Strontium-89 plus zoledronic acid versus zoledronic acid for patients with painful bone metastatic breast cancer.

INTRODUCTION: ß-ray strontium-89 (Sr-89) intra-irradiation therapy has been approved and clinically used to reduce bone metastasis pain not alleviated by bone-modifying agents, external radiation, and analgesic agents. We examined the efficacy of zoledronic acid (ZOL) and Sr-89 combination therapy compared with ZOL alone in breast cancer patients with bone metastases. MATERIALS AND METHODS: A randomized controlled trial was conducted on breast cancer patients with bone metastasis to compare the efficacy between ZOL monotherapy and ZOL plus Sr-89 combination therapy. The primary endpoints were changes in urinary NTX levels at 13 weeks and brief pain inventory scores. The secondary endpoints were analgesic drug usages, response rates, changes in bone metabolism markers, quality of life, and adverse event rates. RESULTS: Thirty of the planned 60 cases were randomly assigned to ZOL alone or ZOL + Sr-89. There were no significant differences in the changes in urinary NTX levels between the 2 groups (P = 0.365). There was no consistent difference in the pain score changes between the 2 groups. Sr-89 addition to ZOL slightly reduced the white blood cell and platelet counts. However, all adverse events were Grade 1. Safety and analgesic drug dose reduction were more evident in ZOL + Sr-89. CONCLUSION: This trial showed the lack of benefits from Sr-89 addition to ZOL for breast cancer patients with painful bone metastases. However, safety and analgesic drug dose reduction were more evident in ZOL + Sr-89, indicating its potential for pain control. Sr-89 therapy is safe, thus more effective radiopharmaceuticals are anticipated.

Prediction of pathological response to neoadjuvant chemotherapy in breast cancer patients by imaging.

BACKGROUND: Diagnostic imaging is important for predicting the pathological response to chemotherapy during neoadjuvant chemotherapy (NAC) and for considering the surgical management with appropriate resection after NAC. This study was performed to examine the accuracy of the present radiological imaging for predicting the pathological complete response (pCR). METHODS: From 188 patients in our previous JONIE1 Study, a randomized controlled trial comparing chemotherapy with and without zoledronic acid for patients with human epidermal growth factor receptor 2-negative breast cancer, we evaluated 122 patients whose tumor size was examined by magnetic resonance imaging or ultrasound at three points: before NAC; after administering fluorouracil, epirubicin, and cyclophosphamide; and after NAC. The maximum tumor diameter was evaluated by magnetic resonance imaging or ultrasound. Tumor reduction ratios were calculated at the same three points. The association between the radiological clinical response and the pCR was examined. RESULTS: Among the 122 patients evaluated, there were 98 and 24 patients with luminal (Lum) and triple-negative (TN) subtypes, respectively. There were no patients who showed tumor progression after treatment. The radiological size of the tumors was finally reduced by an average of 58.4%. Clinical complete response and pCR were achieved in 22 (18.0%) and 15 (12.3%) patients, respectively. In the overall population (n = 122), the accuracy, sensitivity, and specificity for predicting pCR were 86.1%, 88.8%, and 66.7%, respectively. The negative predictive value and false-negative rate were 45.5% and 11.2%, respectively. According to subtypes, the accuracies were 83.7% and 95.8% in Lum and TN, respectively. Negative predictive value and false-negative rate were markedly different between the Lum (29.4% and 13.5%) and TN subtypes (100% and 0%), respectively. CONCLUSIONS: This randomized clinical trial demonstrated that NAC was safe for operable breast cancer patients with appropriate radiological monitoring. Radiological evaluation after NAC may be a reliable method for predicting pathological response in the TN subtype, but not in the Lum subtype.

Survival outcomes of neoadjuvant chemotherapy with zoledronic acid for HER2-negative breast cancer.

