Prognostic value of the 21-Gene Breast Recurrence Score® assay for hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer: subanalysis from Japan Breast Cancer Research Group-M07 (FUTURE trial).

PURPOSE: This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial). METHODS: Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV). RESULTS: In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04-0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06-0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B. CONCLUSION: We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required.

Prognostic Value of MRI Assessment of Residual Peritumoral Edema in Breast Cancer Treated With Neoadjuvant Chemotherapy.

BACKGROUND: Peritumoral edema (PE) identified on T2-weighted breast MRI is a factor for poor prognosis in breast cancer. PURPOSE: To assess the prognostic value of residual PE (rPE) in patients with PE positive breast cancer prior to neoadjuvant chemotherapy (NACT) who subsequently underwent curative surgery. STUDY TYPE: Retrospective. POPULATION: In total, 128 patients with nonmetastatic invasive breast cancer who underwent breast MRI before and after NACT. FIELD STRENGTH/SEQUENCE: Axial precontrast 2D fast spin echo T2W fat-suppressed sequence. Axial dynamic 3D gradient echo T1W fat-suppressed sequence. ASSESSMENT: PE was diagnosed when a signal intensity as high as water was detected surrounding the tumor on a T2-weighted breast MRI. PE was qualitatively evaluated by three readers with more than 20 years of experience in interpreting breast field imaging findings. Residual cancer burden (RCB) were assessed post-NACT. Recurrence-free survival (RFS) and overall survival (OS) were evaluated as the endpoints of this study. STATISTICAL TESTS: Chi-square test; Kaplan-Meier method, log-rank test, and Cox proportional hazard model. A P-value <0.05 was considered statistically significant. RESULTS: Pre-PE was observed in 64 out of 128 patients. Of these, rPE was observed in 21. In the log-rank test, breast cancer with rPE had significantly worse RFS and OS than that without rPE. Cox proportional hazard analysis identified rPE as a significant prognostic factor for recurrence (hazard ratio, 11.6; 95% confidence interval [CI], 3.05-43.8) and death (hazard ratio, 17.8; 95% CI, 3.30-96.3). Breast cancer with rPE had significant worse RFS and OS than that without rPE in RCB class II, and significant worse OS in pathological complete response, class I and class II in the log-rank test. DATA CONCLUSION: rPE on a T2-weighted breast MRI was a significant factor for breast cancer recurrence and death in patients with pre-PE-positive breast cancer treated with NACT. TECHNICAL EFFICACY: Stage 2.

A nomogram to predict the pathological complete response in patients with breast cancer based on the TILs-US score.

BACKGROUND: The tumor-infiltrating lymphocytes-ultrasonography score is a calculation system for predicting lymphocyte-predominant breast cancers in surgical specimens. A nomogram based on the tumor-infiltrating lymphocytes-ultrasonography score was developed to predict the pathological complete response in breast cancer treated with neoadjuvant chemotherapy. METHODS: A retrospective evaluation was conducted on 118 patients with breast cancer treated with neoadjuvant chemotherapy at Hiroshima University Hospital. Tumor-infiltrating lymphocytes-ultrasonography scores ≥4 were classified as high. A nomogram was developed using a stepwise logistic regression model for pathological complete response (ypT0 ypN0), based on the smallest Akaike information criterion. The predictive ability and clinical usefulness of the nomogram were also evaluated. RESULTS: Among 118 patients, 34 (28.8%) achieved a pathological complete response, and 52 (44.1%) exhibited high tumor-infiltrating lymphocytes-ultrasonography. In multivariate logistic regression analysis, high tumor-infiltrating lymphocytes-ultrasonography (odds ratio, 6.01; P < 0.001), clinical complete response (odds ratio, 4.83; P = 0.004) and hormone receptor (odds ratio, 3.48; P = 0.038) were independent predictors of pathological complete response. A nomogram based on tumor-infiltrating lymphocytes-ultrasonography score, clinical complete response, hormone receptor and clinical N status was developed. The nomogram showed an area under the curve of 0.831 and a bias-corrected area under the curve of 0.809. The calibration plot showed a good fit between the expected and actual pathological complete response values. Decision curve analysis also showed the clinical utility of the nomogram for predicting pathological complete responses. CONCLUSIONS: A nomogram based on the tumor-infiltrating lymphocytes-ultrasonography score exhibited a favorable predictive ability for pathological complete response in patients with breast cancer, which can be useful in predicting the residual disease status after neoadjuvant chemotherapy.

