Radiological predictive factors on preoperative multimodality imaging are related to Oncotype DX recurrence score in estrogen-positive/human epidermal growth factor receptor 2-negative invasive breast cancer: a cross-sectional study.

OBJECTIVE: The Oncotype DX (ODX) estimates the 10-year risk of metastasis or recurrence of breast cancer and indicates whether chemotherapy is likely to be effective; however, the high cost of this test may limit its use for patients. The aim of this study was to evaluate the potential of preoperative imaging using mammography (MMG), ultrasonography (US), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and positron emission tomography/computed tomography (PET/CT) metabolic parameters in predicting the ODX recurrence score (ODXRS), which prognosticates estrogen receptor-positive (ER +)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. METHODS: This retrospective study was conducted on 51 patients with ER+/ HER2- early-stage breast cancer with preoperative images available. Surgical specimens were sent for ODX assay and the ODXRS was categorized as low (<18) or intermediate/high (≥18). MMG/US findings were classified according to BI-RADS categories. For MRI analysis, tumor growth orientation was evaluated in addition to morphological assessment in BI-RADS. For PET/CT analysis, standardized uptake value (SUV) of the tumor were measured. Patient, tumor, and image characteristics were compared between the two groups, and predictors of the low ODXRS group were determined by logistic regression analysis. Two-sided P values less than 0.05 were considered statistically significant. RESULTS: Thirty-two (63%) and 19 (37%) patients were categorized as low and intermediate/high ODXRS, respectively. On univariate analysis, nuclear grade, tumor margin, and tumor growth orientation on MRI, and SUVmax on PET/CT were significantly associated with a low ODXRS. Multivariate analysis revealed that tumor growth orientation perpendicular to the Cooper's ligament on MRI (P = 0.031) and a low SUVmax on PET/CT (P = 0.016) were independent prognostic factors for a low ODXRS. As a predictor of low ODXRS, the receiver operating characteristic (ROC) analysis of the SUVmax showed that using 3.0 as the optimal cut-off value has a sensitivity and specificity of 94.4% and 73.0%, respectively, with an area under the curve (AUC) of 0.923. CONCLUSIONS: The combination of perpendicular tumor growth orientation to Cooper's ligaments on MRI and a low SUVmax on PET/CT may predict a low ODXRS.

Clinical pharmacokinetics of oxaliplatin in a hemodialysis patient with advanced gastric cancer.

We administered FOLFOX (oxaliplatin (L-OHP) plus infusional 5-fluorouracil (5-FU) and leucovorin) to an hemodialysis (HD) patient with advanced gastric cancer (AGC), and investigated pharmacokinetics (PKs) and dialyzability of L-OHP. The patient was a 54-year-old Japanese man with a diagnosis of inoperable AGC. FOLFOX was instituted 3 h prior to the start of a 4 h HD period with the L-OHP and 5-FU doses reduced by 50% for the first cycle, and 30% reduced dose was administered for the second cycle. We performed an analysis of the PKs of L-OHP during these two cycles. Volume of distribution and area under the curve of the 30% reduced L-OHP dose were 56.7 L and 30.0 µg·h/mL, respectively. A dose reduction of L-OHP by 30%-50% may be advisable for the initial administration, given the need for careful administration of chemotherapy in HD patients, with particular attention to the development of hematological toxicities and neuropathy.

Development of in vitro endothelialized drug-eluting stent using human peripheral blood-derived endothelial progenitor cells.

