The Presence of Serum p53 Antibody Predicts the Pathological Tumor Response to Neoadjuvant Chemotherapy with Docetaxel,Cisplatin and Fluorouracil (DCF) in Esophageal Squamous Cell Carcinoma

Background

Docetaxel, cisplatin and fluorouracil (DCF) is a candidate neoadjuvant chemotherapy (NAC) regimen for esophageal squamous cell carcinoma (ESCC). Although the efficacy and safety of DCF have been reported, the markers that predict the patient’s response are still unknown. The aim of this study was to identify the predictive markers for a response to NAC with DCF in patients with ESCC.

Methods

A total of 79 patients who received preoperative DCF followed by esophagectomy between August 2008 and December 2014 were enrolled in this study. All of the patients completed 2 preoperative courses of DCF. The clinical and pathological responses to DCF were investigated, and the associations between the pathological response, the clinicopathological factors and the prognosis were retrospectively analyzed.

Results

Among the 79 patients, the pathological response to DCF (evaluated according to the Japanese Classification of Esophageal Cancer) was grade 3 (complete pathological response) in 7 patients (8.9 %), grade 2 in 13 patients (16.5 %), grade 1b in 8 patients (10.1 %) and grade 1a in 51 patients (64.6 %). A good pathological response (grade 2–3) was significantly associated with both favorable disease-free survival (P = 0.0051) and favorable cancer-specific survival (P = 0.0366). A multivariate analysis revealed that a good clinical response (HR 13.743, 95 % CI 2.455–76.917) and the presence of serum p53 antibody before treatment (HR 3.987, 95 % CI 1.103–14.416) were independent predictors of good pathological response.

Conclusions

The presence of serum p53 antibody can be used as a novel, noninvasive predictor of the pathological tumor response to NAC with DCF in ESCC patients.

     

A Phase II Study of Partial and Subtotal Thymectomy for Thymoma (JART02)

Background

We believe the merit of preservation of a part of the thymus following surgery for thymoma. We evaluated the efficacy of partial or subtotal thymectomy for early-stage thymoma in the prospective study.

Methods

The Japanese Association for Research on the Thymus conducted a multiple institutional study of thymectomy for thymoma localized in the thymus without total thymectomy. Patients without autoimmune disease who had an anterior mediastinal tumor that had been clinically diagnosed as an early-stage thymoma were enrolled in the study. Patients who were positive for anti-acetylcholine receptor antibodies were excluded.

Results

Sixty-three patients were enrolled preoperatively; 27 patients were judged as being inappropriate based on the other thymic pathologies or tumor invasion. The remaining 36 cases were diagnosed as early-staged thymoma and analyzed. The mean age of the patients was 61 years. The mean maximal tumor diameter in the resected specimens was 3.6 cm. The most common pathological types of thymoma were AB (n = 10) and B1 (n = 10). The Masaoka stages were classified as stage I (n = 22) and II (n = 14). The mean observation period was 63 months. Two patients died due to respiratory dysfunction, which was not related to thymoma. One hundred percent of the patients remained recurrence-free.

Conclusions

This prospective study suggested the efficacy of partial or subtotal thymectomy for early-stage thymoma in patients without any apparent evidence of autoimmune disease. We can preserve a part of the thymus even following surgery for thymoma to prepare the possible second malignancies or diseases in future.

     

Outcome of metastatic urothelial carcinoma treated by systemic chemotherapy: Prognostic factors based on real-world clinical practice in Japan

Aim

To clarify prognostic factors of metatstatic urothelial carcinoma treated by systemic chemotherapy in real-world clinical practice in the Japanese population.

Nontoxic concentration of kanamycin and gentamicin for intravitreal use — evaluated by in vitro ERG

The effects of kanamycin (KM) and gentamicin (GM) on the in-vitro electroretinogram of the albino rabbit were studied. The b-wave and oscillatory potentials (OPs) were unchanged by 0.1 mM KM. The photopic b-wave and OPs were slightly suppressed by 0.4 mM. The b-wave and OPs were not deteriorated by 23 µg/ml (approximately 0.05 mM) GM. The photopic b-wave and OPs were slightly suppressed by 46 µg/ml (approximately 0.1 mM) GM. The minimum concentration affecting the ERG was tentatively defined as the mean of the minimum concentration needed to change the ERG and the maximum concentration which induced no discernible changes in the ERG. The minimum concentration of KM and GM affecting the ERG were 0.25mM (approximately 150 g/ml) and 35 g/ml (approximately 0.075 mM) respectively. The minimum concentration of KM affecting the ERG was higher than its minimum inhibitory concentration against Staphylococcus aureus and Streptococcus pneumoniae. The minimum concentration of GM affecting the ERG was higher than its mimimum inhibitory concentration against Staphylococcus aureus, Streptococcus pneumoniae and Pseudomonas aeruginosa.     