Methylprednisolone pulse therapy in 31 patients with refractory epilepsy: A single-center retrospective analysis.

PURPOSE: We investigated the efficacy of methylprednisolone pulse therapy (MP) and responder characteristics in patients with refractory epilepsy. METHODS: We reviewed medical records of our center to identify patients with refractory epilepsy treated with MP other than continuous spikes and waves during slow sleep (CSWS), Landau-Kleffner syndrome (LKS), or Rasmussen's syndrome (RS) between 2004 and 2015. A course of MP consisted of intravenous methylprednisolone (30 mg/kg/day) on three consecutive days. Patients received multiple courses at intervals of four weeks. We examined seizure outcome, developmental outcome, antibodies to N-methyl-d-aspartate (NMDA)-type glutamate receptors (GluRs), cerebral spinal fluid (CSF)-albumin/serum-albumin ratio, and interictal electroencephalograms (EEGs). Responder to MP was defined as maintaining seizure reduction rate (SRR) ≥50% for three months after the first course of MP. RESULTS: Thirty-one consecutive patients treated with MP at our center were studied. Seizure types were focal onset impaired awareness seizure (FIAS) only (n = 23), FIAS with epileptic spasms (ES) (n = 7), and ES only (n = 1). Responder rate was 32.2% (10/31 patients), and seizure-free rate was 9.7% (3/31). Responders constituted 43.5% of patients without ES. No patient with ES was responder. Behavior and cognition also improved in 6 of 10 responders. History of seizure aggravation after inactivated vaccine before MP was found significantly higher rate in responder patients, comparing with nonresponder patients (p = 0.01). CONCLUSION: Methylprednisolone pulse therapy may be considered for possible treatment in patients with focal epilepsy with drug-resistant seizures without ES, and it may improve cognitive function and behavioral comorbidities.

Omitting surgery for early breast cancer showing clinical complete response to primary systemic therapy.

Breast cancer is highly sensitive to systemic therapy. High probability of pathological complete response suggests a clinical question that omitting surgery is an effective alternative to surgery in breast cancer showing clinical complete response to primary systemic therapy. However, the validity of omitting surgery for early breast cancer after primary systemic therapy has not been sufficiently established; thus, even if pathological complete response is expected in patients showing clinical complete response, excision of the primary tumor site remains the standard treatment of breast cancer. Inappropriate omitting surgery increases the incidence of local recurrence, which can be the risk of a subsequent distant metastasis and reduced overall survival. To achieve acceptable local control rate, omitting surgery should be investigated in patients with early breast cancer where a high percentage of pathological complete response, a high concordance rate between clinical complete response and pathological complete response and an acceptable local control rate are expected. This review presents concept and ongoing clinical trials for omitting surgery for patients with breast cancer showing clinical complete response to primary systemic therapy.

Cryotherapy for the prevention of weekly paclitaxel-induced peripheral adverse events in breast cancer patients.