We propose in vitro endothelialization of drug-eluting stents (DES) to overcome late stent thrombosis by directly introducing late-outgrowth human endothelial progenitor cells (EPCs) at the target site utilizing abluminal DES. Isolated EPCs were confirmed as late-outgrowth EPCs by flow cytometric analysis. Abluminally paclitaxel-loaded stents were seeded with different cell concentrations and durations to determine optimal seeding conditions, in both uncrimped and crimped configurations. The seeding yield was determined by evaluating the percent coverage of the stent struts' area. The EPC-seeded DES were exposed to arterial shear stress to evaluate the effect of high shear stress on EPCs. To investigate how much paclitaxel elutes during the seeding procedure, a pharmacokinetic analysis was performed. Finally, to validate the proof of concept, EPC-seeded DES were placed on a fibrin matrix with and without smooth muscle cells (SMCs) and cultured for 3 days under perfusion. The seeding procedure resulted in 47% and 26% coverage of the stent surface in uncrimped and crimped conditions, respectively. After the optimal seeding, almost 99% of drug was still available. When EPC-seeded DES were placed on a fibrin matrix and cultured for 3 days, the EPCs confluently covered the stent surface and spread to the surrounding fibrin gel. When EPC-seeded DES were placed on SMC-containing fibrin layers, cells in contact with the struts died. EPCs can be successfully seeded onto DES without losing drug-eluting capability, and EPCs exhibit sufficient proliferative ability. EPC-seeded DES may combine early re-endothelialization ability with the antirestenotic effectiveness of DES.

Vancomycin pharmacokinetics in critically ill patients receiving continuous haemodiafiltration with a polyethyleneimine-coated polyacrylonitrile membrane.

WHAT IS KNOWN AND OBJECTIVE: We investigated the elimination efficiency and pharmacokinetics (PK) parameters of vancomycin (VCM) in patients undergoing continuous haemodiafiltration (CHDF) using a polyethyleneimine-coated polyacrylonitrile membrane (AN69ST) for dosage adjustment. METHODS: We conducted a retrospective study of CHDF patients treated with VCM from December 2017 to August 2019. We calculated PK parameters of VCM and determined the 24-hour dose required to maintain the target trough concentration of VCM (VCM_trough ). RESULTS AND DISCUSSION: The average (95% CI) volume of distribution and total clearance of VCM were 75.5 L (63.7-87.3 L) and 1.84 L/h (1.38-2.30 L/h), respectively, and the elimination rate constant and half-life were 0.026/h (0.017-0.034/h) and 31.2 h (22.8-39.5 h), respectively. The average AN69ST clearance of VCM (CL_CHDF ) was 0.69 L/h (0.52-0.86 L/h). The estimated average doses required to maintain VCM_trough of 10, 15 and 20 µg/mL were 623.1 mg (379.8-866.4 mg), 934.6 mg (569.7-1299.5 mg) and 1246.2 mg (759.6-1732.8 mg), respectively. WHAT IS NEW AND CONCLUSION: The PK of VCM and CL_CHDF of AN69ST were clarified. These results suggest that it is possible to adjust the dose of VCM in using AN69ST, which efficiently removes cytokines, and contributes to improvement of serious infections.

[A Case of Advanced Esophageal Cancer Treated with Nedaplatin in a Patient Undergoing Maintenance Hemodialysis].

Herein, we investigated the pharmacokinetic (PK) profile of nedaplatin (cis-diamine-glycolateplatinum; CDGP) in a hemodialysis (HD) patient with advanced esophageal squamous cell carcinoma (ESCC) by administering the CDGP immediately prior to HD. Our patient was treated with CDGP (45 mg/m2 for a total dose of 60.2 mg) and 5-fluorouracil (560 mg/m2 for a total dose of 750 mg) before initiating HD. The total platinum (Pt) concentration (Pt_total) and free Pt concentration (Pt_free) 2 h after completion of HD were 0.4 µg/mL and 0.3 µg/mL, respectively. The removal rates of Pt_total and Pt_free by the dialyzer were 76.5% and 84.6%, respectively. Twenty-four hours after CDGP administration, the Pt_free was below the detection limit of the method of analysis. Pt_free within the range of the recommended CDGP target AUC0-24 was 8-10 µg/mL•h, the AUC0-24 of Pt_total and Pt_free were 16.5 µg/mL•h and 8.8 µg/mL•h, respectively. We conclude that HD should be performed after the end of CDGP infusion as part of the CDGP chemotherapy regimen for HD patients with ESCC, and suggest that HD is effective for obtaining a PK profile of CDGP similar to patients with normal renal function.

[Evaluation of Intervention by an Antimicrobial Stewardship Team for Patients with Bacteremia].

