Third Report of the Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer: Summary of the results of a questionnaire survey of oncologists and diabetologists-Secondary publication.

The Japan Diabetes Society and the Japan Cancer Association launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and health-care providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology and the Japanese Society of Medical Oncology, reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey indicated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

Efficacy and safety of bone management agents administered at 12 weeks vs. 4 weeks in patients with bone metastases: A systematic review.

BACKGROUND: Bone modifying agents (BMAs) have been used to prevent skeletal-related events (SRE) in cancer patients with bone metastases. In this meta-analysis, efficacy and adverse events (AEs) were studied based on a de-escalation strategy in which the BMA dosing interval was prolonged from 4 to 12 weeks. METHODS: PubMed, Cochrane, ICHUSHI, and CINAHL were searched for articles on BMA dosing intervals from outcomes measured were the incidence of SRE and related various AEs. A quantitative meta-analysis was performed using a random-effects model to calculate relative risk ratios (RRs) and 95% confidence intervals (CIs). RESULT: The meta-analysis included three randomized controlled studies (RCTs) of Zoledronic acid hydrate (ZA) (n = 2663) and six RCTs (n = 141) on BMA other than ZA. There was no difference in the incidence of SREs when comparing the dosing frequency of 12 versus 4 weeks for BMA (RR = 1.21, 95% CI [0.82-1.78], p = 0.33). Further, AEs related to treatment discontinuation were significantly less frequent with ZA given every 12 weeks than when given every 4 weeks (RR = 0.51 [0.30-0.89], p = 0.02). In particular, renal dysfunction leading to grade ≥3 or discontinuation of treatment with ZA occurred significantly less frequently with every 12-week dosing (RR = 0.33 [0.12-0.91], p = 0.33). CONCLUSION: This meta-analysis showed no influence of BMA de-escalation on the incidence of SRE; nevertheless, AEs appeared to reduce with the de-escalated usage of ZA.

Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor-positive advanced breast cancer.

Taselisib is a potent and selective phosphatidylinositide 3-kinase (PI3K) inhibitor. The present article reports the first study of taselisib administration in Japanese patients. The aim of this 2-stage, phase I, multicenter, open-label, dose-escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)-positive locally advanced or recurrent breast cancer (stage 2). In stage 1, oral taselisib tablets 2, 4, and 6 mg/d were given in 28-day cycles. In stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/d) with i.m. fulvestrant 500 mg. Nine and 6 patients were enrolled in stage 1 and stage 2, respectively. Taselisib was well tolerated. No dose-limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment-related adverse events in stage 1 and stage 2, respectively, were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), and stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after dosage; its half-life was 12.9-32.0 hours in stage 1 and 16.1-26.5 hours in stage 2. Two patients achieved partial response (PR), 5 patients had stable disease (SD) and 2 patients had progressive disease (PD) in stage 1, and 1 patient had PR and 3 patients had SD in stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA-mutated solid tumors or HR-positive advanced breast cancer.

Phase 1 study of olaratumab plus doxorubicin in Japanese patients with advanced soft-tissue sarcoma.

Olaratumab, a monoclonal antibody targeting human platelet-derived growth factor receptor α, plus doxorubicin significantly improved overall survival in patients with advanced soft-tissue sarcoma (STS) in a prior phase 1b/2 randomized trial. Subsequent exposure-response analysis suggested that higher olaratumab exposures earlier might improve outcomes in patients at risk of early disease progression. This phase 1 study (3 treatment cohorts; minimum 6 patients each) investigated the safety, pharmacokinetics and antitumor activity of olaratumab plus doxorubicin in Japanese patients with STS. Patients received olaratumab 15 mg/kg on Days 1 and 8 during each 21-day cycle until disease progression. Patients in Cohort 3 received a 20 mg/kg loading dose of olaratumab in Cycle 1. Doxorubicin was administered for up to 6 cycles. Patients in Cohort 1 received doxorubicin 25 mg/m2 on Days 1, 2 and 3. Patients in Cohorts 2 and 3 received doxorubicin 75 mg/m2 on Day 1. One patient in Cohort 2 experienced a dose-limiting toxicity of Grade 3 febrile neutropenia. Most treatment-emergent adverse events were of mild and moderate severity, and were known doxorubicin toxicities. Olaratumab serum concentrations in Cohort 3 reached a steady-state exceeding the target level in Cycle 1. Partial response was confirmed in 4 patients (2 each in Cohorts 2 and 3). Olaratumab plus doxorubicin had an acceptable safety profile in patients with STS. A loading dose of olaratumab 20 mg/kg was effective for achieving minimum serum concentrations above the target trough level in Cycle 1.