PURPOSE: This randomized phase II study was conducted to investigate the efficacy of cryotherapy in preventing peripheral neuropathy and dermatological adverse events in breast cancer patients treated with weekly paclitaxel. METHODS: Patients treated with 12 weekly doses of paclitaxel for breast cancer were randomized (1:1) into a cryotherapy or control group. The primary endpoint was the percentage of patients with a marked decrease in the Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-NTX) score. The secondary endpoints were Patient Neurotoxicity Questionnaire (PNQ), Common Terminology Criteria for Adverse Event (CTCAE) for peripheral neuropathy, and FACT-Taxane score. RESULTS: Forty-four patients were randomly assigned to the cryotherapy (n = 22) or control groups (n = 22). The percentage of patients with a marked decrease in FACT-NTX scores was significantly lower in the cryotherapy group than in the control group (41 vs. 73%, p = 0.03). The incidence of CTCAE grade ≥ 2 sensory (p = 0.001) and motor peripheral neuropathy (p = 0.01), and PNQ grade D or higher for sensory peripheral neuropathy (p = 0.02), and decrease in the FACT-Taxane score (p = 0.02) were also significantly lower in the cryotherapy group than in the control group. There were no serious side effects associated with cryotherapy. CONCLUSION: Cryotherapy is an effective approach for prevention of peripheral neuropathy and dermatological adverse events in breast cancer patients treated with weekly paclitaxel.

[Prognostic Value of Basal Marker Expression in Early Stage Breast Cancer].

The expression of basal marker could be a significant factor for poor prognosis in early stage breast cancer. We evaluated the prognostic value of basal marker in each breast cancer subtype. According to immunohistochemistry assay, CK5/6-posi- tive and/or EGFR-positive was defined as basal marker-positive. A total of 497 consecutive, non-metastatic invasive breast cancers were evaluated, and 166 cases(33%)were defined as basal marker-positive. Overall, basal marker expression was not a significant prognostic factor for breast cancer recurrence. However, according to Cox regression analysis, basal markerpositivity was significantly associated with poor recurrence-free survival in 63 cases with TNBC(hazard ratio: 2.9, 95% confidence interval: 1.5-5.8, p=0.001). Therefore, evaluation of basal marker expression could be useful for the risk estimation of recurrence in TNBC.

Minimal prognostic significance of sentinel lymph node metastasis in patients with cT1-2 and cN0 breast cancer.

BACKGROUND: The prognostic value of sentinel lymph node (SLN) metastases may be minimized by the limited disease burden of lymph node metastases and tailoring adjuvant therapy based on breast cancer biology. The aim of this study is to assess the prognostic significance of SLN metastasis in patients with cT1-2N0M0 breast cancer. PATIENTS AND METHODS: Between January 2006 and December 2015, 582 patients underwent SLN biopsy for cT1-2N0M0 breast cancers. cN0 was essentially diagnosed by ultrasound sonography. The prognostic values of SLN metastases were retrospectively evaluated. RESULTS: Among 582 patients with cT1-2N0M0 breast cancer, 111 patients (19.1%) were positive for SLN metastasis, including 39 cases (6.7%) of micrometastasis and 72 cases (12.4%) of macrometastases. The median size of SLN metastasis was 3.0 mm (range 0.2-16 mm, mean 4.1 mm). In log-rank test, presence of SLN metastasis was not associated with breast cancer recurrence (p = 0.21); 5-year and 10-year recurrence-free survival (RFS) were 93.0% and 96.5%, and 93.0% and 90.4% in the SLN-positive and SLN-negative groups, respectively. In the propensity score matching cohort (n = 178), there was no significant difference in RFS between the SLN-positive and SLN-negative groups (p = 0.90). In Cox regression analysis, a continuous value of Ki67 expression was a significant prognostic factor (HR 1.03; 95% CI 1.01-1.05, p = 0.017). CONCLUSION: SLN metastasis has a minimal impact on RFS for patients with cT1-2N0M0 breast cancer in the modern medical era. A proliferation marker is a better factor for poor prognosis than the presence of SLN metastases in this population.

Ability of contrast-enhanced ultrasonography to determine clinical responses of breast cancer to neoadjuvant chemotherapy.

