Sentinel node tumour burden quantified based on cytokeratin 19 mRNA copy number predicts non-sentinel node metastases in breast cancer: Molecular whole-node analysis of all removed nodes

ObjectiveThe one-step nucleic acid amplification (OSNA) assay can assess an entire lymph node and detect clinically relevant metastases quantified based on cytokeratin 19 (CK19) mRNA copy number. The OSNA assay of all sentinel lymph nodes (SNs) and non-sentinel nodes (non-SNs) allows for the accurate measurement of tumour burden in either situation. We aim to reveal the usefulness of the OSNA assay regarding the prediction of non-SN metastasis.MethodsThe subjects consisted of 185 breast cancer patients who underwent axillary dissection after a metastatic SN biopsy and whose SNs and non-SNs were examined using the OSNA whole-node assay between 2009 and 2011. The non-SN tumour burden was classified as macrometastasis (CK19 mRNA ?5000 copies/μl) or micrometastasis (250–5000 copies/μl). The relationship between SN and non-SN tumour burdens and predictors of non-SN metastasis were investigated.ResultsAmong these 185 patients, 38 patients (20.5%) had macrometastasis and 58 (31.4%) had micrometastasis only in the non-SNs. Non-SN macrometastasis rates increased in direct proportion to the SN copy number: approximately 5% in patients with SNs with 250–500 copies; 20%, 500–5000 copies and 30%, ?5000 copies. However, non-SN micrometastasis rates were approximately 30% regardless of the SN copy number. In multivariate analyses, the mean SN copy number, number of macrometastatic SN and lymphovascular invasion were significant for identifying non-SN macrometastases.ConclusionsThe SN tumour burden quantified using the OSNA assay predicts non-SN metastases. A novel mathematical model to predict the non-SN tumour burden can be generated using the results of the OSNA assay.     

Optimization algorithm for overlapping-field plans of scanned ion beam therapy with reduced sensitivity to range and setup uncertainties

A 'patch-field' strategy is often used for tumors with large volumes exceeding the available field size in passive irradiations with ion beams. Range and setup errors can cause hot and cold spots at the field junction within the target. Such errors will also displace the field to miss the target periphery. With scanned ion beams with fluence modulation, the two junctional fields can be overlapped rather than patched, which may potentially reduce the sensitivity to these uncertainties. In this study, we have developed such a robust optimization algorithm. This algorithm is composed of the following two steps: (1) expanding the target volume with margins against the uncertainties, and (2) solving the inverse problem where the terms suppressing the dose gradient of individual fields are added into the objective function. The validity of this algorithm is demonstrated through simulation studies for two extreme cases of two fields with unidirectional and opposing geometries and for a prostate-cancer case. With the proposed algorithm, we can obtain a more robust plan with minimized influence of range and setup uncertainties than the conventional plan. Compared to conventional optimization, the calculation time for the robust optimization increased by a factor of approximately 3.     

Comparison of gender-specific mortality in patients < 70 years versus ≥ 70 years old with acute myocardial infarction

The aim of the present study was to investigate the gender-specific mortality after acute myocardial infarction in those aged < 70 years versus ≥ 70 years. The present study consisted of 2,677 consecutive patients with acute myocardial infarction who had undergone coronary angiography within 24 hours after the onset of symptoms. The patients were divided into 2 groups: 1,810 patients < 70 years old and 867 patients ≥ 70 years old. Women were older and had a greater incidence of hypertension and diabetes mellitus and a lower incidence of current smoking and previous myocardial infarction in both groups. The in-hospital mortality rate was significantly greater in women ≥ 70 years old age than in men ≥ 70 years old (16.2% vs 9.3%, respectively; p = 0.003) but was comparable between women and men in patients < 70 years old (5.7% vs 4.9%, respectively; p = 0.59). On multivariate analysis, the association between female gender and in-hospital mortality in patients ≥ 70 years old remained significant (odds ratio 1.78, 95% confidential interval 1.05 to 3.00), but the gender difference was not observed in patients < 70 years old (odds ratio 1.09, 95% confidence interval 0.53 to 2.24). In conclusion, female gender was associated with in-hospital mortality after acute myocardial infarction in patients ≥ 70 years old but not in patients < 70 years old.     

CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity

CRM1 plays an important role in the nuclear export of cargo proteins bearing nuclear exporting signal sequences. Leptomycin B (LMB), a well-known CRM1 inhibitor, possesses strong antitumor properties. However, its toxicity prevents it from being clinically useful. In this study, we demonstrate that a novel compound, CBS9106, inhibits CRM1-dependent nuclear export, causing arrest of the cell cycle and inducing apoptosis in a time- and dose-dependent manner for a broad spectrum of cancer cells, including multiple myeloma cells. CBS9106 reduces CRM1 protein levels significantly without affecting CRM1 mRNA expression. This effect could be reversed by adding bortezomib or LMB. Moreover, CBS9106-biotin allows capture of CRM1 protein by streptavidin beads in a competitive manner with LMB and vice versa. Mass spectrometric analysis shows that CBS9106 reacts with a synthetic CRM1 peptide that contains Cys528 but not with a Cys528 mutant peptide. Oral administration of CBS9106 significantly suppresses tumor growth and prolongs survival in mice bearing tumor xenograft without a significant loss in body weight. A reduced level of CRM1 protein is also observed in tumor xenografts isolated from mice treated with CBS9106. Taken together, these results indicate that CBS9106 is a novel reversible CRM1 inhibitor and a promising clinical candidate.     

EUS-FNA for suspected malignant biliary strictures after negative endoscopic transpapillary brush cytology and forceps biopsy

Background

Endoscopic transpapillary brush cytology and forceps biopsy are widely used for the pathological diagnosis of suspected malignant biliary strictures (MBS). However, the sensitivity of these methods remains insufficient, and it can be difficult to confirm the diagnosis. We aimed to evaluate the diagnostic ability of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and the impact of this technique on clinical management in patients with suspected MBS where endoscopic brush cytology and biopsy yielded negative results.

Methods

This study included 225 consecutive patients with suspected MBS, who underwent endoscopic brush cytology and biopsy at our institutions. Negative results were obtained for these pathological tests in 75 patients, and EUS-FNA was performed in 22 of these patients. We retrospectively compared the EUS-FNA results with the final diagnosis and examined the influence of the EUS-FNA diagnosis on treatment selection.

Results

FNA specimens were successfully obtained in all patients, and the pathological results confirmed malignancy in 16 cases and predicted that the other 6 cases were benign. Of the 6 cases that were suspected to be benign, 3 patients were diagnosed with xanthogranulomatous cholecystitis by surgical pathology, and the remaining 3 patients were diagnosed with benign diseases at a follow-up after 12?C18?months. Thus, the EUS-FNA-based diagnosis was proven correct for all the patients. In addition, the treatment strategy was altered as a result of the EUS-FNA results in the above 6 patients (27%).

Conclusions

EUS-FNA is a sensitive and safe diagnostic modality for patients with suspected MBS and can be an additional option in cases where endoscopic brush cytology and biopsy have produced negative results.     

Diagnostic value of antigenemia assay for cytomegalovirus gastrointestinal disease in immunocompromised patients

AIM:To investigate the utility of the cytomegalovirus(CMV)antigenemia assay for the diagnosis of CMV gastrointestinal disease(GID). METHODS:One hundred and thirty immunocompromised patients were enrolled in this study.Patients with a history of anti-CMV treatment and who had not undergone examination using the antigenemia assay were excluded.CMV-GID was defined as the detection of large cells with intranuclear inclusions alone or associated with granular cytoplasmic inclusions by biopsy.Biopsy sections were...     

Varicella vaccine potency and stability during transport and delivery

Oka varicella vaccine was developed to confer active immunity to varicella-zoster virus (VZV) in immunocompromized and immunocompetent children. It is now used to prevent varicella in about 20 million people worldwide. Although VZV infectivion is relatively unstable compared to other viruses, cell-free virus is stabilized and lyophilized vaccine has been developed. Virus titers were evaluated in vaccine distributed to six clinics in 5 years. Yearly mean virus titers at the vaccine producer were 42,000-67,000 plaque-forming units per dose, corresponding to Oka varicella vaccine (Zostavax) used to prevent zoster and postherpetic neuralgia by Oxman et al. Virus titer was found to be stable during delivery to clinics. Virus titers of varicella vaccine were equivalent to Zostavax and vaccine delivered to clinics had enough virus titer to confer active immunity to VZV in this study.     

Recent trends in orthopedic surgery performed in Japan for rheumatoid arthritis

The aim of this report was to review the use of orthopedic surgeries performed to manage rheumatoid arthritis (RA). Our review of studies published in English indicates that there has been a decrease in RA-associated surgeries in Western countries. Improvements in medical treatment may partly explain the reduction in numbers of orthopedic joint surgeries, which also suggests a worldwide trend toward improved long-term outcomes. However, the results of our multicenter study in Japan indicate that the number of RA-associated operations has not decreased, and that the numbers of operations performed annually have been relatively stable from 1998 to 2008. Although there definitely has been a decline in the numbers of synovectomy surgeries, the numbers of operations on the upper limbs and foot arthroplasties have increased. With the trend toward milder disease because of improved medical treatment, we speculate that RA patients may want and need better function for the activities of daily living. The combination of medical treatment and surgical intervention is thought to improve outcomes in RA patients who will develop joint destruction. Additional studies, including analyses of RA databases containing long-term data on a variety of surgical interventions, are needed.