BACKGROUND: A randomized phase 2 trial in women with HER2-negative breast cancer has shown that adding zoledronic acid (ZOL) to neoadjuvant chemotherapy (CT) has potential anticancer benefits in postmenopausal and triple-negative (TN) breast cancer patients. We report the data for the secondary end point of disease-free survival (DFS). METHODS: Patients were randomly assigned to receive CT or CT + ZOL (CT-Z). All patients received four cycles of FEC100 followed by 12 cycles of paclitaxel weekly. ZOL (4 mg) was administered 3-4 times weekly for 7 wk to the CT-Z group patients. The primary end point was pathologic complete response (pCR). The secondary end points were the clinical response rates, rate of breast-conserving surgery, safety, and DFS. RESULTS: Of the 188 patients enrolled, 95 were assigned to the CT group and 93 to the CT-Z group. DFS and overall survival were analyzed in 92 and 88 patients with the mean times of 5.15 y and 5.38 y, respectively. The 3-y DFS rate was 84.6% in the CT group and 90.8% in the CT-Z group (P = 0.188). The particular benefit from ZOL for the neoadjuvant CT seen as improvement of the pCR rate was indicated in the 3-y DFS period for TN cancer cases (CT versus CT-Z: 70.6% versus 94.1%) but not for postmenopausal cases. CONCLUSIONS: ZOL did not improve DFS when combined with CT. However, the improvement of the pCR rate translated to survival outcomes in TN breast cancer. The short-term application of ZOL may not be sufficient to improve the outcome in postmenopausal patients.

Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism.

Pharmacological treatment of hypercalcemia is essential for patients with parathyroid carcinoma and intractable primary hyperparathyroidism (PHPT). Use of the calcimimetic cinacalcet hydrochloride (cinacalcet) is an option to treat such patients. We investigated the efficacy and safety of cinacalcet in Japanese patients with parathyroid carcinoma and intractable PHPT. Five Japanese patients with parathyroid carcinoma and two with intractable PHPT were enrolled in an open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated until the albumin-corrected serum calcium concentration decreased to 10.0 mg/dL or less or until dose escalation was considered not necessary or feasible. Serum calcium concentration at the baseline was 12.1 ± 1.3 mg/dL (mean ± standard deviation; range 10.4-14.6 mg/dL) and decreased to 10.1 ± 1.6 mg/dL (range 8.6-13.3 mg/dL) at the end of the titration phase with cinacalcet at a dosage of up to 75 mg three times a day. At the end of the titration phase, at least a 1 mg/dL reduction in serum calcium concentration from the baseline was observed in five patients (three with carcinoma and two with PHPT), and it decreased to the normocalcemic range in five patients (three with carcinoma and two with PHPT). Common adverse events were nausea and vomiting. One patient discontinued participation in the study because of an adverse event, liver disorder. Cinacalcet effectively relieved hypercalcemia in 60% of the Japanese patients with parathyroid carcinoma and might be effective in those with intractable PHPT. The drug might be tolerable and safe at a dosage of at most 75 mg three times a day.

Ultrasonographic evaluation of parathyroid hyperplasia in multiple endocrine neoplasia type 1: Positive correlation between parathyroid volume and circulating parathyroid hormone concentration.

There are few reports on parathyroid ultrasonography of multiple endocrine neoplasia type 1 (MEN1). This study investigated the ultrasonographic features of parathyroid glands in 10 patients with MEN1 who underwent preoperative neck ultrasonography and parathyroidectomy between 2006 and 2010 at Toranomon Hospital. We retrospectively analyzed clinical features, laboratory and ultrasonographic data, and pathological diagnosis. A total of 38 parathyroid glands were surgically removed (three to five glands from each patient). All removed parathyroids were pathologically diagnosed as hyperplasia. Seven cases (70.0 %) had adenomatous thyroid nodules. Twenty-five enlarged parathyroid glands (65.8 %) were detected by preoperative ultrasonography with a detection rate of 81.8 % (9/11) and 59.3 % (16/27) for patients without and with adenomatous nodules, respectively. Total parathyroid gland weight and potentially predictable total parathyroid volume by preoperative ultrasonography were significantly correlated with preoperative serum intact parathyroid hormone (iPTH) concentration (R = 0.97, P < 0.001 and R = 0.96, P < 0.001, respectively). The equation used for prediction of the total volume by ultrasonography was 15 × iPTH (pg/ml) - 1,000 and that for total weight was 20 × iPTH (pg/ml) - 1,400. Although adenomatous nodules often coexisted with MEN1 and made identification of enlarged parathyroid glands by ultrasonography difficult, the positive correlation between the predictable parathyroid volume by ultrasonography and serum iPTH suggests that their measurement is useful in the preoperative detection and localization of enlarged parathyroid glands in patients with MEN1. Furthermore, the presence of parathyroid glands that should be resected can be predicted before surgery using the equation proposed here.