Prognostic impact of presumed breast or ovarian cancer among patients with unfavorable-subset cancer of unknown primary site.

BACKGROUND: The clinical utility and prognostic impact of presumed primary breast or ovarian cancer among patients with an unfavorable subset of cancer of unknown primary site (CUP) remains unclear. We aimed to evaluate the clinical relevance of the presumed primary site of CUP and the clinical outcome of site-specific therapy based on such presumptions. METHODS: Patients referred to our center who were diagnosed with unfavorable-subset CUP and treated between April 2007 and March 2015 were enrolled in this study. Data were collected retrospectively from the hospital database and electronic medical records. Presumptive primary breast or ovarian cancer was based on histological and immunohistochemical analyses and metastatic patterns. The outcomes of patients with unfavorable-subset CUP with a putative primary site in the breast or ovary (P-CUP) and of patients with unfavorable-subset CUP, but without P-CUP (U-CUP), were assessed. RESULTS: A total of 780 patients were referred to our hospital with malignancy of unknown origin. Of these, 409 patients were diagnosed with CUP and 344 patients with unfavorable-subset CUP. Following clinicopathological examination, 40 (11.6%) of the 344 patients had P-CUP and the remaining 303 (88.3%) patients had U-CUP. In total, 136 patients received chemotherapy (22 with P-CUP and 114 with U-CUP). Among the 22 patients with P-CUP, three received hormonal therapy for breast cancer, and 19 received chemotherapy based on the presumed primary organ (breast, 4; ovaries, 15). Conventional platinum-based chemotherapy was administered to 105 patients with U-CUP and non-platinum drug treatment to nine patients. The objective response rates were 61.1% (95% confidence interval [CI]: 38.6-83.6) and 41.1% (95% CI: 31.8-50.4) for patients with P-CUP and U-CUP, respectively. The median overall survival durations were 50.0 months and 16.9 months (log-rank: P = 0.002) for patients with P-CUP and U-CUP, respectively. P-CUP was identified as an independent predictor of good prognosis according to multivariate analysis. CONCLUSIONS: Patients with P-CUP had higher response rates and a better prognosis compared with patients with U-CUP. It might thus be reasonable to classify this subset as a new category of CUP with a favorable prognosis.

A case of heavily pretreated metastatic cardiac angiosarcoma treated successfully using eribulin.

Eribulin mesylate (eribulin) is a nontaxane microtubule inhibitor approved in Japan for treating soft tissue sarcoma irrespective of histological subtypes. Thus, our department routinely uses eribulin to treat any histological subtype of sarcoma for patients who have experienced disease progression during standard therapy. However, evidence on the efficacy of eribulin in treating sarcomas that are neither liposarcoma nor leiomyosarcoma is limited. Recently, we encountered a case of a heavily pretreated cardiac angiosarcoma that responded well to eribulin treatment. The patient was a 34-year-old Japanese woman with advanced angiosarcoma, who had been pretreated heavily using several lines of chemotherapy. Eribulin was administered as the eighth line of treatment and the dose was adjusted because of grade 4 neutropenia. After three cycles of treatment, contrast-enhanced computed tomography showed a partial tumor response, which was sustained for ~4 months. This case suggests that eribulin may be a potential therapeutic option for angiosarcoma. Further studies are needed to confirm the benefit of eribulin for patients with angiosarcoma and to establish predictive markers for eribulin sensitivity.

Symptom management: the utility of regional cooling for hand-foot syndrome induced by pegylated liposomal doxorubicin in ovarian cancer.

