Yoshinori Fujiwara

Successful Chemotherapeutic Modality of Doxorubicin Plus Dacarbazine for the Treatment of Desmoid Tumors in Association With Familial Adenomatous Polyposis

PURPOSE Desmoid tumors are locally aggressive and can be fatal in familial adenomatous polyposis (FAP) patients if they are not suitable for surgery or radiation therapy. Here, we prospectively investigated the efficacy of a chemotherapeutic regimen involving doxorubicin (DOX) and dacarbazine (DTIC) for inoperable FAP-associated desmoid tumors. PATIENTS AND METHODS From an initial group of 120 FAP patients, seven of the 11 individuals with symptomatic unresectable desmoid tumors that were unresponsive to conventional hormone therapy were enrolled onto this study. The general chemotherapy regimen comprised four or five cycles of DOX (20 mg/m2 daily) plus DTIC (150 mg/m2 daily) throughout 4 days of drip intravenous infusion (day 1 through 4) every 28 days, followed by the cyclooxygenase-2 inhibitor meloxicam (10 mg/m2). The primary end point was relapse-free survival. The secondary end points included toxicity, clinical improvement, and tumor regression according to computed tomography. RESULTS Significant tumor regression was observed clinically and radiologically in all seven patients. Three patients showed a complete response. The average progression-free survival period was 74.0 months (range, 32.5 to 107.5 months). Three patients showed grade 3 adverse events with no treatment-related mortality. All seven patients survived and remained without tumor progression. An adenomatous polyposis coli germline-mutation analysis revealed no mutations in the specified regions. CONCLUSION A chemotherapeutic regimen of DOX plus DTIC followed by meloxicam is an effective and safe treatment for FAP-associated desmoid tumors. This modality should be considered for use as first-line chemotherapy in symptomatic desmoid tumors that are unresponsive to conventional medical therapy, due to the absence of useful presymptomatic markers.

Diagnostic value of ultrasound-guided fine-needle aspiration biopsy, core-needle biopsy, and evaluation of combined use in the diagnosis of breast lesions

BACKGROUND To investigate whether ultrasound-guided core-needle biopsy (US-CNB) has more diagnostic value for breast tumors than ultrasound-guided fine-needle aspiration biopsy (US-FNAB) and to evaluate their combined use in patients with breast tumors. STUDY DESIGN US-FNAB was carried out in 233 patients with breast tumors (254 lesions); both US-FNAB and US-CNB (combined biopsy) were performed in 81 of these patients (82 lesions). The diagnosis obtained by US-FNAB and US-CNB was compared with the surgical findings and the diagnostic value of US-CNB and combined biopsy were retrospectively evaluated. RESULTS The sensitivity of US-FNAB was 86.9%, the specificity was 78.6%, and the accuracy was 84%. In contrast, the sensitivity of US-CNB was 86.2%, the specificity was 95.8%, and the accuracy was 89%. The specificity of US-CNB was significantly higher than that of US-FNAB and the inadequate biopsy rate of US-CNB was significantly lower than that of US-FNAB. For combined biopsy, the sensitivity, specificity, and accuracy were all 100%. The sensitivity, specificity, and accuracy of combined biopsy were significantly higher than those of US-FNAB. CONCLUSIONS These findings suggest that US-CNB is more useful than US-FNAB, and that a combination of US-CNB and US-FNAB can markedly improve the preoperative diagnosis of breast cancer.

Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy.