OBJECTIVE: We aimed to determine whether contrast-enhanced ultrasonography can predict the effects of neoadjuvant chemotherapy on breast cancer. METHODS: The clinical responses of 63 consecutive patients with breast cancer (T1-4, N0-1, M0) to neoadjuvant chemotherapy between October 2012 and May 2015 were assessed using contrast-enhanced magnetic resonance imaging, positron emission tomography/computed tomography and contrast-enhanced ultrasonography. Perfusion parameters for contrast-enhanced ultrasonography were created from time-intensity curves based on enhancement intensity and temporal changes to objectively evaluate contrast-enhanced ultrasonography findings. The sensitivity, specificity and accuracy of contrast-enhanced ultrasonography, magnetic resonance imaging and positron emission tomography/computed tomography to predict a pathological complete response were compared after confirming the pathological findings of surgical specimens. RESULTS: Twenty-three (36.5%) of the 63 patients achieved pathological complete response. The sensitivity, specificity and accuracy of contrast-enhanced ultrasonography for predicting pathological complete response were 95.7% (82.5-99.2%), 77.5% (69.9-79.5%) and 84.1% (74.5-86.7%). The sensitivity of contrast-enhanced ultrasonography was significantly greater than that of magnetic resonance imaging (95.7 vs. 69.6%, P = 0.047). The specificity and accuracy were significantly greater and tended to be greater, respectively, for contrast-enhanced ultrasonography than positron emission tomography/computed tomography (specificity, 77.5 vs. 52.5%, P = 0.02; accuracy, 84.1 vs. 69.8%, P = 0.057). CONCLUSIONS: Contrast-enhanced ultrasonography might serve as a new diagnostic modality when planning therapeutic strategies for patients with breast cancer after neoadjuvant chemotherapy.

Utility of (18)F FDG-PET/CT for predicting prognosis of luminal-type breast cancer.

Postoperative prognosis is better for hormonal receptor-positive breast cancer than for other phenotypes; however, there are no definitive predictive factors for relapse or survival. This study aimed to evaluate the maximum standardized uptake value (SUVmax) on (18)F-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) and clinicopathological characteristics as possible predictors of postoperative relapse-free survival (RFS) and overall survival (OS) in hormonal receptor-positive breast cancer patients. We evaluated 262 patients with Stage I-III breast cancer diagnosed as luminal type (luminal A, 166; luminal B, 96 patients) who underwent preoperative FDG-PET/CT between January 2006 and December 2011 at two institutions. The relationships among SUVmax and clinicopathological factors (age, clinical T/N stage, nuclear grade, lymph node metastasis and vascular invasion) were evaluated. A phantom study was performed to correct differences in PET/CT analysis between two institutions. The patients were divided according to the SUVmax cutoff on receiver operating characteristic (ROC) analysis for OS (≤6.0 group vs. >6.0 group, AUC = 0.742). Clinical T-factor and nuclear grade were significantly correlated with SUVmax (p < 0.0001 and p = 0.0092, respectively). In the uni- and multivariate analyses using the Cox model for relapse, SUVmax was significant (p = 0.013 and p = 0.055, respectively) among characteristics. RFS curves showed that prognosis was significantly better for the SUVmax ≤ 6.0 group than for the SUVmax > 6.0 group (p = 0.004). Similarly, SUVmax was significant for OS (p = 0.007 and p = 0.008). OS was significantly different between the SUVmax ≤ 6.0 and >6.0 groups (p < 0.001). SUVmax was useful for predicting outcomes in patients with luminal-type breast cancer.

Clinical Significance of Extracapsular Invasion at Sentinel Lymph Nodes in Breast Cancer Patients with Sentinel Lymph Node Involvement.