PURPOSE: Hand-foot syndrome (HFS) is a major side effect of pegylated liposomal doxorubicin (PLD). Regional cooling during PLD infusion was shown to improve severe HFS. We investigated the utility of frozen gloves and socks (FGS) as a simpler cooling method. METHODS: To evaluate the utility and safety of regional cooling with FGS for PLD-induced HFS, we retrospectively analyzed patients with advanced ovarian cancer who used FGS during PLD-containing regimens. RESULTS: Ninety-six patients were analyzed. The incidence of HFS was 51% (≥ grade 2, 32%) in the PLD group and 38% (≥ grade 2, 6%) in the PLD + CBDCA group. The respective percentages of patients who underwent PLD dose modification/discontinuation were 41%/75% in the PLD group and 9%/30% in the PLD + CBDCA group. The reasons for discontinuation of PLD and PLD + CBDCA therapy were progressive disease, HFS, allergy, oral mucositis, and others. HFS was the only reason for PLD dose modification in both the PLD and PLD + CBDCA groups. The completion rate of FGS was 96%, with discontinuation in three cases due to pain from cooling. CONCLUSIONS: Our study indicates that FGS is a safe, simple method with good tolerability. A prospective study is needed for further assessment.

Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities.

A growing number of studies suggest critical tumor suppressor roles of the SWI/SNF chromatin remodeling complex in a variety of human cancers. The recent discovery of SMARCA4-deficient thoracic sarcomas has added to the list of tumor groups with the SMARCA4 inactivating mutation. To better characterize these tumors and establish their nosological status, we undertook a clinicopathological and molecular analysis of 12 SMARCA4-deficient thoracic sarcomas and compared them with three potentially related disease entities. Eleven men and one woman with SMARCA4-deficient thoracic sarcomas (aged 27-82 years, median 39 years) were included in the study. Most of the patients had heavy smoking exposure and pulmonary emphysema/bullae. The primary tumors were large and involved the thoracic region in all cases and simultaneously affected the abdominal cavity in 3 cases. The patients followed a rapid course, with a median survival of 7 months. Histologically, all tumors showed diffuse sheets of mildly dyscohesive, relatively monotonous, and undifferentiated epithelioid cells with prominent nucleoli. Immunohistochemically, all tumors demonstrated a complete absence (8 cases) or diffuse severe reduction (4 cases) of SMARCA4 expression. Cytokeratin, CD34, SOX2, SALL4, and p53 were expressed in 6/12, 10/12, 10/12, 10/12, and 7/10 cases, respectively. SMARCA2 expression was deficient in 11/12 cases, and none (0/8) expressed claudin-4. Targeted sequencing was performed in 5 cases and demonstrated the inactivating SMARCA4 mutation in each case and uncovered alterations in TP53 (5/5), NF1 (2/5), CDKN2A (2/5), KRAS (1/5), and KEAP1 (1/5), among others. Comparative analysis supported the distinctiveness of SMARCA4-deficient thoracic sarcomas as they were distinguishable from 13 malignant rhabdoid tumors, 15 epithelioid sarcomas, and 12 SMARCA4-deficient lung carcinomas based on clinicopathological and immunohistochemical grounds. SMARCA4-deficient thoracic sarcomas constitute a unique, highly lethal entity that requires full recognition and differentiation from other epithelioid malignancies involving the thoracic region.

Efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer not meeting trial eligibility criteria: a retrospective study.

