Feasibility of transanal minimally invasive surgery for total pelvic exenteration for advanced primary and recurrent pelvic malignancies.

BACKGROUND: The purpose of this study was to clarify the efficacy and safety of transanal minimally invasive surgery (TAMIS) for total pelvic exenteration (TPE) in advanced primary and recurrent pelvic malignancies. METHODS: Using a prospectively collected database, we retrospectively analyzed the clinical, surgical, and pathological outcomes of TAMIS for TPE. Surgery was performed between September 2019 and April 2023. The median follow-up period was 22 months (2-45 months). RESULTS: Fifteen consecutive patients were included in this analysis M:F = 14:1 and median (range) age was 63 (36-74). Their diagnoses were as follows: primary rectal cancer (n = 5; 33%), recurrent rectal cancer (n = 4; 27%), primary anorectal cancer (n = 5; 33%), and gastrointestinal stromal tumor (n = 1; 7%). Bladder-sparing TPE was selected for two patients (13%). In nine of 15 patients (60%) the anal sphincter could be successfully preserved, five patients (33%) required combined resection of the internal iliac vessels, and two (13%) required rectus muscle flap reconstruction. The median operative time was 723 min (561-1082), and the median intraoperative blood loss was 195 ml (30-1520). The Clavien-Dindo classifications of the postoperative complications were as follows: grade 0-2 (n = 11; 73%); 3a (n = 3; 20%); 3b (n = 1; 7%); and ≥ 4 (n = 0; 0%). No cases of conversion to laparotomy or mortality were observed. The pathological results demonstrated that R0 was achieved in 14 patients (93%). CONCLUSIONS: The short-term outcomes of this initial experience proved that this novel approach is feasible for TPE, with low blood loss, acceptable postoperative complications, and a satisfactory R0 resection rate.

Tongue Muscle for the Analysis of Head Muscle Regeneration Dynamics.

Tongue muscle damage impairs speaking and eating, thereby degrading overall health and quality of life. Skeletal muscles of the body are diverse in embryonic origin, anatomic location, and gene expression profiles. Responses to disease, atrophy, aging, or drugs vary among different muscles. Currently, most muscle studies are focused on limb muscles and the tongue is neglected. The regenerative ability of tongue muscle remains unknown, and thus there is need for tongue muscle research models. Here, we present a comprehensive characterization of the spatiotemporal dynamics in a mouse model of tongue muscle regeneration and establish a method for the isolation of primary tongue-derived satellite cells. We compare and contrast our observations with the tibialis anterior (TA) limb muscle. Acute injury was induced by intramuscular injection of cardiotoxin, a cytolytic agent, and examined at multiple timepoints. Initially, necrotic myofibers with fragmented sarcoplasm became infiltrated with inflammatory cells. Concomitantly, satellite cells expanded rapidly. Seven days postinjury, regenerated myofibers with centralized nuclei appeared. Full regeneration, as well as an absence of fibrosis, was evident 21 d postinjury. Primary tongue-derived satellite cells were isolated by enzymatic separation of tongue epithelium from mesenchyme followed by magnetic-activated cell sorting. We observed that tongue displays an efficient regenerative response similar to TA but with slightly faster kinetics. In vitro, tongue-derived satellite cells differentiated robustly into mature myotubes with spontaneous contractile behavior and myogenic marker expression. Comparison of gene expression signatures between tongue and TA-derived satellite cells revealed differences in the expression of positional-identity genes, including the HOX family. In conclusion, we have established a model for tongue regeneration useful for investigations of orofacial muscle biology. Furthermore, we showed that tongue is a viable source of satellite cells with unique properties and inherited positional memory.

Cerebrospinal fluid orexin-A levels in systemic lupus erythematosus patients presenting with excessive daytime sleepiness.