BACKGROUND: A certain number of patients have extracapsular invasion (ECI) at the sentinel lymph node (SLN), but only a few reports describe its clinical significance. This study aimed to determine the clinical significance of ECI at SLN in breast cancer patients with involved SLN. METHODS: This study evaluated ECI at SLN in 131 consecutive SLN-positive patients who underwent axillary lymph node dissection between 2003 and 2008 at the National Kyushu Cancer Center with regard to their long-term prognosis and non-SLN metastasis. RESULTS: Of the 131 patients, 46 (35 %) tested positive for ECI at SLN. Of these 46 patients, 61 % (28/46) had non-SLN metastasis compared with 28 % (24/85) in ECI-negative group (χ (2) test; P < 0.001). Multivariate analysis showed that ECI at SLN is significantly predictive for non-SLN metastasis [hazard ratio (HR) 3.2; 95 % confidence interval (CI) 1.4-7.1; P = 0.005]. The 5-year recurrence-free survival (RFS) rates were 71.3 % in the ECI-positive group and 89.9 %in the ECI-negative group (P = 0.001, log-rank test). Cox-regression analysis showed that ECI at SLN independently predicts lower RFS (HR 4.5; 95 % CI 1.8-11.7; P = 0.002). CONCLUSIONS: The findings show that ECI at SLN is an independent predictor of both non-SLN metastasis and poor prognosis for breast cancer patients with involved SLN. The clinical significance of ECI at SLN in operable-stage breast cancer warrants further study.

Individualized phenytoin therapy for Japanese pediatric patients with epilepsy based on CYP2C9 and CYP2C19 genotypes.

BACKGROUND: The aims of this study were to identify the target dose of phenytoin (PHT) and to compare the treatment continuation rate between patients receiving conventional therapy and patients receiving individualized therapy based on genotyping of the CYP2C9*3, CYP2C19*2, and CYP2C19*3 alleles. The operational definition for the target dose of PHT used in this study was the dose that yielded a steady-state PHT concentration within the range of 15-20 mcg/mL without dose-related adverse effects. METHODS: We investigated 394 samples from 170 Japanese pediatric patients aged 9 months to 15 years to identify factors that influenced the target dose of PHT. We also analyzed the clinical records of 156 patients who commenced PHT therapy at our hospital and retrospectively assessed the time to treatment failure within 1 year after starting PHT therapy. During the study period, 17 patients underwent genotyping at the start of PHT therapy. If the patients had the CYP2C9*3, CYP2C19*2, or CYP2C19*3 alleles, the initial dose of PHT was reduced by 10%-50% according to previous reports. The other 139 patients received conventional PHT therapy. RESULTS: According to multiple regression analysis, the body weight, concomitant use of sulthiame, and the CYP2C9*3, CYP2C19*2, and CYP2C19*3 alleles influenced the target dose of PHT. Our model explained 74% of the interindividual variability of the target dose of PHT. The total withdrawal rate in the individualized therapy group and the conventional therapy group was 23.5% and 33.1%, respectively. The adjusted hazard ratio for withdrawal of PHT therapy in the individualized therapy group was 0.37 (95% confidence interval; 0.12-1.10, P = 0.074). CONCLUSIONS: These findings suggest that genotyping can help to estimate the optimum target dose of PHT and may contribute to avoid intoxication and concentration-dependent adverse effects.

Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.

OBJECTIVE: This study attempted to clarify the long-term course of Dravet syndrome (DS). METHODS: Sixty-four patients diagnosed with DS (44 with typical DS, and 20 with atypical DS) were studied. The long-term outcomes of clinical seizures, electroencephalographic findings, neuropsychological findings, and social situation were analyzed. The follow-up period ranged from 11 to 34 years 5 months (median 24 years). RESULTS: At the last visit, the ages ranged from 19 years to 45 years (median 30 years). Fifty-nine patients continued to have generalized tonic-clonic seizures (GTCS). Status epilepticus and unilateral seizures were not observed and myoclonic seizures, atypical absence seizures, and photosensitive seizures were resolved in most patients. The frequency of complex partial seizures was equally low, with five patients at presentation and six patients at the last visit, respectively. Five patients achieved seizure remission (seizure-free for 1 year or longer). Only 1 of 44 patients with typical DS had seizure remission, whereas 4 of 20 patients with atypical DS remitted, with a statistically significant difference between the two phenotypes (p = 0.03). Intellectual disability was found in all patients; especially, severe intellectual disability was prevalent. Patients with atypical DS tended to have milder intellectual disability compared to those with typical DS (p = 0.0283). Occipital alpha rhythm in the basic activity was associated with milder intellectual disability (p = 0.0085). The freedom from seizures correlated with appearance of occipital alpha rhythms (p = 0.0008) and disappearance of epileptic discharges (p = 0.0004). Two patients with GTCS died. Mutations of the neuronal voltage-gated sodium channel alpha subunit type 1 gene were detected at a high frequency (33 of 36 patients examined). Seizure remission was found only in the missense mutation group. SIGNIFICANCE: The long-term seizure and intellectual outcomes are extremely poor in patients with typical DS compared to those with atypical DS. Epilepsy phenotype may influence long-term course of DS.