BACKGROUND: The efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer has been demonstrated in phase III trials. However, as patients receiving eribulin in daily practice do not necessarily meet all the eligibility criteria of clinical trials, data for such patients are limited. METHODS: We identified patients with locally advanced or metastatic breast cancer, treated with eribulin monotherapy between July 2011 and December 2015 at the National Cancer Center Hospital, Tokyo, Japan. Patients who would have met the following eligibility criteria from the EMBRACE trial were included in the eligible group, and the rest were included in the ineligible group: 1) Eastern Cooperative Oncology Group Performance status 0-2; 2) adequate function of principal organs; and 3) absence of active infection. We compared the relative dose intensity (RDI), tumor response, progression-free survival (PFS), overall survival (OS), and adverse events between the groups. Nominal and continuous values were compared using the Fisher's exact test and Mann-Whitney U test, respectively. Survival outcomes were determined using Kaplan-Meier estimation, and between-group differences were assessed using the log-rank test. RESULTS: Of the 203 patients included, 34 were classified into the ineligible group and 169 into the eligible group. Initial dose reduction and treatment discontinuation due to adverse events (AEs) were more common in the ineligible group (initial dose reduction: 23.5% in the ineligible group vs. 7.7% in the eligible group, p = 0.011; treatment discontinuation due to AEs: 11.8% vs. 3.0%, p = 0.045). However, RDI (66% vs. 71%, p = 0.130), response rate (15.6% vs. 18.1%, p = 1.000), PFS (3.7 months vs. 4.0 months, p = 0.913), OS (11.5 months vs. 16.1 months, p = 0.743), AEs requiring hospitalization (5.9% vs. 6.5%, p = 1.000), and grade 3/4 AEs were similar in both groups. PFS, OS, AEs requiring hospitalization, and discontinuation due to AEs in the eligible group were comparable to those found in previous phase III trials. CONCLUSION: The safety and efficacy of eribulin monotherapy was demonstrated in a broader patient population than that eligible for clinical trials. Eribulin may be a treatment option in these patients with locally advanced or metastatic breast cancer, considering dose reduction and pre-existing dysfunctions.

The Prognostic Impact of the Pathological Response to Neoadjuvant Dose-Dense Therapy for Ovarian Carcinoma.

OBJECTIVE: The aim of this study was to assess the use of the pathological response to neoadjuvant chemotherapy (NAC) for predicting disease prognosis in patients with advanced ovarian cancer who received neoadjuvant dose-dense weekly paclitaxel and carboplatin (dd-TC) therapy. METHODS: We retrospectively investigated patients with advanced epithelial ovarian, tubal, or peritoneal carcinoma treated at our hospital from July 2004 to October 2014. Patients received dd-TC therapy as NAC followed by interval debulking surgery (IDS). Specimens resected during IDS were divided into 4 groups based on pathological response: grade 1, most tumor cells appeared to be viable; grade 2a, most tumor cells had disappeared, whereas the remaining tumor cells were vacuolated or degenerated; grade 2b, small numbers of viable tumor cells were observed; and grade 3, small aggregations of macrophages were seen. RESULTS: Sixty-eight patients were enrolled. The median number of NAC cycles was 3 (range, 2-6), and 51 patients (75.0%) achieved complete resection at IDS. Regarding pathological response, 7 (10.3%) patients were classified as grade 1, 11 (16.2%) as grade 2a, 46 (67.7%) as grade 2b, and 4 (5.9%) as grade 3. In univariate and multivariate analyses, grades 2b and 3 pathological responses were significant favorable prognostic factors for progression-free survival (P = 0.028; hazard ratio, 0.48; 95% confidence interval, 0.26-0.92). CONCLUSIONS: Although the pathological complete response rate to NAC was low in this study, both complete and good pathological responses to NAC might be favorable prognostic factors for PFS in patients with advanced ovarian cancer who receive dd-TC.

Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients.

This phase I study in Japanese patients evaluated the safety, pharmacokinetics, and preliminary efficacy of palbociclib, a highly selective and reversible oral cyclin-dependent kinase 4/6 inhibitor, as monotherapy for solid tumors (part 1) and combined with letrozole as first-line treatment of postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (part 2). Part 1 evaluated palbociclib 100 and 125 mg once daily (3 weeks on/1 week off; n = 6 each group) to determine the maximum tolerated dose. Part 2 evaluated palbociclib maximum tolerated dose (125 mg) plus letrozole 2.5 mg (n = 6). The most common treatment-related adverse event was neutropenia (all grades/grade 3/4): 100 mg, 83%/67%; 125 mg, 67%/33%; and palbociclib plus letrozole, 100%/83%. Heavier pretreatment with chemotherapy may have resulted in higher neutropenia rates observed with the 100-mg dose. Palbociclib exposure was higher with 125 vs 100 mg (mean area under the plasma concentration-time curve over dosing interval [τ]: 1322 vs 547.5 ng·h/mL [single dose], 2838 vs 1276 ng·h/mL [multiple dose]; mean maximum plasma concentration: 104.1 vs 41.4 ng/mL [single dose], 185.5 vs 77.4 ng/mL [multiple dose]). Half-life was 23-26 h. No drug-drug interactions between palbociclib and letrozole occurred. Four patients had stable disease (≥24 weeks in one patient with rectal cancer [100 mg] and one with esophageal cancer [125 mg]) in part 1; two patients had partial response and two had stable disease (both ≥24 weeks) in part 2. Palbociclib at the 125-mg dose (schedule 3/1) was tolerated and is the recommended dose for monotherapy and letrozole combination therapy in Japanese patients. The trials are registered with www.ClinicalTrials.gov: A5481010 and NCT01684215.