Objective Involvement of the hypothalamus is rare in patients with systemic lupus erythematosus (SLE). In this study, we measured cerebrospinal fluid (CSF) orexin-A levels in SLE patients with hypothalamic lesions to investigate whether the orexin system plays a role in SLE patients with hypothalamic lesions who present with excessive daytime sleepiness (EDS). Methods Orexin-A levels were measured in CSF from four patients with SLE who presented with hypothalamic lesions detected by MRI. Three patients underwent repeated CSF testing. All patients met the updated American College of Rheumatology revised criteria for SLE. Results Tests for serum anti-aquaporin-4 antibodies, CSF myelin basic protein and CSF oligoclonal bands were negative in all patients. All patients presented with EDS. Low to intermediate CSF orexin-A levels (92-180 pg/ml) were observed in three patients in the acute stage, two of whom (patients 1 and 2) underwent repeated testing and showed increased CSF orexin-A levels, reduced abnormal hypothalamic lesion intensities detected by MRI and EDS dissipation at follow-up. In contrast, CSF orexin-A levels were normal in one patient (patient 4) while in the acute stage and at follow-up, despite improvements in EDS and MRI findings. Patient 4 showed markedly increased CSF interleukin-6 levels (1130 pg/ml) and a slightly involved hypothalamus than the other patients. Conclusions Our findings suggest that the orexinergic system has a role in EDS in SLE patients with hypothalamic lesions. Furthermore, cytokine-mediated tissue damage might cause EDS without orexinergic involvement.

Simultaneous detection of ABL1 mutation and IKZF1 deletion in Philadelphia chromosome-positive acute lymphoblastic leukemia using a customized target enrichment system panel.

INTRODUCTION: Recent clinical outcomes of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) vastly improved owing to tyrosine kinase inhibitor (TKI). However, the genetic status would be different in each case with ABL1 gene mutation or copy number variants (CNVs) such as IKZF1 deletion. In particular, the TKI resistant clone with ABL1 kinase mutation remains problematic. The comprehensive assessment of genetic status including mutation, insertion and deletion (indel) and CNVs is necessary. METHODS: We evaluated a next-generation sequencing (NGS)-based customized HaloPlex target enrichment system panel to simultaneously detect coding mutations, indel and CNVs. We analysed approximately 160 known genes associated with hematological disorders in 5 pediatric Ph+ALL patients. RESULTS: Mono-allelic IKZF1 deletions were found in 4 patients at diagnosis. Furthermore, the mono-allelic deletions were found in exons of RB1, EBF1, PAX5 and ETV6 genes. Bi-allelic deletions were detected in CDKN2A and CDKN2B genes in 1 patient. ABL1 mutation was also detected in 1 patient at relapse. These results were almost comparable with the results of the multiplex ligation-dependent probe amplification (MLPA) method or Sanger sequence. CONCLUSION: Next-generation sequencing-based custom HaloPlex target enrichment system panel allows us to detect the coding mutations, indel, and CNVs in pediatric Ph+ALL simultaneously, and its results seem comparable with those of other methods.

Prognostic significance of preoperative inflammatory response biomarkers in patients undergoing curative thoracoscopic esophagectomy for esophageal squamous cell carcinoma.

BACKGROUND: Recent studies have revealed significant relationships between the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) and survival in various cancers. The purpose of this study was to confirm whether the LMR, NLR, and PLR have prognostic values, independent of clinicopathological criteria, in patients undergoing curative resection for esophageal cancer. METHODS: The LMR, NLR and PLR were calculated in 147 consecutive patients who underwent curative esophagectomy between January 2006 and December 2014. Receiver operating characteristics (ROC) curve analysis was conducted to identify the optimal cutoff values of each biomarkers. RESULTS: In multivariate analysis for cancer-specific survival (CSS), pTNM stage (p < 0.0001) and low LMR (p = 0.0081) were selected as independent prognostic factor. Similarly, pTNM stage(p < 0.0001) and low LMR (p = 0.0225) were found to be independent prognostic factor for overall survival (OS). There was no significant relationship between LMR, NLR and PLR and survival in patients with stage I or II, however, significant relationships between LMR and CSS or OS were observed in patients with stage III esophageal cancer. CONCLUSIONS: LMR can be used as a novel predictor of postoperative CSS and OS in patients with esophageal cancer and that it may be useful in identifying patients with a poor prognosis even after radical esophagectomy.