The effectiveness of busulfan‐based conditioning regimens for stem cell transplantation against lymphomas in children,adolescents, and young adults in Japan

Conditioning regimens for stem cell transplantation (SCT) involving total body irradiation (TBI) are generally preferred over busulfan (BU)‐based ones for lymphoid malignancies. However, reports of favorable results using BU against lymphomas have recently emerged. This study sought to compare the effectiveness of BU and TBI regimens for SCT against lymphomas. We retrospectively analyzed 893 lymphoma patients who underwent primary SCT in Japan between 1980 and 2015. The median age of all patients was 18 years (range, 0–30 years) with 589 males, 303 females, and 1 patient whose sex was unknown. Overall survival (OS) was not different between those receiving BU and TBI (P = 0.672). OS in patients receiving autologous SCT was significantly better with BU over TBI regimens (P = 0.038), particularly in children (0–15 years) (P = 0.024). Conversely, OS in adolescents and young adults (AYAs; 16–30 years) receiving allogeneic SCT was significantly worse with BU over TBI regimens (P = 0.035). Overall, BU regiments had comparable effectiveness to TBI conditioning regimens, and, although less effective for AYAs with allogeneic SCT, were particularly more effective than TBI regimens for children who received autologous SCT.     

Extranodal Multiple Involvement of Enteropathy-Type T-Cell Lymphoma without Expression of CC Chemokine Receptor 7

Enteropathy-type T-cell lymphoma (ETCL) is a rare extranodal lymphoma that tends to disseminate into the intestines and other extranodal organs. We present a case of ETCL with involvement of the lungs and kidneys and report CC chemokine receptor 7 (CCR7) expression of lymphoma cells. A 73-year-old man was admitted to the hospital with a complaint of abdominal pain. Multiple ulcers and perforations were observed in the small intestine, and partial resection of the ileum was performed. Histological examination of the resected specimen revealed diffuse proliferation of atypical large lymphoid cells. The diagnosis was ETCL with dissemination into the lungs and kidney. Lymphoma cells of the small intestine and in pleural effusion were CD3+, CD4+, CD7+, CD8-, CD25-, CD56-, CD103 +/-, and TIA-1+. Rearrangement of the T-cell receptor beta gene was detected, and human T-lymphotropic virus was not integrated. Combination chemotherapy did not result in a sustained response. The results for CCR7 expression of lymphoma cells in the lung and pleural effusion were negative. Therefore we concluded that lymphoma cells did not migrate into the lymph nodes but instead spread into the extranodal organs.     

Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy

The fact that small cell lung cancer (SCLC) is commonly incurable despite being initially responsive to chemotherapy, combined with disappointing results from a recent SCLC clinical trial with imatinib, has intensified efforts to identify mechanisms of SCLC resistance. Adhesion to extracellular matrix (ECM) is one mechanism that can increase therapeutic resistance in SCLC cells. To address whether adhesion to ECM increases resistance through modulation of signaling pathways, a series of SCLC cell lines were plated on various ECM components, and activation of two signaling pathways that promote cellular survival, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathway, was assessed. Although differential activation was observed, adhesion to laminin increased Akt activation, increased cellular survival after serum starvation, and caused the cells to assume a flattened, epithelial morphology. Inhibitors of the PI3K/Akt/mTOR pathway (LY294002, rapamycin) but not the MEK/ERK pathway (U0126) abrogated laminin-mediated survival. SCLC cells plated on laminin were not only resistant to serum starvation-induced apoptosis but were also resistant to apoptosis caused by imatinib. Combining imatinib with LY294002 or rapamycin but not U0126 caused greater than additive increases in apoptosis compared with apoptosis caused by the inhibitor or imatinib alone. Similar results were observed when adenoviruses expressing mutant Akt were combined with imatinib, or when LY294002 was combined with cisplatin or etoposide. These studies identify laminin-mediated activation of the PI3K/Akt/mTOR pathway as a mechanism of cellular survival and therapeutic resistance in SCLC cells and suggest that inhibition of the PI3K/Akt/mTOR pathway is one strategy to overcome SCLC resistance mediated by ECM.     