[Efficacy of repeated adrenocorticotropic hormone therapy in patients with intractable epileptic spasms].

OBJECTIVE: We examined the effectiveness of repeated adrenocorticotropic hormone (ACTH) therapy in short-term and long-term seizure control in patients with intractable epileptic spasms. METHODS: Twenty-five patients with intractable spasms, in whom epileptic seizures were not controlled or relapsed after the first ACTH therapy, were given repeated ACTH therapy. The short-term effect (seizure control longer than two months) of repeated ACTH therapy was analyzed, and the long-term effect was estimated by Kaplan-Meier method. RESULTS: Short-term seizure control by repeated ACTH therapy was achieved in 13 of 25 patients (52.0%), and in 5 of 13 patients, seizures were controlled by ACTH therapy at higher doses compared with the first ACTH therapy. Short-term effectiveness was obtained in 76.5% of patients who had epileptic spasms alone at the time of the second ACTH therapy, but was ineffective in all 8 patients who had multiple types of seizures, with relapses within 2 months. Short-term effectiveness was not associated with clinical factors such as onset age, age of repeated ACTH treatment, and EEG findings. Regarding the long-term effect of repeated ACTH therapy, the period until seizure relapse was significantly longer in patients with epileptic spasms alone compared to patients with multiple seizure types. Spasms were controlled in 5 of 25 cases (20.0%) at the final observation. In patients with multiple seizure types and patients with onset age older than eight months, seizure control was not obtained. Long-term outcome was good in patients with treatment lag within 2 months. CONCLUSION: In repeated ACTH therapy, seizure type seems to be one of the major determinants for short- and long-term seizure outcome.

Persistent weekly paclitaxel-induced peripheral neuropathy in early breast cancer patients enrolled in a randomized trial of cryotherapy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of weekly paclitaxel-based chemotherapy for breast cancer, that can persist for years. Cryotherapy therapy is effective for preventing early CIPN, but its protective effect on persistent CIPN is uncertain. This is a cross-sectional study conducted as an ancillary analysis of a randomized trial investigating the preventive effect of cryotherapy on CIPN in breast cancer patients receiving weekly paclitaxel-based chemotherapy (UMIN000034966). Eligible patients were evaluated for CIPN at more than a year after completion of the chemotherapy (persistent CIPN). CIPN was defined as a 6 or more points reduction from baseline in the Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-NTX) score. The incidence of early and persistent CIPN was compared between cryotherapy and control groups. Thirty-eight patients were examined for both early and persistent CIPN. The median time from completion of the weekly paclitaxel-based chemotherapy to the questionnaire for persistent CIPN was 2.3 (1.3-3.1) years. In all 38 patients, persistent CIPN was demonstrated in 10 (26.3%), respectively. There was a numerical, however not significant, reduction in the incidence of persistent CIPN (15.8% vs 36.8%, P = .1) in the cryotherapy group compared with the control group, respectively. In multivariate logistic regression analysis, age ≥ 65 was a substantial risk factor for persistent CIPN (HR: 14.7, 95%CI: 1.7-130.7, P = .01). In breast cancer patients receiving adjuvant weekly paclitaxel-based chemotherapy, cryotherapy resulted in a numerical, however not significant, reduction in the incidence of persistent CIPN and age>=65 was a risk factor for persistent CIPN.