Impact of inflammation-based prognostic score on survival after curative thoracoscopic esophagectomy for esophageal cancer.

BACKGROUND: Despite recent improvements in early detection, progress in surgical techniques, and development of chemoradiation therapies, prognosis of esophageal cancer remains poor. The aim of the present study was to assess whether Glasgow Prognostic Score (GPS), an inflammation-based prognostic score, has prognostic value independent of conventional clinicopathological criteria in patients undergoing curative resection for esophageal cancer, even in elderly patients. METHODS: We retrospectively reviewed the database of 141 consecutive patients with histologically verified esophageal squamous cell carcinoma who underwent potentially curative surgery in our institute, between January 2006 and December 2014. GPS and neutrophil lymphocyte ratio (NLR) were calculated. RESULTS: On multivariate analysis, TNM stage (p < 0.0001) and GPS (p = 0.041) were independently associated with worse prognosis in overall patients with esophageal cancer. Multivariate analysis evaluated the prognostic factors in two different patient groups: patients younger than 70 years (non-elderly) and those aged 70 years or more (elderly). Multivariate analysis demonstrated that TNM stage (p = 0.0003) was an only independent risk factor for a worse prognosis among non-elderly group. Meanwhile, multivariate analysis demonstrated that TNM stage (p = 0.001) and GPS (p = 0.043) were the independent risk factor for a worse prognosis among elderly group. CONCLUSION: The present study demonstrated that GPS is associated with prognosis and can be considered as an independent prognostic marker in patients who underwent esophagectomy. Moreover, the GPS has the advantage of being simple to measure, routinely available and well standardized. But the present study failed to confirm the NLR as a significant predictor of survival following resection for esophageal cancer.

The value of the high-sensitivity modified Glasgow prognostic score in predicting the survival of patients with a soft-tissue sarcoma.

The aim of this study was to determine whether the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) could predict the disease-specific survival and oncological outcome in adult patients with non-metastatic soft-tissue sarcoma before treatment. A total of 139 patients treated between 2001 and 2012 were retrospectively reviewed. The Hs-mGPS varied between 0 and 2. Patients with a score of 2 had a poorer disease-specific survival than patients with a score of 0 (p < 0.001). The estimated five-year rate of disease-specific survival for those with a score of 2 was 0%, compared with 85.4% (95% CI 77.3 to 93.5) for those with a score of 0. Those with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (75.3%, 95% CI 55.8 to 94.8; p < 0.001). Patients with a score of 2 also had a poorer event-free rate than those with a score of 0 (p < 0.001). Those with a score of 2 also had a poorer event-free survival than did those with a score of 1 (p = 0.03). A multivariate analysis showed that the Hs-mGPS remained an independent predictor of survival and recurrence. The Hs-mGPS could be a useful prognostic marker in patients with a soft-tissue sarcoma.

Droplet digital PCR measurement of HER2 in patients with gastric cancer.

BACKGROUND: Although there are some new criteria for human epidermal growth factor receptor 2 (HER2) expression with immunohistochemistry/fluorescence in situ hybridisation (IHC/FISH) in gastric cancer, the method is still ambiguous and is somewhat dependent on the subjective qualities of the evaluator. METHODS: We used droplet digital polymerase chain reaction (ddPCR) to evaluate HER2 amplification in formalin-fixed and paraffin-embedded (FFPE) samples and cell-free serum circulating tumour DNA (ctDNA) in 25 patients with gastric cancer. RESULTS: The concordance rate of HER2 amplification examined in FFPE samples with ddPCR and IHC/FISH was 92% (23 out of 25). The concordance rate of FFPE with ctDNA was not high (62.5%); however, patients who were HER2-positive by ctDNA had significantly shorter survival compared with HER2-negative patients. CONCLUSIONS: Our results demonstrated that this ddPCR method was as effective as IHC/FISH and therefore might become a standard method for analysing not only FFPE but also ctDNA.