The zinc finger protein glioma-associated oncogene homologue 1 (Gli-1) is a critical component of the Hedgehog (Hh) signalling pathway, which is essential for morphogenesis and stem-cell renewal, and is dysregulated in many cancer types. As data were not available on the role of Gli-1 expression in oesophageal cancer progression, we analysed whether it could be used to predict disease progression and prognosis in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Among 69 patients with histologically confirmed oesophageal squamous cell carcinomas (ESCCs), 25 showed a pathological complete response after preoperative CRT. Overall survival (OS) was significantly associated with lymph-node metastasis, distant metastasis, and CRT, and was further correlated with the absence of both Gli-1 nuclear expression and residual tumour. All patients with Gli-1 nuclear expression (10.1%) had distant or lymph-node metastasis, and six out of seven died within 13 months. Furthermore, patients with Gli-1 nuclear-positive cancers showed significantly poorer prognoses than those without (disease-free survival: mean DFS time 250 vs 1738 months, 2-year DFS 0 vs 54.9%, P=0.009; OS: mean OS time 386 vs 1742 months, 2-year OS 16.7 vs 54.9%, P=0.001). Our study provides the first evidence that Gli-1 nuclear expression is a strong and independent predictor of early relapse and poor prognosis in ESCC after CRT. These findings suggest that Hh signal activation might promote cancer regrowth and progression after CRT.

Interobserver agreement in endoscopic evaluation of reflux esophagitis using a modified Los Angeles classification incorporating grades N and M: A validation study in a cohort of Japanese endoscopists

The Los Angeles classification system is the most widely employed criteria associated with the greatest interobserver agreement among endoscopists. In Japan, the Los Angeles classification system has been modified (modified LA system) to include minimal changes as a distinct grade of reflux esophagitis, rather than as auxiliary findings. This adds a further grading M defined as minimal changes to the mucosa, such as erythema and/or whitish turbidity. The modified LA system has come to be used widely in Japan. However, there have been few reports to date that have evaluated the interobserver agreement in diagnosis when using the modified LA classification system incorporating these minimal changes as an additional grade. A total of 100 endoscopists from university hospitals and community hospitals, as well as private practices in the Osaka-Kobe area participated in the study. A total of 30 video clips of 30-40 seconds duration, mostly showing the esophagocardiac junction, were created and shown to 100 endoscopists using a video projector. The participating endoscopists completed a questionnaire regarding their clinical experience and rated the reflux esophagitis as shown in the video clips using the modified LA classification system. Agreement was assessed employing kappa (kappa) statistics for multiple raters. The kappa-value for all 91 endoscopists was 0.094, with a standard error of 0.002, indicating poor interobserver agreement. The endoscopists showed the best agreement on diagnosing grade A esophagitis (0.167), and the poorest agreement when diagnosing grade M esophagitis (0.033). The kappa-values for the diagnoses of grades N, M, and A esophagitis on identical video pairs were 0.275-0.315, with a standard error of 0.083-0.091, indicating fair intraobserver reproducibility among the endoscopists. The study results consistently indicate poor agreement regarding diagnoses as well as fair reproducibility of these diagnoses by endoscopists using the modified LA classification system, regardless of age, type of practice, past endoscopic experience, or current workload. However, grade M reflux esophagitis may not necessarily be irrelevant, as it may suggest an early form of reflux disease or an entirely new form of reflux esophagitis. Further research is required to elucidate the pathophysiological basis of minimal change esophagitis.

Gastroesophageal Reflux After Distal Gastrectomy: Possible Significance of the Angle of His

Objective:We investigated whether the angle of His influences gastroesophageal reflux after distal gastrectomy.Methods:Thirty-eight patients having distal gastrectomy and 10 controls underwent upper gastroesophageal fluoroscopy to measure the angle of His, and gastroesophageal reflux was assessed by scintigraphy. The association between scintigraphic reflux and the angle of His was then evaluated.Results:In distal gastrectomy patients with and without reflux symptoms, the angle was 108.82 ± in 21.88° and 96.07 ± 13.25°, respectively; it was 74.14 ± 10.85° in the controls. The angle was significantly larger in the patients than in the controls (p < 0.01). In addition, the angle in the symptomatic gastrectomy group tended to be larger than in the asymptomatic group. The angle was also significantly larger in patients with a scintigraphic reflux index ≥6% than in those with an index < 6% (p < 0.05).Conclusions:These findings suggest that the angle of His plays a role in reflux after distal gastrectomy and that the severity of reflux may be estimated by measuring this angle.