In this study, antimicrobial stewardship team (AST) intervention was evaluated by comparing patient outcomes and consumption of broad-spectrum antibiotics [carbapenem antibiotics and tazobactam/piperacillin (TAZ/PIPC)] before and after the intervention. There was no fluctuation in the consumption rate of carbapenem, TAZ/PIPC and other antibiotics, but there was a decreased annual consumption of antibiotics after AST intervention compared to before intervention. For the carbapenems, antimicrobial use density (AUD) of meropenem (MEPM) was highest in both periods, at 20.1 and 20.4 before and after AST intervention, respectively, with no significant change after AST intervention. However, the days of therapy (DOT) for MEPM were 27.4 and 24.8 d, respectively, with a decreasing trend after AST intervention. AUD and DOT for TAZ/PIPC after AST intervention were 6.5 and 8.1 d, respectively, which were lower than the pre-intervention values. Rapid identification of the causative strain enables early de-escalation and may improve the economics of antibiotic use, but there was no difference from before to after AST intervention. Compared with before and after strain identification, the carbapenem administration rate after AST intervention was significantly lower than the pre-intervention rate (p<0.01). There was no difference in 28-day mortality and treatment period before and after AST intervention, and there were no differences in outcomes such as resolution of bacteremia, mortality, exacerbation and no change from before to after AST intervention. Based on these results, we suggest that AST intervention can reduce consumption of antibiotics without altering patient outcomes.

Pharmacokinetics and pharmacodynamics of daptomycin in a clinical setting.

We investigated achievement of a target 24-h area under the concentration-time curve to minimum inhibitory concentration ratio (AUC/MIC) ≥666 and the factors influencing this ratio in patients who received daptomycin (DAP) for infectious disease treatment in a clinical setting. The target AUC/MIC was obtained in 6 patients (35.3%) at a 4-6 mg/kg dose (Group_4-6 mg/kg) and in 4 (18.2%) at a >6 mg/kg dose (Group_>6 mg/kg). There was a significant difference in clearance of DAP (CL_DAP) between these groups, but no other difference in characteristics. Multiple linear regression analysis was performed for prediction of AUC ≥666 based on patient factors and the presence or absence of sepsis. In a stepwise analysis, serum creatinine (SCr) was a significant predictor of AUC, but this parameter explained only 13% of the variance in achievement of the target AUC. These results show that the target AUC/MIC may or may not be achieved at the doses used in Group_4-6 mg/kg and Group_>6 mg/kg. Receiver operating characteristic analysis suggested that a CL_DAP >0.450 L/hr may lead to failure to reach the target AUC/MIC. Therefore, regardless of dose, the efficacy of DAP should be monitored closely to prevent failure of infectious disease treatment, particularly because therapeutic drug monitoring of DAP is limited by difficulty measuring the DAP serum concentration at many medical facilities. Our findings are preliminary, and a further study is required to identify factors that increase CL_DAP and to enable dose adjustment of DAP.

Accuracy of multi-parametric breast MR imaging for predicting pathological complete response of operable breast cancer prior to neoadjuvant systemic therapy.

OBJECTIVES: To evaluate whether multiparametric breast-MRI, obtained before the initiation of neoadjuvant systemic therapy (NST) for operable breast cancer, predicts which cancer will achieve a pathological complete response (pCR) after the completion of NST. METHODS: This was an IRB-approved retrospective study on 31 consecutive patients (median age, 56 years) with operable invasive breast cancer (median size: 22 mm; triple-negative: 11/31 [35%], HER2-positive: 7/31 [23%], triple-positive: 13/31 [42%]) who underwent multiparametric DCE-MRI before the initiation of NST. The MRI protocol consisted of high-resolution dynamic contrast-enhanced MRI (DCE-MRI), T2-TSE, and DWI (b-values 0, 100, 800 s/mm2). The results of surgical pathology after the completion of NST served as a standard of reference. Patient characteristics (age and menopausal status), pathological tumor characteristics (type, stage, nuclear grade, ER/PR and HER2 receptor status, and Ki-67 staining), and MRI characteristics (size, morphology, T2 signal intensity, enhancement kinetics, and ADC values) before NST were evaluated and compared between patients achieving pCR vs. non-pCR. RESULTS: Among 31 patients, 17 achieved pCR (55%) and 14 non-pCR (45%). No correlation was observed between patient- or tumor pathology-derived characteristics and pCR vs. non-pCR. Among MRI-derived tumor characteristics, tumor growth orientation parallel to Cooper's ligaments (p = 0.002) and wash-out rates (p = 0.019) correlated with pCR. Pre-NST ADC values were lower in patients achieving pCR (P = 0.086). CONCLUSIONS: A tumor growth pattern parallel with Cooper's ligaments and a fast wash-out rate on pre-treatment multiparametric MRI are predictive of pCR and more closely associated with pCR than ADC values.