An automated method for detecting architectural distortions on mammograms using direction analysis of linear structures.

Architectural distortion is one of the most important findings when evaluating mammograms for breast cancer. Abnormal breast architecture is characterized by the presence of spicules, which are distorted mammary structures that are not accompanied by an increased density or mass. We have been developing an automated method for detecting spiculated architectural distortions by analyzing linear structures extracted by normal curvature. However, some structures that are possibly related to distorted areas are not extracted using this method. The purpose of this study was to develop a new automated method for direction analysis of linear structures to improve detection performance in mammography. The direction of linear structures in each region of interest (ROI) was first determined using a direction filter and a background filter that can define one of eight directions (0°, 22.5°, 45°, 67.5°, 90°, 112.5°, 135°, and 157.5°). The concentration and isotropic indexes were calculated using the determined direction of the linear structures in order to extract the candidate areas. Discriminant analysis was performed to eliminate false positives results. Our database consisted of 168 abnormal images containing 174 distorted areas and 580 normal images. The sensitivity of the new method was 81%. There were 2.6 and 4.2 false positives per image using the new and previous methods, respectively. These findings show that our new method is effective for detecting spiculated architectural distortions.

Acute pericardial effusion representing the TNF-α-mediated severe inflammation but not the coronary artery outcome of Kawasaki disease.

OBJECTIVES: To establish the optimal inflammation control of Kawasaki disease (KD), we investigated the clinical and pathophysiological basis of pericardial effusion (PE) during the acute phase of KD. METHOD: Clinical and laboratory features of Japanese KD children with PE (PE group: n = 9) and without PE (non-PE group: n = 89) were studied retrospectively by using the medical records. Serum levels of soluble tumour necrosis factor receptor 1 (sTNFR1), interleukin 6 (IL-6), and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assays (ELISAs). RESULTS: PE group patients had coronary artery lesions (CALs) more frequently than non-PE group patients during the acute phase of KD (33% vs. 5.6%, p = 0.024). PE patients also showed lower levels of haemoglobin (p < 0.01) and serum albumin (p < 0.01) and higher platelet counts (p = 0.013) than non-PE patients. The proportion of neurological symptoms, but not other manifestations, in the PE group was higher than in the non-PE group (p = 0.022). All patients survived free from coronary artery aneurisms. Serum levels of sTNFR1, but not the other cytokines, in the PE group were higher than those in the non-PE group (p < 0.001). The sTNFR1 levels correlated positively with C-reactive protein (CRP) (r = 0.30, p = 0.019) or total bilirubin (r = 0.40, p < 0.01) levels. CONCLUSIONS: Acute PE in KD patients indicated the severity of TNF-mediated vascular inflammation and concurrent CALs. According to the progression, these patients might need more targeted therapy of anti-inflammation for a better coronary outcome.

Pregnancy in women with a history of Kawasaki disease: management and outcomes.

OBJECTIVE: To characterise the obstetrical management and outcomes in a series of women with a history of Kawasaki disease (KD) in childhood. DESIGN: Retrospective case series. SETTING: Tertiary healthcare setting in the USA. POPULATION: Women with a history of KD in childhood. METHODS: Women completed a detailed health questionnaire and participated in research imaging studies as part of the San Diego Adult KD Collaborative Study. MAIN OUTCOME MEASURES: Obstetrical management, complications during pregnancy and delivery, and infant outcomes. RESULTS: Ten women with a history of KD in childhood carried a total of 21 pregnancies to term. There were no cardiovascular complications during labour and delivery despite important cardiovascular abnormalities in four of the ten subjects. Pregnancy was complicated by pre-eclampsia and the post-partum course was complicated by haemorrhage in one subject each. Two of the 21 progeny subsequently developed KD. CONCLUSIONS: Women with important cardiovascular sequelae from KD in childhood should be managed by a team that includes both a maternal-fetal medicine specialist and a cardiologist. Pre-pregnancy counselling should include delineation of the woman's current functional and structural cardiovascular status and appropriate adjustment of medications, but excellent outcomes are possible with appropriate care. Review of the English and Japanese literature on KD and pregnancy revealed the occurrence of myocardial infarction during pregnancy in women with missed KD and aneurysms that were not diagnosed until their acute event. Our study highlights the need for counselling with regard to the increased genetic risk of KD in offspring born to these mothers.

