Safety of early pelvic drain removal in colorectal surgery based on drainage quantity.

BACKGROUND: This study aimed to investigate the association between the drainage quantity of pelvic drains and postoperative complications in colorectal surgery. MATERIALS AND METHODS: This retrospective single-center study enrolled 122 colorectal surgery patients between January 2017 and December 2020. After restorative proctectomy or proctocolectomy with gastrointestinal anastomosis, a continuous, low-pressure suction pelvic drain was placed and its contents measured. Removal ensued following the absence of turbidity and a drainage quantity of ≤ 150 mL/day. RESULTS: Seventy-five patients (61.5%) and 47 patients (38.5%) underwent restorative proctectomy and proctocolectomy, respectively. Drainage quantity changes were observed on postoperative day (POD) 3, regardless of the surgical procedure or postoperative complications. The median (interquartile range) number of PODs before drain removal and organ-space surgical site infection (SSI) diagnosis were 3 (3‒5) and 7 (5‒8), respectively. Twenty-one patients developed organ-space SSIs. Drains were left in place in two patients after POD 3 owing to large drainage quantities. Drainage quality changes enabled diagnosis in two patients (1.6%). Four patients responded to therapeutic drains (3.3%). CONCLUSIONS: The drainage quantity of negative-pressure closed suction drains diminishes shortly after surgery, regardless of the postoperative course. It is not an effective diagnostic or therapeutic drain for organ-space SSI. This supports early drain removal based on drainage quantity changes in actual clinical practice. TRIAL REGISTRATION: The study protocol was retrospectively registered and carried out per the Declaration of Helsinki and approved by the Hiroshima University Institutional Review Board (approval number: E-2559).

Pharmacokinetics of cefmetazole in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue of patients scheduled for lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment.

INTRODUCTION: Cefmetazole (CMZ) has gained interest as a carbapenem-sparing alternative to the epidemic of extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales (ESBL-E). In this study, we investigated the pharmacokinetics (PK) of CMZ in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue to assess the dosing regimen needed to achieve pharmacodynamic (PD) goals at the target site. METHODS: Patients scheduled for elective lower gastrointestinal surgery were intravenously administered CMZ. Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected after CMZ infusion and during the surgery, and CMZ concentrations were measured. The non-compartmental and compartmental PK parameters were estimated and used to evaluate site-specific PD target attainment. RESULTS: A total of 38 plasma, 27 peritoneal fluid, 36 peritoneum, and 38 subcutaneous adipose tissue samples were collected from 10 patients. The non-compartmental PK analysis revealed the ratios of the mean area under the drug concentration-time curve (AUC0-3.5 h) of peritoneal fluid-to-plasma, peritoneum-to-plasma, and subcutaneous adipose tissue-to-plasma were 0.60, 0.36, and 0.11, respectively. The site-specific PD target attainment analyses based on the breakpoints for ESBL-E per the Japanese surgical site infection (SSI) surveillance (MIC90 = 8 mg/L) revealed that 2 g CMZ every 3.5 h achieved desired bactericidal effect at all sites and 2 g CMZ every 6 h achieved PD goals at peritoneum and peritoneal fluid. CONCLUSION: These findings clarify the PK of CMZ in abdominal tissues and could help decide optimal dosing regimens to treat intra-abdominal infection and prophylaxis of SSI.

Ceftolozane-Tazobactam Pharmacokinetics in the Abdominal Tissue of Patients Undergoing Lower Gastrointestinal Surgery: Dosing Considerations Based on Site-Specific Pharmacodynamic Target Attainment.