Risk Factors for Developing Skeletal-Related Events in Breast Cancer Patients With Bone Metastases Undergoing Treatment With Bone-Modifying Agents.

BACKGROUND: Bone-modifying agents (BMAs) reduce the incidence of skeletal-related events (SREs) and are thus recommended for breast cancer patients with bone metastases. However, the risk factors for SREs during BMA treatment are not well-understood. This study evaluated the number and timing of SREs from case studies to identify these factors. METHODS: The medical records of 534 women with breast cancer who developed bone metastases between 1999 and 2011 were reviewed. SREs were defined as a pathologic fracture, spinal cord compression, or the need for bone irradiation or surgery. Multiple variables were assessed and were analyzed by using the Cox proportional hazard analyses and the Andersen and Gill method. RESULTS: Multivariate analyses for both the time to the first SRE and the primary and subsequent SRE frequency demonstrated that significant baseline risk factors included luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at the time of the initial BMA dose. Additionally, for the time to the first SRE and for the primary and subsequent SRE frequency, the presence of extraskeletal metastases and BMA administration initiation ≥6 months after the detection of bone metastases were also significant risk factors, respectively. CONCLUSION: In breast cancer patients with bone metastases, more vigilant observation should be considered for patients with the identified risk factors. To reduce the risk for SRE, BMAs should be administered within 6 months of bone metastases diagnosis and before palliative radiation therapy. IMPLICATIONS FOR PRACTICE: Retrospectively, risk factors were identified for skeletal-related events (SREs) in breast cancer patients with bone metastasis who were treated with bone-modifying agents (BMAs). For the time to the first SRE and for the SRE frequency, presence of extraskeletal metastases and BMA initiation ≥6 months after the detection of bone metastases were risk factors, respectively. Luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at initial BMA dose were risk factors for both first SRE and SRE frequency. More vigilant observation should be considered for patients with these risk factors.

A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors.

Farletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400 mg/m(2)). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20 months was observed in one patient with clear cell OC (100 mg/m(2)) and one patient with GC (400 mg/m(2)), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).

Third Report of the Japan Diabetes Society (JDS)/Japanese Cancer Association (JCA) Joint Committee on diabetes and cancer: summary of the results of a questionnaire survey of oncologists and diabetologists-secondary publication.

The Japan Diabetes Society (JDS) and the Japan Cancer Association (JCA) launched a joint committee and published their "First Joint Committee Report on Diabetes and Cancer" in 2013, compiling recommendations for physicians and healthcare providers as well as for the general population. In 2016, the "Second Joint Committee Report on Diabetes and Cancer" summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current "Third Joint Committee Report on Diabetes and Cancer", for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology (JSCO) and the Japanese Society of Medical Oncology (JSMO), reports on the results from the questionnaire survey, "Diabetes Management in Patients Receiving Cancer Therapy," which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey demonstrated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

Efficacy of everolimus, a novel mTOR inhibitor, against basal-like triple-negative breast cancer cells.