Regression of sporadic intra-abdominal desmoid tumour following administration of non-steroidal anti-inflammatory drug.

BackgroundDesmoid tumours or fibromatoses are rare entities characterized by the benign proliferation of fibroblasts, which can be life-threatening due to their locally aggressive properties. Surgery is widely accepted as the first line of treatment for extra-abdominal desmoids; however, it is not recommended for intra-abdominal desmoids because of the high-risk of recurrence and difficulties with the operation. Here, we report on a patient with sporadic intra-abdominal desmoid tumours, who showed partial response following the intake of non-steroidal anti-inflammatory drugs.Case presentationA 73-year-old man presented with swelling and pain of the right leg. Computed tomography showed an abnormal multilocular soft-tissue mass (95 × 70 mm) in the right pelvis, which was revealed by biopsy to be a desmoid tumour. Immunohistochemical analysis showed that the tumour cells expressed vimentin, but not smooth-muscle actin, CD34, or desmin. Very few Ki-67-positive cells were found. Non-cytotoxic treatment with etodolac (200 mg/day) was chosen because of the patients age, lack of bowel obstruction, and the likelihood of prostate cancer. Two years after the commencement of non-steroidal anti-inflammatory drug administration, computed tomography showed a decrease in tumour size (63 × 49 mm), and the disappearance of intratumoural septa.ConclusionOur case report suggests that non-steroidal anti-inflammatory drug treatment should be taken into consideration for use as first-line treatment in patients with sporadic intra-abdominal desmoid tumours.

Evaluation of J-Pouch Reconstruction after Total Gastrectomy: ρ-Double Tract vs. J-Pouch Double Tract

Objective: Various enteric reservoirs have been advocated to improve the quality of life after total gastrectomy. We evaluated the advantages of pouch reconstruction compared with traditional ρ-double tract reconstruction. Design: Prospective randomized study. Setting: Second Department of Surgery, Hyogo College of Medicine, Japan. Subjects: Forty patients who underwent total gastrectomy for cancer of the stomach were studied. Intervention: Forty patients were randomly divided into two groups: 20 patients received ρ-double tract reconstruction (RDT group), and 20 underwent J-pouch double tract reconstruction (PDT group) group. Main Outcome Measures: We compared the body weight, serum nutritional parameters, reflux score, scintigraphic esophageal reflux, food intake, and emptying time of the J-pouch or ρ-limb between the two groups. Results: No difference was noted between the two groups with regard to body weight, but food intake tended to be higher in the PDT group than in the RDT group. Total protein and albumin levels were higher in the PDT group than in the RDT group, while scintigraphic reflux was significantly less prominent in the PDT group. Conclusions: J-pouch reconstruction was superior with respect to protein metabolism, food intake and reduction of reflux esophagitis compared with the traditional RDT method. However, use of pouch reconstruction did not improve postoperative weight gain.

Long-term Effects Of Small Bowel Transplantation On Intestinal Motility

We previously found that the contractile motility of the jejunum was increased 4 weeks after transplantation, and that the dominant intrinsic neural component was changed from cholinergic to nonadrenergic, noncholinergic (NANC). The present study investigated the long-term effects of transplantation on jejunal motility using rats that survived for 2 years after surgery. Jejunal strips were harvested from various groups of rats, and intestinal motility was assessed by electrical transmural stimulation. Stimulation produced a similar increase of contraction at 4 weeks and 2 years after grafting. Pretreatment with atropine showed that the cholinergic component of contraction was 45%, 24%, 32%, and 24% in controls, rats 4 weeks after transplantation, 2-year-old controls, and rats 2 years after transplantation, respectively. The NANC component (obtained with atropine and guanethidine) in each group was, respectively, 56%, 73%, 60%, and 69%. The actual value of the tetrodotoxin-insensitive myogenic component was significantly increased at 2 years after transplantation. A substance P antagonist ([Arg6, D-Trp7,9, Mephe8], substance P 6–11), inhibited most of the NANC contraction after transplantation. These results suggested that substance P has a key role in the motility of transplanted small bowel throughout the life of the grafts.