INTRODUCTION: Recently, complicated intra-abdominal infections (cIAI) have been caused not only by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa, but also by extended-spectrum ß-lactamase-producing Enterobacterales members. Ceftolozane-tazobactam (CTLZ-TAZ) is considered to exhibit therapeutic effects against cIAI. Studies on the concentrations of antibiotics in abdominal tissues directly affected by cIAI are limited. Therefore, in this study, we investigated the pharmacokinetics of CTLZ-TAZ in abdominal tissue and simulated the administration regimen required to achieve the pharmacodynamic target for cIAI-causing bacteria. METHODS: Patients scheduled for elective lower gastrointestinal surgery were intravenously administered preoperative CTLZ-TAZ (1 g CTLZ and 0.5 g TAZ). Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected during the surgery, and CTLZ as well as TAZ concentrations were measured. The noncompartmental and compartmental pharmacokinetic parameters were then estimated. Site-specific pharmacodynamic target attainment analysis using 1.5 g of CTLZ-TAZ was performed. RESULTS: CTLZ-TAZ was administered to nine patients (once to five patients and twice to four patients). The mean peritoneal fluid-to-plasma ratio (one dose/two doses) for CTLZ was 0.74/1.15, which was slightly higher than the mean peritoneal fluid-to-plasma ratio for TAZ (0.95/1.13). The ratio for subcutaneous adipose was lower than those for peritoneal fluid and peritoneum tissues. We also discovered that the average ratio of CTLZ and TAZ concentrations in all tissues was maintained at or above 2:1. In our investigation of pharmacodynamic target attainment in each tissue, the desired bactericidal effect was attained with all CTLZ-TAZ (1.5 g) administration regimens [q12h (3 g/day), q8h (4.5 g/day), and q6h (6 g/day)]. CONCLUSION: To the best of our knowledge, this is the first study investigating the optimal pharmacodynamic level of CTLZ-TAZ in the abdominal tissue against cIAI-causing bacteria. This study also serves as a guideline for designing an optimal administration regimen based on pharmacodynamic target attainment for cIAI-causing bacteria. DETAILS OF THE TRIAL REGISTRATION: The institutional review board of Hiroshima University Hospital, CRB6180006. The Japan Registry of Clinical Trials, jRCTs061190025.

Pharmacokinetics of flomoxef in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue of patients undergoing lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment.

INTRODUCTION: Flomoxef is generally used to treat abdominal infections and as antibiotic prophylaxis during lower gastrointestinal surgery. It is reportedly effective against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and an increasingly valuable alternative to carbapenems. However, its abdominal pharmacokinetics remain unclear. Herein, pharmacokinetic analysis of flomoxef in the abdominal tissue was conducted to simulate dosing regimens for pharmacodynamic target attainment in abdominal sites. METHODS: Flomoxef (1 g) was administered intravenously to a patient 30 min before commencing elective lower gastrointestinal surgery. Samples of plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue were collected during surgery. The flomoxef tissue concentrations were measured. Accordingly, non-compartmental and compartmental pharmacokinetic parameters were calculated, and simulations were conducted to evaluate site-specific pharmacodynamic target values. RESULTS: Overall, 41 plasma samples, 34 peritoneal fluid samples, 38 peritoneum samples, and 41 subcutaneous adipose samples from 10 patients were collected. The mean peritoneal fluid-to-plasma ratio in the areas under the drug concentration-time curve was 0.68, the mean peritoneum-to-plasma ratio was 0.40, and the mean subcutaneous adipose tissue-to-plasma was 0.16. The simulation based on these results showed the dosing regimens (q8h [3 g/day] and q6h [4 g/day]) achieved the bactericidal effect (% T > minimum inhibitory concentration [MIC] = 40%) in all tissues at an MIC of 1 mg/L. CONCLUSIONS: We elucidated the pharmacokinetics of flomoxef and simulated pharmacodynamics target attainment in the abdominal tissue. This study provides evidence concerning the use of optimal dosing regimens for treating abdominal infection caused by strains like ESBL-producing bacteria.

Introduction of C-alkyl branches to L-iminosugars changes their active site binding orientation.

L-ido-Deoxynojirimycin (L-ido-DNJ) itself showed no affinity for human lysosomal acid α-glucosidase (GAA), whereas 5-C-methyl-L-ido-DNJ showed a strong affinity for GAA, comparable to the glucose analog DNJ, with a Ki value of 0.060 µM. This excellent affinity for GAA and enzyme stabilization was observed only when methyl and ethyl groups were introduced. Docking simulation analysis revealed that the alkyl chains of 5-C-alkyl-L-ido-DNJs were stored in three different pockets, depending on their length, thereby the molecular orientation was changed. Comparison of the binding poses of DNJ and 5-C-methyl-L-ido-DNJ showed that they formed a common ionic interaction with Asp404, Asp518, and Asp616, but both the binding orientation and the distance between the ligand and each amino acid residue were different. 5-C-Methyl-L-ido-DNJ dose-dependently increased intracellular GAA activity in Pompe patient fibroblasts with the M519V mutation and also promoted enzyme transport to lysosomes. This study provides the first example of a strategy to design high-affinity ligands by introducing alkyl branches into rare sugars and L-sugar-type iminosugars to change the orientation of binding.