Patients with triple-negative breast cancers (TNBCs) typically have a poor prognosis because such cancers have no effective therapeutic targets, such as estrogen receptors for endocrine therapy or human epidermal growth factor receptor 2 (HER2) receptors for anti-HER2 therapy. As the phosphatidylinositol 3' kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) cascade is activated in TNBCs, mTOR is a potential molecular target for anticancer therapy. In this study, we investigated the antitumor activities of everolimus, an oral mTOR inhibitor, in nine TNBC cell lines. Everolimus effectively inhibited cell growth at concentrations under 100 nM (IC(50)) in five cell lines and even in the 1-nM range in three of the five cell lines. To identify specific characteristics that could be used as predictive markers of efficacy, we evaluated the expressions of proteins in the mTOR cascade, basal markers, and cancer stem cell markers using western blotting, fluorescent in situ hybridization (FISH), or immunohistochemistry. All five of the sensitive cell lines were categorized as a basal-like subtype positive for either epidermal growth factor receptor (EGFR) or CK5/6, although resistant cell lines were not of this subtype and tended to exhibit the characteristics of cancer stem cells, with decreased E-cadherin and the increased expression of Snail or Twist. In vivo assays demonstrated antitumor activity in a mouse xenograft model of basal-like breast cancer, rather than non-basal breast cancer. These results suggest that everolimus has favorable activity against basal-like subtypes of TNBCs. Epidermal growth factor receptor and CK5/6 are positive predictive markers of the TNBC response to everolimus, while cancer stem cell markers are negative predictive markers.

Hematologic safety of breast cancer chemotherapies in patients with hepatitis B or C virus infection.

BACKGROUND: Information regarding hematological toxicities in breast cancer chemotherapy patients with hepatitis B (HBV) or C virus (HCV) infection is limited. METHODS: We retrospectively reviewed the presence of hepatotoxicities (i.e. aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin elevation) and hematotoxicities (i.e. leukopenia and thrombocytopenia) among breast cancer patients with HBV or HCV infection who received chemotherapy from 1999 to 2010. All of the patients included in this analysis were classified as Child-Pugh A. RESULTS: Among 32 patients with HBV infection who underwent chemotherapy (total cycles, 378), 3 experienced grade 3/4 hepatotoxicities, requiring 2 treatment delays and 1 treatment revision. Further, 9 patients experienced grade 3/4 hematotoxicities; of these, 2 required treatment delays and 3 required treatment revisions. Fifty-two HCV patients underwent a total of 570 cycles of chemotherapy. Five patients experienced grade 3/4 hepatotoxicities and required treatment delays, whereas 10 patients experienced grade 3 hematotoxicities; 3 of these patients required treatment delays. CONCLUSION: Hematotoxicities requiring chemotherapy dose or treatment revision were not highly prevalent among breast cancer chemotherapy patients with HBV or HCV infection and a normal range of liver function. Under careful monitoring, chemotherapy dosage or schedule adjustments may not be necessary in similar patients positive for HBV or HCV.

Prospective evaluation of incidence and severity of oral mucositis induced by conventional chemotherapy in solid tumors and malignant lymphomas.

PURPOSE: Oral mucositis (OM), a complication frequently associated with cancer chemotherapy, may decrease treatment efficacy due to dose reduction or impair the patient's quality of life. The purpose was to determine the incidence and severity of OM and its sequelae in patients receiving conventional chemotherapy for various malignancies. METHODS: Two hundred twenty-seven patients (male, 33%; female, 66%) who received chemotherapy for head and neck cancer, esophageal cancer, colorectal cancer, breast cancer, and malignant lymphomas at the Cancer Institute Hospital between January 2007 and December 2008 were examined with questionnaires, prospectively. RESULTS: The incidence of OM was highest in patients with breast cancer (76.5%), then head and neck cancer (67.7%), colorectal cancer (63%), esophageal cancer (57.8%), and malignant lymphoma (42.9%). However, patients who experienced severe OM (≥grade 3) were rare: at most 4.8%. The high-risk regimens for OM were TPF (85.7%), FOLFIRI (80%), CAF (78.8%), AC (70.6%), and FOLFOX (60%). OM was associated with gastrointestinal adverse events, anorexia, diarrhea, and dysphagia, which aggravated quality of life. There was no correlation between incidence of OM and prior therapy, PS, oral care, or laboratory data. There was no statistically significant correlation between OM and overall survival. The predictive factor was history of OM in previous chemotherapy. CONCLUSION: OM frequently occurs in patients with various tumors receiving conventional chemotherapy. Despite low-grade OM, they might cause gastrointestinal adverse events. Adequate preventive treatment for OM is required depending on each chemotherapy regimen and each patient's OM history.

The Incidence of Nonmalignant Diseases among Patients with Suspected Carcinoma of Unknown Primary Site.