Ipsilateral breast tumor recurrence (IBTR) in patients with operable breast cancer who undergo breast-conserving treatment after receiving neoadjuvant chemotherapy: risk factors of IBTR and validation of the MD Anderson Prognostic Index.

BACKGROUND: There is limited information about the risk factors for ipsilateral breast tumor recurrence (IBTR) after patients undergo breast-conserving surgery plus radiotherapy (breast-conserving treatment [BCT]) subsequent to neoadjuvant chemotherapy (NAC). The objective of the current study was to analyze these risk factors. METHODS: The authors collected data from 375 patients who underwent BCT and received NAC and analyzed the risk of IBTR associated with undergoing BCT after NAC. The usefulness of the MD Anderson Prognostic Index (MDAPI) for IBTR also was validated using the current data set. RESULTS: The median follow-up was 47.8 months, and the 4-year IBTR-free survival rate was 95.6%. Multivariate analysis demonstrated that estrogen receptor (ER) status and multifocality of the residual tumor were associated significantly with IBTR-free survival. In addition, patients who had ER-positive and human epidermal growth factor 2 (HER2)-negative tumors did not develop IBTR during the observation period. Although prognostic stratification according to MDAPI was relatively good for the prediction of IBTR in the study patients, the IBTR rate in the high-risk group was not very high and was lower than that in the intermediate-risk group. Multivariate analyses demonstrated that IBTR was an independent predictive factor for overall survival. CONCLUSIONS: ER status and multifocality of the residual tumor after NAC were independent predictors of IBTR after BCT. The MDAPI was barely adaptable to the study patients in terms of predicting IBTR. Patients with ER-positive and HER2-negative tumors had a favorable prognosis, whereas patients who developed IBTR after NAC had significantly worse overall survival. The authors propose a new IBTR prognostic index using the 2 factors that were identified as predictive of IBTR: ER status and multifocality of the residual tumor.

[Sleepiness:a frequent adverse reaction of antiepileptic drugs in patients with epilepsy after encephalitis/encephalopathy].

OBJECTIVE: Patients with epilepsy after encephalitis/encephalopathy (EAE) are often on polytherapy with anti-epileptic drugs (AEDs), and are at risk of adverse reactions. We examined the adverse effects of AEDs, especially sleepiness, in these patients. METHODS: In this retrospective study, the medical records of 66 patients who were diagnosed with EAE in our hospital were reviewed and the clinical characteristics were analyzed. Immunological biomarkers including cytokines, chemokines, granzyme B, soluble tumor necrosis factor receptor 1, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 were also investigated. RESULT: The mean onset age of acute encephalitis was 9 years and 1 month and the mean interval from onset of acute encephalitis to onset of epilepsy was 6.4 months. Sleepiness induced by AEDs was observed in 26 of 66 patients (39.3%). The incidence of sleepiness was high in patients treated with clorazepate (75%), lamotrigine (66.7%), and ethosuximide (40%). Comparing the AEDs used by more than 20 patients, the incidence of sleepiness was high for clonazepam (30.4%) and phenytoin (25.8%). IgG, protein, and albumin levels in cerebrospinal fluid were significantly higher in patients affected by sleepiness than in those not affected. IL-8 in cerebrospinal fluid was significantly higher in the group with sleepiness compared to that without. Serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels were not different between the two groups. CONCLUSION: Long-lasting blood-brain barrier dysfunction and proliferation of immature vessels induced by IL-8 may contribute to the occurrence of sleepiness as an adverse effect of AEDs in patients with EAE. We recommend to assess for blood-brain barrier dysfunction when choosing AEDs for treating patients with intractable EAE.

[High incidence-rate of oral mucositis in breast cancer patients receiving anthracycline-based chemotherapy (FEC100)].