5-C-Branched Deoxynojirimycin: Strategy for Designing a 1-Deoxynojirimycin-Based Pharmacological Chaperone with a Nanomolar Affinity for Pompe Disease.

In recent years, the function of pharmacological chaperones as a "thermodynamic stabilizer" has been attracting attention in combination therapy. The coadministration of a pharmacological chaperone and recombinant human acid α-glucosidase (rhGAA) leads to improved stability and maturation by binding to the folded state of the rhGAA and thereby promotes enzyme delivery. This study provides the first example of a strategy to design a high-affinity ligand toward lysosomal acid α-glucosidase (GAA) focusing on alkyl branches on 1-deoxynojirimycin (DNJ); 5-C-heptyl-DNJ produced a nanomolar affinity for GAA with a Ki value of 0.0047 µM, which is 13-fold more potent than DNJ. The protein thermal shift assay revealed that 10 µM 5-C-heptyl-DNJ increased the midpoint of the protein denaturation temperature (Tm) to 73.6 °C from 58.6 °C in the absence of the ligand, significantly improving the thermal stability of rhGAA. Furthermore, 5-C-heptyl-DNJ dose dependency increased intracellular GAA activities in Pompe patient's fibroblasts with the M519V mutation. The introduction of C5 alkyl branches on DNJ provides a new molecular strategy for pharmacological chaperone therapy for Pompe disease, which may lead to the development of higher-affinity and practically useful chaperones.

Post-traumatic rectourethral fistula in an adolescent managed via a transperineal approach using a local gluteal tissue interposition flap: a case report.

BACKGROUND: Rectourethral fistula is a rare disease with a wide variety of etiologies and clinical presentations. A definitive surgical procedure for rectourethral fistula repair has not been established. CASE PRESENTATION: A 13-year-old boy sustained a penetrating injury to the perineum, and developed a symptomatic rectourethral fistula thereafter. Conservative management through urinary diversion and transanal repair was unsuccessful. Fecal diversion with loop colostomy was performed, and three months later, a fistula repair was performed via a transperineal approach with interposition of a local gluteal tissue flap. There were no postoperative complications, and magnetic resonance imaging studies confirmed the successful closure of the fistula. The urinary and fecal diversions were reverted 1 and 6 months after the fistula repair, respectively, and postoperative excretory system complications did not occur. CONCLUSIONS: The transperineal approach with interposition of a local gluteal tissue flap provides a viable surgical option for adolescent patients with rectourethral fistulas who are unresponsive to conservative management.

Small intestinal mucosa-associated lymphoid tissue lymphoma with deep ulcer and severe stenosis: A case report.

INTRODUCTION: Although eosinophils are commonly present on the mucosa of the gastrointestinal tract, various pathological conditions may cause a secondary increase in eosinophil quantity. PRESENTATION OF CASE: A 78-year-old man was referred to our hospital due to abdominal pain. Examinations revealed an ulcerative lesion with white moss in the terminal ileum and severe stenosis on the oral and anal sides. Tissue biopsies obtained from the ulcer margins showed a predominance of chronic inflammatory cells and abundant eosinophils in addition to lymphocytes/plasma cells. Secondary causes of tissue eosinophilia were suspected; however, the diagnosis could not be confirmed because of atypical endoscopic findings. Partial resection of the ileum was performed for therapeutic and diagnostic purposes. Histopathology of the resected specimen identified a lymphoepithelial lesion with an invasive tendency. While CD20 staining was positive, MUM-1 and Bcl-6 staining were negative. Based on these findings, the lesion was diagnosed as a small intestinal mucosa-associated lymphoid tissue lymphoma (Lugano staging, stage II1). DISCUSSION: Hypereosinophilia in this lesion was suggested to be secondary to chronic inflammation due to tumor growth or impaired transit. CONCLUSION: There is a type of gastrointestinal MALT lymphoma showing an invasive tendency. In such cases, it may demonstrate atypical findings and hypereosinophilia in gastrointestinal tissues.