Prognostic value ​of Lung Cancer Subscale in older patients with advanced non-small cell lung cancer: An integrated analysis of JCOG0207 and JCOG0803/WJOG4307L (JCOG1414A).

OBJECTIVE: The Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire is commonly used for evaluating lung cancer-specific symptoms. The objective of this study was to elucidate the prognostic value of the LCS in older patients with advanced non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: We conducted an integrated analysis of data from two randomized phase III trials (JCOG0207, JCOG0803/WJOG4307L) including patients aged 70 years or older with advanced NSCLC to evaluate the prognostic value of LCS scores at baseline (Aim 1) and for symptom improvement (an increase in LCS of two points or more during treatment) (Aim 2). Multivariable analyses for survival, adjusted for baseline factors, were performed using a stratified Cox regression model with treatment regimen as a stratum. RESULTS: A total of 327 patients were included in the analysis for Aim 1 and 373 patients for Aim 2. Approximately 70% of patients were aged 75 or older. In Aim 1, use of descriptive statistics determined a cutoff point for baseline LCS score of 21. Multivariable analysis showed that higher baseline LCS was associated with favorable overall survival (OS) (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.52-0.89) and progression-free survival (HR: 0.68; 95% CI: 0.52-0.89). In Aim 2, symptom improvement was not associated with favorable OS (HR: 0.97; 95% CI: 0.72-1.23). CONCLUSION: It is recommended to consider baseline LCS scores while determining treatment strategies for older patients with advanced NSCLC.

Radiation recall dermatitis occurring 6 years and 4 months after breast-conserving surgery: A case report.

Currently in Japan, breast-conserving therapy, consisting of breast-conserving surgery and post-operative radiation therapy, is performed frequently for the treatment of invasive breast cancer. It has been demonstrated that radiation therapy not only prevents recurrence in the preserved breast, but that it also contributes to improved patient survival. The present study describes the case of a 37-year-old woman with radiation recall dermatitis that occurred 6 years and 4 months after breast-conserving surgery. Erythema with a relatively distinct border was observed at the irradiated site on the left breast; eczema was diagnosed by a dermatologist. Inflammatory breast cancer was ruled out, since chest X-ray, abdominal ultrasound and bone scintigraphy were negative. Following ~1 month of topical corticosteroid application and oral second generation antihistamine treatment, the erythema was alleviated and the subjective symptoms also disappeared. Only a few cases of radiation recall dermatitis have been described in the fields of radiology and dermatology, but not yet in the surgical field. In the future, the incidence of radiation recall dermatitis is predicted to increase due to the increasing number of patients undergoing breast-conserving therapy. Whether in the surgical, radiological or dermatological field, if erythema is detected at the irradiated site during post-operative follow-up, routine care should be provided, keeping in mind the possibility of radiation recall dermatitis and inflammatory breast cancer.

Randomized controlled trial comparing docetaxel-cisplatin combination with weekly docetaxel alone in elderly patients with advanced non-small-cell lung cancer: Japan Clinical Oncology Group (JCOG) 0207†.