Preoperative biliary drainage for biliary tract and ampullary carcinomas

We posed six clinical questions (CQ) on preoperative biliary drainage and organized all pertinent evidence regarding these questions. CQ 1. Is preoperative biliary drainage necessary for patients with jaundice? The indications for preoperative drainage for jaundiced patients are changing greatly. Many reports state that, excluding conditions such as cholangitis and liver dysfunction, biliary drainage is not necessary before pancreatoduodenectomy or less invasive surgery. However, the morbidity and mortality of extended hepatectomy for biliary cancer is still high, and the most common cause of death is hepatic failure; therefore, preoperative biliary drainage is desirable in patients who are to undergo extended hepatectomy. CQ 2. What procedures are appropriate for preoperative biliary drainage? There are three methods of biliary drainage: percutaneous transhepatic biliary drainage (PTBD), endoscopic nasobiliary drainage (ENBD) or endoscopic retrograde biliary drainage (ERBD), and surgical drainage. ERBD is an internal drainage method, and PTBD and ENBD are external methods. However, there are no reports of comparisons of preoperative biliary drainage methods using randomized controlled trials (RCTs). Thus, at this point, a method should be used that can be safely performed with the equipment and techniques available at each facility. CQ 3. Which is better, unilateral or bilateral biliary drainage, in malignant hilar obstruction? Unilateral biliary drainage of the future remnant hepatic lobe is usually enough even when intrahepatic bile ducts are separated into multiple units due to hilar malignancy. Bilateral biliary drainage should be considered in the following cases: those in which the operative procedure is difficult to determine before biliary drainage; those in which cholangitis has developed after unilateral drainage; and those in which the decrease in serum bilirubin after unilateral drainage is very slow. CQ 4. What is the best treatment for post-drainage fever? The most likely cause of high fever in patients with biliary drainage is cholangitis due to problems with the existing drainage catheter or segmental cholangitis if an undrained segment is left. In the latter case, urgent drainage is required. CQ 5. Is bile culture necessary in patients with biliary drainage who are to undergo surgery? Monitoring of bile cultures is necessary for patients with biliary drainage to determine the appropriate use of antibiotics during the perioperative period. CQ 6. Is bile replacement useful for patients with external biliary drainage? Maintenance of the enterohepatic bile circulation is vitally important. Thus, preoperative bile replacement in patients with external biliary drainage is very likely to be effective when highly invasive surgery (e.g., extended hepatectomy for hilar cholangiocarcinoma) is planned.     

The new therapeutic concept of using a rho kinase inhibitor for the treatment of corneal endothelial dysfunction

Corneal endothelial cells (CECs) show poor regenerative ability in humans, and noncompensatory damage of CECs causes irreversible corneal haziness in cases of bullous keratopathy. Although corneal transplantations provide considerable clinical benefits, allograft rejection, primary graft failure, and the shortage of donor corneas are problems that still need to be overcome. The establishment of new treatment therapies is the key to solving these problems, and we have attempted to establish a new clinical intervention for corneal endothelial dysfunction. We previously demonstrated that the inhibition of Rho/Rho kinase (ROCK) signaling by Y-27632, a specific ROCK inhibitor, promoted cell adhesion, inhibited apoptosis, and enhanced cell proliferation in cultured primate CECs. These results raise the possibility that the ROCK inhibitor might serve as a new tool for establishing an effective culture method for newly emerging cultivated CEC transplantation therapies. Moreover, because Y-27632 enhances cell proliferation in vitro, we hypothesized that the use of a ROCK inhibitor could be a new pharmacological intervention for the treatment of corneal endothelial dysfunction. We demonstrated that the topical instillation of a ROCK inhibitor promotes corneal endothelium wound healing in an animal model. This indicates that use of a ROCK inhibitor is a less invasive and novel therapy that should prove promising for the treatment of corneal endothelial dysfunction.