The oncoprotein and stem cell renewal factor BMI1 associates with poor clinical outcome in oesophageal cancer patients undergoing preoperative chemoradiotherapy

BackgroundThe polycomb group (PcG) family BMI1, acting downstream of the hedgehog (Hh) pathway, plays an essential role in the self-renewal of haematopoietic, neural, and intestinal stem cells, and is dysregulated in many types of cancer. Our recent report has demonstrated that Hh signalling activation can predict very earlier relapse of oesophageal cancers. As data were not available on the clinical role of BMI1 expression in oesophageal cancers after chemoradiotherapy (CRT), we analysed whether it could be also used to predict disease progression and prognosis in oesophageal cancer patients undergoing trimodality therapy of preoperative CRT and oesophagectomy.MethodsExpressions of BMI1 and p16INK4A, a downstream target of PcG, were analysed in 78 patients with histologically confirmed oesophageal squamous cell carcinoma (ESCC) after preoperative CRT by immunohistochemical staining. The association of BMI1 and p16INK4A expression with clinicopathologic characteristics was analysed by χ2-test. Survival analysis was carried out by the log-rank test using Kaplan-Meier method.ResultsAmong 78 ESCC patients, 24 patients (30.8%) showed BMI1 positivity, mainly localised in the nuclei of tumour cells. Patients harbouring BMI1-positive tumour cells showed significantly poorer prognoses than those without such cells or residual tumours (mean disease-free survival (DFS) time 16.8 vs 71.2 months; 3-yr DFS 13.3% vs 49.9%, P=0.002; mean OS time 21.8 vs 76.6 months; 3-yr OS 16.2% vs 54.9%, P=0.0005). There was no significant correlation between p16INK4A expression and BMI1 expression.ConclusionsOur study shows that BMI1 expression is a predictor of early relapse and poor prognosis in ESCC after CRT. These findings suggest that BMI1 signal activation might be involved in promoting cancer regrowth and progression after CRT, and might be indicative of emergence of ‘more aggressive’ cancer progenitor cells.

Predictive factors for pericardial effusion identified by heart dose–volume histogram analysis in oesophageal cancer patients treated with chemoradiotherapy

OBJECTIVE To identify predictive factors for the development of pericardial effusion (PCE) in patients with oesophageal cancer treated with chemotherapy and radiotherapy (RT). METHODS From March 2006 to November 2012, patients with oesophageal cancer treated with chemoradiotherapy (CRT) using the following criteria were evaluated: radiation dose >50 Gy; heart included in the radiation field; dose-volume histogram (DVH) data available for analysis; no previous thoracic surgery; and no PCE before treatment. The diagnosis of PCE was independently determined by two radiologists. Clinical factors, the percentage of heart volume receiving >5-60 Gy in increments of 5 Gy (V5-60, respectively), maximum heart dose and mean heart dose were analysed. RESULTS A total of 143 patients with oesophageal cancer were reviewed retrospectively. The median follow-up by CT was 15 months (range, 2.1-72.6 months) after RT. PCE developed in 55 patients (38.5%) after RT, and the median time to develop PCE was 3.5 months (range, 0.2-9.9 months). On univariate analysis, DVH parameters except for V60 were significantly associated with the development of PCE (p < 0.001). No clinical factor was significantly related to the development of PCE. Recursive partitioning analysis including all DVH parameters as variables showed a V10 cut-off value of 72.8% to be the most influential factor. CONCLUSION The present results showed that DVH parameters are strong independent predictive factors for the development of PCE in patients with oesophageal cancer treated with CRT. ADVANCES IN KNOWLEDGE A heart dosage was associated with the development of PCE with radiation and without prophylactic nodal irradiation.