OBJECTIVE: Prospective trials specifically designed for elderly patients with advanced non-small-cell lung cancer demonstrating the benefit of platinum-based therapies are still lacking. This trial was designed to clarify whether the addition of cisplatin to monotherapy could improve survival for elderly patients. METHODS: Elderly patients (age ≥70 years, ECOG performance Status 0-1) with advanced non-small-cell lung cancer were randomized to receive docetaxel 20 mg/m(2) plus cisplatin 25 mg/m(2) on Day 1, 8 and 15 (docetaxel plus cisplatin) or docetaxel 25 mg/m(2) on the same schedule (docetaxel). Both regimens were repeated every 4 weeks until disease progression. RESULTS: One hundred and twenty-six patients were enrolled. Sixty-three were randomly assigned docetaxel plus cisplatin and 63 docetaxel monotherapy. Median age was 76 years (range 70-88). The second planned interim analysis was performed on 112 assessable patients (docetaxel/docetaxel plus cisplatin: 56/56). Although the formal criterion for stopping the trial was not met, the Data and Safety Monitoring Committee recommended study termination on ethical grounds based on the interaction (two-sided P = 0.077, hazard ratios for ≤74/≥75: 0.23/0.72) between age and subgroup and treatment arm, which suggested that docetaxel may not represent an adequate control arm regimen for the age subgroup of 70-74 years. CONCLUSIONS: The interpretation of study results is limited due to early stopping. Further study is needed to confirm survival benefit of platinum-based chemotherapy for elderly non-small-cell lung cancer [UMIN-CTR (www.umin.ac.jp/ctr/) ID: C000000146].

Diagnostic yield of preoperative computed tomography imaging and the importance of a clinical decision for lung cancer surgery.

PURPOSE: This study aimed to evaluate the diagnostic yield of preoperative computed tomography (CT) imaging and the validity of surgical intervention based on the clinical decision to perform surgery for lung cancer or suspected lung cancer. METHODS: We retrospectively evaluated 1755 patients who had undergone pulmonary resection for lung cancer or suspected lung cancer. CT scans were performed on all patients. Surgical intervention to diagnose and treat was based on a medical staff conference evaluation for the suspected lung cancer patients who were pathologically undiagnosed. We evaluated the relation between resected specimens and preoperative CT imaging in detail. RESULTS: A total of 1289 patients were diagnosed with lung cancer by preoperative pathology examination; another 466 were not pathologically diagnosed preoperatively. Among the 1289 patients preoperatively diagnosed with lung cancer, the diagnoses were confirmed postoperatively in 1282. Among the 466 patients preoperatively undiagnosed, 435 were definitively diagnosed with lung cancer, and there were 383 p-stage I disease patients. There were 38 noncancerous patients who underwent surgery with a diagnosis of confirmed or suspected lung cancer. Among the 1755 patients who underwent surgery, 1717 were pathologically confirmed with lung cancer, and the diagnostic yield of preoperative CT imaging was 97.8%. Among the 466 patients who were preoperatively undiagnosed, 435 were compatible with the predicted findings of lung cancer. CONCLUSION: Diagnostic yields of preoperative CT imaging based on clinical evaluation are sufficiently reliable. Diagnostic surgical intervention was acceptable when the clinical probability of malignancy was high and the malignancy was pathologically undiagnosed.

[Chronic intestinal pseudo-obstruction as a paraneoplastic presentation of limited-stage small cell lung cancer].

A 53-year-old woman with chief complaints of vomiting and constipation was given a diagnosis of ileus and admitted to a local hospital. The origin of the ileus was unknown despite intensive examinations. However, her chest X-ray film and CT showed left hilar and mediastinal lymphadenopathy. Her pro-gastrin-releasing peptide (ProGRP) levels were elevated. After transfer to our hospital, the diagnosis of small cell lung cancer (SCLC) was confirmed by transbronchial aspiration cytology. Since no cause of ileus was found on laparotomy, her symptoms were considered to indicate chronic intestinal pseudo-obstruction (CIPO), a manifestation of paraneoplastic neurological syndrome. Serum anti-Hu antibody testing was positive. Chemoradiotherapy induced complete remission and her abdominal symptoms markedly improved. This is a very rare case of CIPO accompanied with SCLC, which improved after immediate anti-tumor therapy for lung cancer.

A case of rapidly growing pulmonary carcinosarcoma.

