Phase I and pharmacologic study of oral (E)-2′-deoxy-2′-(fluoromethylene) cytidine: on a daily × 5-day schedule

(E)-2-deoxy-2-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3–4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.     

Histogenesis and clinicopathological characteristics of superficially spreading carcinoma of the esophagus

To explore the possible histogenesis of superficially spreading carcinoma of the esophagus, the clinicopathological features of these tumors (n = 44) were compared with those of ordinary superficial carcinoma (n = 163). Tumors of a heterogeneous histological type and having in situ carcinoma components were significantly more common (P < .05), and the number of residual squamous islands was significantly greater (P < 0.05) in the former group than the latter. Furthermore, the tumor size was not different among in situ, intramucosal, and submucosal carcinomas of the former, whereas the tumors became larger according to the depth of invasion in the latter group. These results indicate that the collision of multiple simultaneously developing superficial tumors is a plausible histogenesis of superficially spreading carcinoma of the esophagus.     

Gallbladder carcinoma presenting as exfoliative dermatitis (erythroderma)

Although exfoliative dermatitis (erythroderma) secondary to malignancy is commonly associated with lymphomas or leukemias, coincident gastrointestinal (GI) malignancy and erythroderma is rare. The authors recently encountered a patient with gallbladder carcinoma presenting as erythroderma. A 77-yr-old Japanese man presented with a 3-mo history of erythematous eruptions with pruritus over almost the entire body. After confirming the diagnosis of erythroderma, asymptomatic gallbladder carcinoma was found. Further investigations detected no malignancies in other organs. An extended cholecystectomy was performed. Histologic examination of resected specimens revealed poorly differentiated adenocarcinoma with negative resection margins. The eruptions with pruritus resolved within 1 wk after the operation. This is the first report, to our knowledge, of coincident biliary malignancy and erythroderma. The experience of the current patient suggests that erythroderma secondary to GI malignancy may resolve spontaneously after curative resection of the tumor.     

Formulas for fetal weight estimation by ultrasound measurements based on neonatal specific gravities and volumes

To improve the accuracy of fetal weight estimation by ultrasound measurement, especially in low birth weight infants, including those with intrauterine growth retardation, two new formulas were developed from a new point of view. The formulas were established by (1) actual measurements of the volumes of the neonatal head and trunk with limbs, (2) analysis of the relationship between the sizes of the parts of the fetal body measured by ultrasound examination before birth and the volumes of the parts of the neonatal body, and (3) calculation of the specific gravities of the parts of the neonatal body. The prospective study showed a high correlation between estimated weights and actual birth weights with a small range of error in infants weighing between 450 and 4800 gm.     

Effectiveness of a new triple-row circular stapler in reducing the risk of colorectal anastomotic leakage: A historical control and propensity score–matched study

Anastomotic leakage (AL) after colorectal surgery is a serious complication. This study aimed to evaluate the effectiveness of the EEA™ circular stapler, a new triple-row circular stapler (TCS), relative to a conventional, double-row circular stapler (DCS).A total of 285 patients who underwent anastomosis with the double stapling technique at the Tokyo Medical University Hospital between 2017 and 2021 were included in this nonrandomized clinical trial with historical controls using a propensity score (PS) analysis. The primary endpoint was the risk of AL.We performed a 1:2 PS matching analysis. Before case matching, AL occurred in 15 (7.4%) and 2 (2.4%) patients in the DCS and TCS groups, respectively, with no significant difference (P = .17). After case matching, AL occurred in 13 patients (11.6%) and 1 patient (1.8%) in the DCS and TCS groups, respectively, revealing a significant difference (P = .04). Cox models were created by applying PS to adjust for group differences via regression adjustment. Odds ratios for AL in the DCS group versus the TCS group were 0.31 (95% confidence interval [CI]: 0.07–1.38) in the entire cohort, 0.15 (95% CI: 0.02–0.64) in the regression adjustment cohort, and 0.14 (95% CI: 0.02–1.09) in the 1:2 PS-matched cohort.PS analysis of clinical data suggested that the use of TCS contributes to a reduced risk of AL after colorectal anastomosis CTwith the double stapling technique.     