BACKGROUND: Oral mucositis is a frequent complication, but is poorly studied among patients with solid tumors. The purpose of this study is to clarify the incidence rate of oral mucositis in Japanese breast cancer patients receiving anthracycline-based chemotherapy(FEC100). METHODS: From June 2007 to July 2008, 61 breast cancer patients eligible for this study received anthracycline-based chemotherapy(FEC100: 5-FU 500mg/m / / 2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)at National Kyushu Cancer Center and Iwate Medical University Hospital. The incidence rate and grade of oral mucositis were evaluated in these patients. RESULTS: The cumulative incidence of oral mucositis was about 50%. Episodes of oral mucositis were more common during courses with febrile neutropenia than during courses without it(75. 0% vs 44. 9%, p=0. 12). The reduction of oral mucositis was only 13. 6% after administering the steroidal ointment and/or mouthwash, including sodium azulene sulfonate. CONCLUSIONS: New methods are needed to prevent and treat oral mucositis in patients receiving anthracycline- based chemotherapy(FEC100).

[A resected case of complete response after treatment with S-1 for recurrent squamous cell carcinoma component of the breast].

A resected case of complete response after treatment with S-1 for recurrent squamous cell carcinoma component of the breast is presented.A 65-year-old woman was admitted to another hospital because of a left breast tumor. A tumor approximately 6 cm in diameter was palpable in the subareolar-lower (DBE) region of the left breast; the diagnosis was breast cancer. We performed mastectomy and axillary lymph node dissection. The pathological diagnosis revealed squamous cell carcinoma of the left breast(pT3N1M0, Stage III A). FEC chemotherapy, a standard chemotherapy regimen for general breast cancer, was performed as first-line adjuvant therapy, but was withdrawn after 1 course due to sepsis shock. Weekly PTX chemotherapy as second-line treatment was also withdrawn after six courses due to interstitial pneumonia. Few skin rashes were observed along the incision scar of the left breast, but biopsy revealed skin invasion by local recurrence of squamous cell carcinoma of the breast. Treatment with S-1 was performed for 8 months, and she underwent resection of left skin, fat tissue, and underlying muscle, including the recurrent region. No residual primary carcinoma foci was found in the resected specimen; therefore, the pathological diagnosis revealed complete response for the squamous cell carcinoma component.

The ratio of CD8 + lymphocytes to tumor-infiltrating suppressive FOXP3 + effector regulatory T cells is associated with treatment response in invasive breast cancer.

PURPOSE: FOXP3 + and CD8 + are recognized markers of tumor-infiltrating lymphocytes (TILs) for breast cancer. FOXP3 + TILs are composed of effector Tregs (eTregs) and other subpopulations that are classified by their differences in suppressive function. In this prospective study, we evaluated Treg subpopulations and CD8 + TILs in breast cancer. METHODS: 84 patients with breast cancer were enrolled. Fresh TILs were extracted andTregs were classified into eTregs (CD4+FOXP3highCD45RA-), other FOXP3+ Treg subsets (naïve and non-Tregs), and total CD8+CD4- TILs using flow cytometry. The suppression strength of each Treg subpopulation was analyzed. The association between TIL subpopulations, clinicopathological characteristics, and response to chemotherapy was evaluated. RESULTS: The mean CD8/eTreg ratio value was 7.86 (interquartile range: 4.08-12.80). The proliferation function of eTregs was significantly suppressed compared with that of the other subpopulations (proliferation rates: control: 89.3%, + naiiveTreg: 64.2%, + non-Treg: 78.2% vs eTreg 1.93%; all P < 0.05). The patients with high with a high CD8 + /eTreg ratio achieved excellent pathological complete response (pCR) rate of neoadjuvant chemotherapy (90.2%) and the CD8/eTreg ratio were independent predictive factors for pCR (odds ratio:18.7(confidence interval 1.25-279) P < 0.05). A detailed assessment of the CD8/eTreg ratio for each patient who underwent NAC revealed that high CD8/eTreg ratio showed a significantly higher pCR rate compared to patients with a low CD8/FOXP3 ratio (39.6% vs 13.3, P < 0.05) in triple negative subtype patients with stromal TILs < 50%. CONCLUSIONS: A high CD8/eTreg ratio enhances pCR rate in patients with invasive breast cancer.