Deep-vein thrombosis after resection of musculoskeletal tumours of the lower limb.

The aim of this study was to define the incidence of venous thromboembolism (VTE) and risk factors for the development of deep-vein thrombosis (DVT) after the resection of a musculoskeletal tumour. A total of 94 patients who underwent resection of a musculoskeletal tumour between January 2003 and December 2005 were prospectively studied. There were 42 men and 52 women with a mean age of 54.4 years (18 to 86). All patients wore intermittent pneumatic compression devices and graduated compression stockings. Ultrasound examination of the lower limbs was conducted to screen for DVT between the fifth and ninth post-operative days. DVT was detected in 21 patients (22%). Of these, two were symptomatic (2%). One patient (1%) had a fatal pulmonary embolism. Patients aged ≥ 70 years had an increased risk of DVT (p = 0.004). The overall incidence of DVT (both symptomatic and asymptomatic) after resection of a musculoskeletal tumour with mechanical prophylaxis was high. It seems that both mechanical and anticoagulant prophylaxis is needed to prevent VTE in patients who have undergone the resection of a musculoskeletal tumour.

Effect of reaction pH and CuSO4 addition on the formation of catechinone due to oxidation of (+)-catechin.

A novel hair dyeing technique being milder and safer for a human body is desired. The oxidation product of (+)-catechin, catechinone, was invented as a safer dyestuff for hair colouring under such the situation. The preparation of catechinone by a chemical oxidation is a practical way and the objective of the study is clarify the effect of the solution pH and in the presence or absence of Cu(2+) on the formation rate and yield of catechinone in order to improve the efficiency of the dye formation. The catechinone formation was monitored by ultraviolet-visible spectroscopy. Catechinone was prepared chemically from (+)-catechin in aqueous solution with O2 gas introduced over a pH range of 7.1-11.7. The rate and amount of the dye formation increase with increasing pH. Dissociation of the hydroxyl group of the catechol part of (+)-catechin is significant for the oxidation of (+)-catechin and promotes the dye production. This is because the deprotonated (+)-catechin has a higher reactivity with O2 . The production of catechinone is accelerated by the addition of CuSO4 and the production rate reaches the maximum at pH = 8.8. (+)-Catechin - Cu(2+) complexes are formed and the formation promotes the oxidation of the catechol part of (+)-catechin at pH ≤ 8.8. On the other hand, the complex becomes too stable to proceed for the oxidation reaction at pH > 8.8.

Impact of diabetes and glycaemic control on peripheral artery disease in Japanese patients with end-stage renal disease: long-term follow-up study from the beginning of haemodialysis.

AIMS/HYPOTHESIS: End-stage renal disease (ESRD) patients with diabetes have been regarded as being at the highest risk of cardiovascular disease. We therefore investigated the relationship between diabetes and the incidence of peripheral artery disease (PAD) in new haemodialysis patients. METHODS: We enrolled 1,513 ESRD patients who had just begun haemodialysis therapy. They were divided into two groups: those with (n = 739) and those without diabetes (n = 774). The endpoint was the development of PAD, defined as ankle brachial pressure index ≤ 0.9 or toe brachial pressure index <0.7 in patients with an ankle brachial pressure index >0.9. RESULTS: According to the Kaplan-Meier method, the 10 year event-free rate for development of PAD and lower limb amputation was significantly lower in the diabetes group than in the non-diabetes group (60.3% vs 82.8%, HR 2.99, 95% CI 2.27, 3.92, p<0.0001 and 93.9% vs 98.9%, HR 5.59, 95% CI 2.14, 14.7, p = .0005 for PAD and lower limb amputation, respectively). In patients with diabetes, quartile analysis of HbA1c levels showed that the highest quartile group (≥ 6.8% [51 mmol/mol]) had significant development of PAD and lower limb amputation compared with lower quartile groups (PAD HR 1.63, 95% CI 1.17, 2.28, p = .0038; lower limb amputation HR 2.99, 95% CI 1.17, 7.70, p = .023). CONCLUSIONS/INTERPRETATION: Diabetes was a strong predictor of PAD after initiation of haemodialysis therapy in patients with ESRD. In addition, higher HbA1c levels were associated with increased risk of developing PAD and requiring limb amputation in such diabetic populations.