Proteome analysis of human placentae: pre-eclampsia versus normal pregnancy

Although placental proteins play multiple roles in fetal and placental development and in the maintenance of pregnancy, many remain inadequately characterized. In the present study, we comprehensively analyzed these proteins by using a proteomic approach. Samples were denatured with guanidine hydrochloride, which was found to be superior to the commonly used urea for the present purpose, and subjected to 2-dimensional (2D) electrophoresis (2-DE) to obtain placental proteome maps. The identified protein spots (ca. 60% of the total) on the proteome maps included several pregnancy-related proteins (PRPs). Furthermore, a novel 2D immunoblotting (2-DI) analysis of molecules related to pre-eclampsia revealed three immunopositive spots that appeared to correspond to dynactin p-50, a protein related to cell turn-over. The rate of positivity for dynactin p-50-reactive antibodies was significantly (P=0.0024) higher in 26 pre-eclamptic women than in 58 normally pregnant women. These results indicate that dynactin p-50 may be involved in the pathophysiology of pre-eclampsia.     

Application of a Machine Learning Algorithm for Structural Brain Images in Chronic Schizophrenia to Earlier Clinical Stages of Psychosis and Autism Spectrum Disorder: A Multiprotocol Imaging Dataset Study

Background and HypothesisMachine learning approaches using structural magnetic resonance imaging (MRI) can be informative for disease classification; however, their applicability to earlier clinical stages of psychosis and other disease spectra is unknown. We evaluated whether a model differentiating patients with chronic schizophrenia (ChSZ) from healthy controls (HCs) could be applied to earlier clinical stages such as first-episode psychosis (FEP), ultra-high risk for psychosis (UHR), and autism spectrum disorders (ASDs).Study DesignTotal 359 T1-weighted MRI scans, including 154 individuals with schizophrenia spectrum (UHR, n = 37; FEP, n = 24; and ChSZ, n = 93), 64 with ASD, and 141 HCs, were obtained using three acquisition protocols. Of these, data regarding ChSZ (n = 75) and HC (n = 101) from two protocols were used to build a classifier (training dataset). The remainder was used to evaluate the classifier (test, independent confirmatory, and independent group datasets). Scanner and protocol effects were diminished using ComBat.Study ResultsThe accuracy of the classifier for the test and independent confirmatory datasets were 75% and 76%, respectively. The bilateral pallidum and inferior frontal gyrus pars triangularis strongly contributed to classifying ChSZ. Schizophrenia spectrum individuals were more likely to be classified as ChSZ compared to ASD (classification rate to ChSZ: UHR, 41%; FEP, 54%; ChSZ, 70%; ASD, 19%; HC, 21%).ConclusionWe built a classifier from multiple protocol structural brain images applicable to independent samples from different clinical stages and spectra. The predictive information of the classifier could be useful for applying neuroimaging techniques to clinical differential diagnosis and predicting disease onset earlier.     

Treatment Options for Patellofemoral Arthritis

Purpose of ReviewTo present a synthesis of recent literature regarding the treatment of patellofemoral arthritisRecent FindingsRisk factors of PFJ OA include patella malalignment or maltracking, injury to supportive structures including the MPFL, dysfunction of hamstring and quadriceps coordination, lower limb alignment, trochlear dysplasia, patellar trauma, or ACL surgery. Special physical exam maneuvers include patellar grind test, apprehension test, and lateral patellar tilt angle. Radiographs that should be obtained first-line include weight bearing bilateral AP, lateral, and Merchant views. CT and MRI are used to assess trochlear dysplasia, excessive patellar height, and TT-TG distance. Non-operative management options discussed include non-pharmacologic treatment (patient education, self-management, physical therapy, weight loss), ESWT, cold therapy, taping, bracing, and orthotics. Pharmacologic management options discussed include NSAIDs, acetaminophen, oral narcotics, and duloxetine. Injection therapies include glucocorticoids, hyaluronic acid, PRP, and other regenerative therapies (BMAC, adipose, or mesenchymal stem cells). Other treatment options include radiofrequency ablation and botulinum toxin. The algorithm for the surgical treatment of PFJ OA can begin with arthroscopic assessment of the PF articular cartilage to address mechanical symptoms and to evaluate/treat lateral soft tissue with or without overhanging lateral osteophytes. If patients fail to have symptomatic improvement, a TTO can be considered in those patients less than 50 years of age or active patients >50 years old. In patients with severe PFJ OA, refractory to the above treatments, PFA should be considered. While early PFA design and technique were less than encouraging, more recent implant design and surgical technique have demonstrated robust results in the literature.SummaryPatellofemoral osteoarthritis is a challenging orthopedic problem to treat, in that it can often affect younger patients, with otherwise well-functioning knees. It is a unique entity compared to TF OA with distinct epidemiology, biomechanics and risk factors and treatment options.     