Ulcerative colitis-associated rectal cancer resected and diagnosed by rectovesical fistula: a case report.

Ulcerative colitis (UC), which mainly consists of mucosal lesions, rarely form colovesical or rectovesical fistulas, although few cases of fistula formation associated with comorbidities have been reported. We report a case of UC-associated rectal cancer diagnosed following symptoms associated with rectovesical fistula. A 40-year-old man with a 31-year history of extensive UC presented with difficulty in defecation. Two years before the current presentation, he had experienced pneumaturia, and the examination then had revealed a rectal neoplastic lesion and rectovesical fistula; however, tissue biopsy showed no malignancy. Therefore, he requested for observation with no further treatment. Current examination suggested the rectal tumor had grown to invade the bladder. Tissue biopsy showed no malignancy. However, the clinical symptoms and examination findings strongly indicated UC-associated rectal cancer with bladder invasion; thus, open total proctocolectomy with partial cystectomy was performed. Histopathological evaluation of the rectal neoplastic lesion revealed UC-associated rectal cancer originating from the inflammatory mucosa, and the rectovesical fistula was found to be caused by the rectal cancer invading the bladder. Therefore, other colorectal cancers should be considered even though tissue biopsy does not reveal malignant lesions in UC patients with fistula.

Improved Description and Efficient Implementation of Spin-Projected Perturbation Theory for Practical Applications.

In this study, we continue to develop the recently proposed second-order perturbation theory for the spin-projected Hartree-Fock method [Tsuchimochi, T.; Ten-no, S. L. J. Chem. Theory Comput. 2019, 15, 6688] in various aspects. A new, stable imaginary level-shift scheme is derived to obtain a well-conditioned equation, enabling a significantly faster convergence. To achieve a further speed-up, we propose a preconditioning scheme considering the pair character on a spin-projected basis. We also eliminate the computational memory bottleneck in solving the linear equation for large systems using a distributed memory parallel implementation. Finally, for the description of open-shell molecules, several modified zeroth-order Hamiltonians are introduced and tested using the Mn2O2(NHCHCO2)4 complex. These developments enable practical calculations of a second-order perturbation theory with improved accuracy at a reduced computational cost.

High incidence of postoperative silent venous thromboembolism in ulcerative colitis: a retrospective observational study.

BACKGROUND: The incidence of postoperative venous thromboembolism (VTE) is high in patients with inflammatory bowel disease. We aimed to analyze the incidence and predictive factors of postoperative VTE in patients with ulcerative colitis. METHODS: Patients with ulcerative colitis who underwent colon and rectum surgery during 2010-2018 were included. We retrospectively investigated the incidence of postoperative VTE. RESULTS: A total of 140 colorectal surgery cases were included. Postoperative VTE was detected in 24 (17.1 %). Portal-mesenteric venous thrombosis was the most frequent VTE (18 cases; 75 %); of these, 15 patients underwent total proctocolectomy (TPC) with ileal pouch-anal anastomosis (IPAA). In univariate analysis, VTE occurred more frequently in patients with neoplasia than in those refractory to medications (27.2 % vs. 12.5 %; p < 0.031). TPC with IPAA was more often associated with VTE development (28 %) than total colectomy (10.5 %) or proctectomy (5.9 %). On logistic regression analysis, TPC with IPAA, total colectomy, long operation time (> 4 h), and high serum D-dimer level (> 5.3 µg/mL) on the day following surgery were identified as predictive risk factors. CONCLUSIONS: Postoperative VTE occurred frequently and asymptomatically, especially after TPC with IPAA. Serum D-dimer level on the day after surgery may be a useful predictor of VTE.

Successful surgical procedure based on careful preoperative imaging for chronic idiopathic colonic pseudo-obstruction: a case report.