Relationship between periodontal status and levels of glycated hemoglobin.

The objective of this study was to assess whether there is a bi-directional relationship between periodontal status and diabetes. Study 1 included 5,856 people without periodontal pockets of ≥ 4 mm at baseline. Relative risk was estimated for the 5-year incidence of periodontal pockets of ≥ 4 mm (CPI scores 3 and 4, with the CPI probe), in individuals with glycated hemoglobin (HbA1c) levels of ≥ 6.5% at baseline. Study 2 included 6,125 people with HbA1c < 6.5% at baseline. The relative risk was assessed for elevation of HbA1c levels in 5 years, with baseline periodontal status, assessed by CPI. Relative risk of developing a periodontal pocket was 1.17 (p = 0.038) times greater in those with HbA1c of ≥ 6.5% at baseline, adjusted for body mass index (BMI), smoking status, sex, and age. Relative risks for having HbA1c ≥ 6.5% at 5-year follow-up in groups with periodontal pockets of 4 to 5 mm and ≥ 6 mm at baseline were 2.47 (p = 0.122) and 3.45 (p = 0.037), respectively, adjusted for BMI, alcohol consumption, smoking status, sex, and age. The risk of developing periodontal disease was associated with levels of HbA1c, and the risk of elevations of HbA1c was associated with developing periodontal pockets of more than 4 mm.

Transfection of NF-κB decoy oligodeoxynucleotide suppresses pulmonary metastasis by murine osteosarcoma.

Nuclear factor-kappa B (NF-κB) has a pivotal role in the progression and distant metastasis of cancers, including malignant bone tumors. To inhibit NF-κB activation, a new molecular therapy using synthetic double-stranded oligodeoxynucleotide (ODN) as a 'decoy' cis element against NF-κB has been developed. To determine whether pulmonary metastasis of osteosarcoma is reduced by inhibiting the action of NF-κB, NF-κB decoy ODN was transfected into the nuclei of murine osteosarcoma cells with high pulmonary metastatic potential, the LM8 cell line, using a three-dimensional alginate spheroid culture model. An in vitro study demonstrated the successful transfection of LM8 cells cultured in alginate beads by 'naked' NF-κB decoy ODN and that the activation of NF-κB signaling was significantly suppressed. Tumor growth was not affected by transfection of NF-κB decoy ODN, however, the expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule 1 (ICAM-1) mRNA was markedly decreased. Furthermore, the transfection of 'naked' NF-κB decoy ODN effectively suppressed pulmonary metastasis in an in vivo alginate bead transplantation model. Our results suggest that NF-κB has a central and specific role in the regulation of tumor metastasis and could be a molecular target for development of anti-metastatic treatments for osteosarcoma.

Photodynamic therapy with acridine orange in musculoskeletal sarcomas.

Limb salvage involving wide resection and reconstruction is now well established for managing musculoskeletal sarcomas. However, involvement of major nerves and vessels with a large volume of muscle and skin may result in a useless limb, contributing to depression and a low quality of life. We have been studying alternative treatments for musculoskeletal sarcoma since 1990, and have recently established a regime using photodynamic surgery with cells labelled with acridine orange, photodynamic therapy with cells treated similarly and radiodynamic treatment using the effect of X-rays on such cells. These techniques have been used after marginal or intralesional resection of tumours since 1999 and have enabled maintenance of excellent limb function in patients with sarcomas.