcinoma type 2.

INTRODUCTION: The efficacy of nivolumab for non-clear cell renal cell carcinoma is still unclear. We present a rare case of metastatic papillary renal cell carcinoma remarkably responded to nivolumab but developed myeloradiculoneuropathy as immune-related adverse event. CASE PRESENTATION: The patient had previously undergone radical nephrectomy for right renal mass and was diagnosed as papillary renal cell carcinoma type 2, pT3bN0M0. Three years after the first surgery, he received 3 mg/kg of nivolumab as a second-line drug for mediastinum lymph nodes and lung metastases. With three cycles of nivolumab, the patient felt progressive weakness of the legs and received two cycles of steroid-pulse therapy based on the diagnosis of myeloradiculoneuropathy. Although nivolumab therapy has been discontinued, the metastases show radiographic complete response at 2 years after the last nivolumab administration without any additional therapy. CONCLUSION: Nivolumab may be a promising treatment option for non-clear cell renal cell carcinoma such as papillary renal cell carcinoma.

How Should We Treat Pancreatic Metastases from Renal Cell Carcinoma? A Meta-Analysis.

BACKGROUND: The treatment strategy for pancreatic metastasis (PM) from renal cell carcinoma (RCC) is unclear due to its rarity. The aim of this study was to reveal the role of surgery for PM from RCC. METHODS: A systematic literature search was conducted using PubMed and the Cochrane Library. The effectiveness of surgery for PM was evaluated based on the primary outcome of overall survival (OS), which was investigated in relation to surgical procedures and metastatic sites via subgroup analyses. RESULTS: There was no significant difference in the rate of 2-year OS between the surgery and control group (OR 0.43, 95% CI 0.14-1.26, P = 0.12). However, the rate of 5-year OS was significantly higher in the surgery group than the control group (OR = 0.41, 95% CI 0.18-0.93, P = 0.03). The rates of the complications and OS were not significantly different between radical and conservative pancreatectomies. The rate of 5-year OS of the patients with PM was higher than that with other metastases (OR 0.38, 95% CI 0.20-0.74, P = 0.004). CONCLUSION: Surgical resection for PM from RCC is associated with good prognosis. Limited surgery may be a useful option depending on the location of the lesion.

Adult-onset Skene's gland cyst following a history of multiple gynecological treatment interventions.

Skene's gland cysts are rare and the cause of adult-onset is still unclear. We report the case of a 34-year-old woman developing a Skene's gland cyst following a history of various gynecological treatment interventions. She finally underwent surgical excision of the cyst and no recurrence has been observed 1 year after the surgery.