We report herein a case of rapidly growing pulmonary carcinosarcoma, a rare and highly malignant lung neoplasm characterized by a biphasic histopathological pattern consisting of both epithelial and sarcomatous components, and we also summarize the clinical features of this entity based on previously reported cases. A 65-year-old man was referred for further examination of a lung tumor after a routine chest X-ray (CXR) showed a tumor shadow in the right upper lung zone. Chest computed tomography (CT) found a 2.0 cm pulmonary mass with suspected chest wall invasion in the right upper lobe, although cytological evidence of malignancy could not be obtained despite repeated preoperative bronchoscopy. The tumor grew rapidly, indicating the possibility of lung cancer. A right upper lobectomy with chest wall excision was performed. The postoperative definitive diagnosis was carcinosarcoma consisting of adenocarcinoma and chondrosarcoma. The pathological stage was p-T3N0M0. The patient subsequently received adjuvant chemotherapy with cisplatin and vinorelbine. Routine follow-up chest CT 7 months after the surgery showed pleural dissemination. Consequently he underwent radiotherapy, but the disseminated tumors enlarged further while he received this treatment. The patient is receiving best supportive care at present. Findings based on previously reported cases and our case suggest that early surgical intervention and combined therapeutic strategy are the most important aspects of treatment for pulmonary carcinosarcoma.

[Successful corticosteroid therapy of a recurrent thymoma with pure red cell aplasia].

A 71-year-old man underwent extended thymomectomy with partial resection of the upper lobe of the left lung and pericardium for stage III invasive thymoma in March, 2000. Postoperative chemotherapy and radiation therapy were carried out. The patient did well until June 2005, when a mediastinal mass and pleural dissemination were detected. The recurrence of the thymoma was strongly suspected radiographically. Combination chemotherapy of carboplatin and paclitaxel achieved partial remission. About three months after the last chemotherapy, the patient had a severe anemia in February 2006. Based on the blood data and the bone marrow examination, pure red cell aplasia was diagnosed. Prednisolone treatment (50 mg daily) resulted in dramatic regression of recurrent mediastinal and pleural tumors, as well as improvement of pure red cell aplasia.

Resected well-differentiated fetal pulmonary adenocarcinoma and summary of 25 cases reported in Japan.

We report a case of well-differentiated fetal adenocarcinoma (WDFA), which is a variant of pulmonary blastoma. A 36-year-old man was found to have a tumor shadow in the right middle field of a chest radiograph as part of a mass screening examination, and chest computed tomography (CT) showed a 4.5-cm pulmonary mass in the right lower lobe. A diagnosis of adenocarcinoma of the lung was made based on a CT-guided needle biopsy, and right middle and lower lobectomy and lymph node dissection were performed. The postoperative pathological diagnosis was well-differentiated fetal adenocarcinoma. WDFA has a better prognosis than conventional pulmonary blastoma (biphasic pulmonary blastoma). We summarize the cases of WDFA reported in Japan and review the literature.

The efficacy of lung cancer screening conducted in 1990s: four case-control studies in Japan.

The efficacy of lung cancer screening is still controversial. In order to evaluate efficacy of mass screening for lung cancer in 1990s, the Japanese Ministry of Health and Welfare planned to conduct four independent case-control studies in four different regions; Miyagi, Gunma, Niigata, and Okayama Prefecture. The study design of all the four studies was a matched case-control study in which the decedents from lung cancer were defined as cases. In Gunma Prefecture, a screening examination is annual miniature chest X-ray only, whereas sputum cytology is added for high-risk screenees in others. Matching conditions were gender, year of birth, smoking histories (except Okayama), and municipality. Smoking adjusted odds ratio (OR) of dying from lung cancer for those screened within 12 months before case diagnosis compared with those not screened ranged 0.40-0.68. Three of four studies revealed statistically significant reduction of the risk for lung cancer death. OR of pooled analysis, where all sets were combined and analyzed, was 0.56 (95% confidence interval: 0.48-0.65). Recent mass screening program for lung cancer in Japan could reduce the risk for lung cancer death. However, the possibility exists that some confounding factors affected the results. In order to elucidate whether the results can be applied to Western countries, further studies will be required.