BACKGROUND: Chronic idiopathic colonic pseudo-obstruction (CICP) is a rare disease, defined as a condition of the chronically damaged colon, without obstruction or stenosis, and a pathological abnormality in the myenteric plexus. To date, there is no effective medication for CICP, and existing medication is not useful, making surgery the only effective treatment. Laparoscopic surgery is useful for reducing surgical trauma and postoperative adhesion. Herein, we report a patient with recurrent laxative-uncontrolled bowel obstruction, who underwent successful treatment with laparoscopic total colectomy based on preoperative detailed evaluation of bowel function. CASE PRESENTATION: A 77-year-old female patient without any past abdominal or psychological medical history was referred to our hospital because of chronic constipation and abdominal pain. Contrast-enhanced computed tomography, barium enema, cine magnetic resonance imaging, and defecography indicated an enlarged colon from the cecum to the transverse colon (proximal to the splenic flexure) without apparent mechanical obstruction, and a collapsed colon from the descending colon to the rectum, with reduced peristalsis. Bowel movements of the rectum and anorectal function were normal. Based on these findings, we diagnosed CICP and performed laparoscopic total colectomy and ileo-rectal anastomosis in this case. Postoperative recovery was good, without the need for postoperative laxatives. Pathologically, no degeneration of the muscle layers or Auerbach's plexus was found in the resected specimen. CONCLUSION: Surgery is the only effective treatment for patients with CICP. Careful imaging before surgery is important for detecting the extent of excision required. This will reduce the need for additional surgery due to symptom relapse in the remnant colon. However, continued observation of the patient is required.

[Locally Advanced Rectal Cancer Presenting with Perforation That Was Successfully Resected after Preoperative Chemotherapy with mFOLFOX6 plus Panitumumab].

We report a case of locally advanced rectal cancer presenting with perforation that was successfully resected after preoperative chemotherapy. A 66-year-old woman visited our emergency room complaining of lower abdominal pain. Abdominal CT showed a rectal tumor with fluid collection and free air in the pelvis. The patient was diagnosed with panperitonitis secondary to cancerous perforation and underwent sigmoid colostomy. A biopsy specimen of the rectal tumor showed well-differentiated tubular adenocarcinoma and wild-type RAS. After 8 courses of mFOLFOX6 plus panitumumab, the tumor shrank remarkably, and radical surgery(low anterior resection with D3 lymph node dissection)was performed. Microscopic examination of the resected specimen showed that almost half of the tumor cells were replaced by histiocytes and necrotic tissue. Preoperative chemotherapy with panitumumab may be an effective treatment for RAS wild-type locally advanced colon cancer, even if the primary tumor develops perforation.

[Nephrotic Syndrome Induced by Ramucirumab for Metastatic Rectal Cancer].

We report a case of nephrotic syndrome induced by ramucirumab for metastatic rectal cancer. A 48-year old woman who had received FOLFIRI plus ramucirumab for rectal cancer with liver, lung, and bone metastases presented to our hospital with edema and increased body weight. Laboratory studies showed hypoalbuminemia and severe proteinuria, and the patient was diagnosed with nephrotic syndrome. After administration of an angiotensin II receptor blocker and thiazide diuretic, her symptoms disappeared and serum albumin level normalized. To the best of our knowledge, this is the first detailed report of nephrotic syndrome related to ramucirumab. This case serves to emphasize that the possibility of nephrotic syndrome should be considered during anti-vascular endothelial growth factor therapy.

Pure Cusp Tear of Trifecta Bioprosthesis 2 Years after Aortic Valve Replacement.

Trifecta is a stented bioprosthetic heart valve with a bovine pericardial sheet externally mounted on a titanium stent. This valve is applied only for aortic valve replacement (AVR), providing excellent hemodynamics and extremely low incidence of structural valve deterioration (SVD). A 76-year-old woman presented with dyspnea on effort 24 months after AVR with a 21-mm Trifecta valve. Echocardiography revealed severe aortic regurgitation with prolapse of a cusp of Trifecta valve, which suggested that she developed acute heart failure due to early SVD. In the operation, Trifecta valve had a cusp tear near the commissure with circumferential fibrous pannus ingrowth only at the inflow side. There was neither calcification nor infection. The Trifecta valve was successfully replaced with a new porcine bioprosthesis.