Comparative study of functional outcomes of three laparoscopic intestinal surgical procedures

ObjectivesLaparoscopic abdominal surgery (LS) has been prevailing over open surgery (OS). However, its functional outcomes in the aging generation have not been sufficiently examined. We compared changes in physical status and earlier resumption of oral intake between LS and OS.MethodsUsing the Japanese administrative database, we matched variables affecting LS and compared them between LS and OS patients. During the 6-month period from July to December of 2006–2010, we examined the data from data from surviving patients of ≥15 year old who underwent isolated gastrectomy, colectomy, or anterior resection. Functional status was estimated by the Barthel index (BI) at admission and discharge. Outcomes were postoperative complications, BI deterioration, change in BI, and day of recommencing postoperative oral intake.ResultsWe identified 30,763 gastrectomies (laparoscopic: 7297), 31,958 colectomies (laparoscopic: 9364), and 12,545 anterior resections (laparoscopic: 4351). Variation in LS indications was observed in patient and hospital mixes. Among the paired-matched gastrectomy, colectomy, and anterior resection groups, LS was associated with fewer complications and earlier recovery of postoperative oral intake. Laparoscopic anterior resection (LAR) and colectomy were associated with less frequent BI deterioration. Longer operative time was associated with more complications, which then influenced BI deterioration in patients who underwent anterior resection.ConclusionsShorter operative time for LAR was associated with less functional deterioration than for laparoscopic gastrectomy and colectomy. Physicians should consider the appropriate indications for LS by concurrently avoiding unnecessary longer operations and their associated complications. More investment in teaching the skills necessary for LAR is recommended.     

Angiographic and intravascular ultrasound findings of the late catch-up phenomenon after intracoronary beta-radiation for the treatment of in-stent restenosis

We report one-year angiographic and intravascular ultrasound (IVUS) outcomes of in-stent restenosis (ISR) patients treated with intravascular brachytherapy (IVBT). The benefit of IVBT for treating ISR is well documented. However, few data exist on significant angiographic and intravascular ultrasonic in-stent lumen deterioration beyond the habitual 6-month analysis after the index radiation procedure or so-called late catch-up process in the treatment of ISR. Twenty-five consecutive patients with ISR were treated with IVBT using the Beta-Cath System (a 40 mm 90 Sr per 90 gamma source). Quantitative angiographic and IVUS analysis was performed in all of them at 6 and 12 months. IVBT was successful in all patients. Four patients (16%) developed recurrent angiographic binary restenosis at 6-month follow-up, all located within the adjacent reference segments, with 2 being associated with geographical miss. An additional 4 patients (16%) presented with recurrent ISR at 12-month follow-up, all within the stented segment. Significant in-stent lumen loss (0.16 +/- 0.42 mm to 0.34 +/- 0.46 mm; p = 0.008) and in-stent intimal hyperplasia growth (+11.2 +/- 0.48 mm3; p = 0.03) was observed between 6 and 12 months. Intracoronary beta-radiation for the treatment of ISR was associated with significant luminal deterioration (late catch-up) within the stents between 6 and 12 months due to an important late progression of in-stent intimal hyperplasia.