Objective Few reports have analyzed the diagnostic process of carcinoma of unknown primary site (CUP) or have focused on the frequency of nonmalignant lesions among patients with suspected malignant diseases. The aim of this study was to investigate the incidence and characteristics of nonmalignant diseases that tend to be mistaken for malignant diseases. Patients We retrospectively analyzed the medical records of patients with suspected CUP who were referred to the National Cancer Center Hospital (Tokyo, Japan) between April 2007 and December 2014. All patients underwent a thorough history and physical examination as well as radiological and ultrasonography imaging tests for the CUP diagnostic work up. Results Among 830 patients with suspected CUP, 46 were diagnosed with nonmalignant diseases, and 780 were diagnosed with a malignant neoplasm (409 neoplasms with detected primary site and 371 CUP neoplasms). Four patients discontinued the diagnostic workup because they refused further examinations or had a poor general status. The final diagnosis of the 46 patients with nonmalignant disease comprised 10 benign tumors, 10 benign diseases, and 26 with no evidence of disease. The nonmalignant tumors comprised three hemangiomas, two schwannomas, two uterine myomas, two pseudomyxoma peritonei, one lymphangioma, one meningioma, and one poroma. Conclusion The incidence of nonmalignant diseases among patients with suspected CUP was 46 out of 830 patients in our institution. It is important to perform a thorough pathological examination in the CUP diagnostic workup. To confirm a diagnosis, some patients may need to visit specialized institutions, especially those with liver and bone lesions.

Bone marrow examination in patients with Ewing sarcoma/peripheral primitive neuroectodermal tumor without metastasis based on 18F-fluorodeoxyglucose positron emission tomography/computed tomography.

Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/PNET) is an aggressive bone tumor. Bone marrow aspiration and biopsy (BMAB) has been recognized as the gold standard for assessing bone marrow status. While the latest guideline suggests the need to omit bone marrow aspiration in patients with no findings on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) based on one retrospective report, there is no study using 18F-FDG PET/computed tomography (CT). We retrospectively reviewed 26 consecutive, previously untreated, ES/PNET patients. We compare the results of bone marrow aspiration and biopsy (BMAB) and those of 18F-FDG PET/CT in ES/PNET patients. All of the 21 patients without metastases on 18F-FDG PET/CT had negative BMAB. The sensitivity of bone marrow involvement in bone metastases positive patients on 18F-FDG PET/CT was 75% (3/4), and the specificity was 100% (22/22). In addition to the metastatic findings on 18F-FDG PET/CT, tumor diameter, lactate dehydrogenase level at diagnosis, and the presence or absence of bone metastasis were factors related to bone marrow involvement. It may be a reasonable option to omit BMAB in ES/PNET patients with no distant metastasis based on 18F-FDG PET/CT findings.

Serum pepsinogens as an early diagnostic marker of H. pylori eradication.

BACKGROUND/AIMS: Helicobacter pylori (H. pylori) eradication increases the serum pepsinogen I/ pepsinogen II ratio and the percentage change in pepsinogen I/pepsinogen II ratios is a useful marker of H. pylori eradication. We studied whether the pepsinogen method could be an early diagnostic marker of H. pylori eradication even in patients persistently treated with a proton pump inhibitor. METHODOLOGY: Sixty-two H. pylori-positive patients underwent H. pylori-eradication therapy, followed by treatment with a proton pump inhibitor to cure ulcers. Serum levels of pepsinogen I and pepsinogen II were measured before, at the end of, and at 4 weeks after the eradication therapy. The cut-off values of percentage changes in pepsinogen I/pepsinogen II ratios for the diagnosis of eradication of H. pylori were set in proportion to pepsinogen I/pepsinogen II ratios before eradication in accordance with a previous report. RESULTS: Using the results of 13C-urea breath test as the standard, the sensitivity, specificity and validity of the pepsinogen method were 100.0%, 89.8% and 90.3%, respectively, at 4 weeks after eradication therapy. CONCLUSION: The percentage change in serum pepsinogen I/pepsinogen II ratios is useful as an early diagnostic marker for judgment of H. pylori eradication irrespective of proton pump inhibitor treatment.