Predictive factors for psychological distress related to diagnosis of breast cancer.

OBJECTIVE: The aims of the present study were as follows: (i) to clarify the proportion of women who experience psychological distress during breast cancer diagnosis and (ii) to identify the predictors of psychological distress related to the diagnostic process. METHODS: This was a longitudinal prospective study of women who required further breast examination. Questionnaires were administered at pre-medical consultations (Time 1), after describing radiological examination (Time 2), and after explaining pathological findings (Time 3). All participants completed Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Cancer Therapy--Breast, and Functional Assessment of Chronic Illness Therapy--Spiritual subscale at Time 1 to identify predictors. Participants also completed HADS at Times 2 and 3 to identify the presence or absence of psychological distress. RESULTS: Of the 222 eligible patients, at Time 2, 31 (22.6%) participants with no clinical abnormalities and 39 (45.9%) participants with abnormal findings had HADS scores of ≥ 11 points (χ2 test, 13.14; p < 0.001). At Time 3, 14 (28.0%) participants with benign breast changes and 24 (68.6%) participants with breast cancer had scores of ≥ 11 (χ2 test, 13.71; p < 0.001). Higher HADS scores at Time 1 were associated with the presence of psychological distress at all stages of breast cancer diagnosis. Advanced tumor stage was a predictor of psychological distress for participants with breast cancer (odds ratios = 3.314, 95% confidence interval = 1.033-9.509; p = 0.044). CONCLUSION: These results suggest that intensive psychological intervention is necessary for breast cancer patients with large tumors, as well as for women with suspected breast cancer with high HADS scores at pre-consultation.

Reduction of toxicity by reversing the order of infusion of docetaxel and cyclophosphamide.

BACKGROUND: This retrospective study aimed to determine whether adverse events are more common in docetaxel followed by cyclophosphamide (TC) as compared to the reverse infusion order (rTC). METHODS: A retrospective analysis was undertaken at a single institution for 92 consecutive cases treated with TC or rTC for stage I-III breast cancer in a neoadjuvant/adjuvant setting between December 2006 and June 2011. TC was administered during the first 2.5 years and rTC in the latter 2 years. RESULTS: Among the 92 cases, 50 were in the TC arm and 42 in the rTC arm. Fatigue (72.0 vs. 23.8%), edema (48.0 vs. 16.7%), peripheral neuropathy (66.0 vs. 14.3%), myalgia (48.0 vs. 9.5%) and stomatitis (48.0 vs. 16.7%) occurred significantly more often in cases receiving TC compared to rTC, respectively. CONCLUSION: Nonhematological toxicities are less common in cases receiving rTC in comparison to those receiving TC.

A large functioning parathyroid cyst in a patient with multiple endocrine neoplasia type 1.

A 62-year-old woman presented with a mass on the left side of the neck. Biochemical testing revealed primary hyperparathyroidism. Further, a prolactinoma was detected, and the patient's son and daughter also had primary hyperparathyroidism, indicating that the patient had multiple endocrine neoplasia type 1 (MEN1). Neck ultrasonography revealed several cystic nodules (≤ 30 mm) that appeared to be adenomatous. After parathyroidectomy with autotransplantation, the largest cystic mass, in the left lower thyroid lobe, was pathologically diagnosed as a functioning parathyroid cyst, and all laboratory data returned to normal. On genetic analysis of blood, we found a novel single base insertion (duplication) in exon 10 codon 552 of the MEN1 gene (c1659dupT) that creates an early stop codon. This is the first case report of a parathyroid cyst resulting from parathyroid hyperplasia in a MEN1 patient.

Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1. DESIGN/PATIENTS: We established a MEN study group designated the 'MEN Consortium of Japan' in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated. Of 680 registered patients, 560 were analysed. MEASUREMENTS: Clinical and genetic features of Japanese patients with MEN1 were examined. RESULTS: Primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumours (GEPNET), and pituitary tumours were seen in 94·4%, 58·6% and 49·6% of patients, respectively. The prevalence of insulinoma was higher in the Japanese than in the West (22%vs 10%). In addition, 37% of patients with thymic carcinoids were women, while most were men in western countries. The MEN1 mutation positive rate was 91·7% in familial cases and only 49·3% in sporadic cases. Eight novel mutations were identified. Despite the availability of genetic testing for MEN1, the application of genetic testing, especially presymptomatic diagnosis for at-risk family members appeared to be insufficient. CONCLUSIONS: We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them.

Delay in the diagnosis of multiple endocrine neoplasia type 1: typical symptoms are frequently overlooked.

The morbidity and mortality of individuals with multiple endocrine neoplasia type 1 (MEN1) can be reduced by early diagnosis of MEN1 and related endocrine tumors. To find factors contributing to early diagnosis, we collected clinical information on MEN1 patients through a MEN study group, "MEN Consortium of Japan" and analyzed the time of initial symptom-dependent detection of parathyroid tumors, gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) and pituitary tumors, and that of tumor detection-dependent MEN1 diagnosis in 560 patients. Main tumors were identified up to 7.0 years after symptoms appeared and there was no difference in age at the diagnosis of GEPNETs alone between probands and family members. In patients with typical symptoms (peptic ulcers, urolithiasis, fasting hypoglycemia, bone fracture/loss and amenorrhea), the mean interval between symptom manifestation and tumor detection was extended up to 9.6 years. In particular, 21.7% (5/23) of patients with amenorrhea were diagnosed with pituitary tumors in under one year. In patients with peptic ulcers (from parathyroid tumors or GEPNETs) and urolithiasis (from parathyroid tumors), the interval was positively correlated with age at tumor detection. The interval between tumor detection and MEN1 diagnosis was also prolonged to approximately four years in patients with fasting hypoglycemia (from GEPNETs) and amenorrhea. A substantial delay in the diagnosis of symptom-related tumors and subsequent MEN1 and inadequate screening of GEPNETs in family members were indicated. A greater understanding of MEN1 may assist medical practitioners to make earlier diagnoses, to share patients' medical information and to give family members sufficient disease information.

A Randomized Controlled Phase 2 Study of Neoadjuvant Eribulin Versus Paclitaxel in Women with Operable Breast Cancer: The JONIE-3 Study.

OBJECTIVE: Neoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel. METHODS: In this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis. RESULTS: One hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E. CONCLUSION: Neuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy.

[Safety and tolerability of docetaxel with cyclophosphamide for early breast cancer].

The US oncology 9735 study showed the superior result of TC (docetaxel/cyclophosphamide) over AC (doxorubicin/cyclophosphamide), and now TC has been widely adopted for the treatment of early breast cancer. But in Japan there are few data on the safety and tolerability of this regimen. From January 2007 to April 2009, we treated 51 early breast cancer patients with TC in our hospital, and we summarized safety and tolerability profile, including hematologic toxicity and nonhematologic toxicity. Our patients experienced more febrile neutropenia (25.5%) compared with the original USO 9735 result (5%). This might be because we did not use prophylactic oral antibiotics. Skin toxicity was sometimes troublesome, including 3 cases (5.9%) of grade 3 skin rash. Toxicity assessment showed more asthenia, edema, neuropathy and myalgia, as is well known. Finally, we recommend prophylactic oral antibiotics, steroid premedication from the day before treatment and skin moisture, which may minimize the toxicity.

Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer.

BACKGROUND: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. PATIENTS AND METHODS: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I-IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1-L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were ETHICS AND DISSEMINATION:: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.

Risk Analysis for Chemotherapy-induced Nausea and Vomiting (CINV) in Patients Receiving FEC100 Treatment.

BACKGROUND/AIM: Risk factors for chemotherapy-induced nausea and vomiting (CINV) with anthracycline-containing regimen for breast cancer patients remain unknown. The risk factors for CINV with FEC100 were investigated. PATIENTS AND METHODS: Data on CINV events and patient backgrounds of 180 patients were collected from the first cycle of FEC100 treatment. In this regimen, patients were administered various antiemetics (ADs). The combinations of ADs were classified into four categories, while body mass index (BMI) was stratified into three categories. Risk factors were selected based on patient characteristics and combination of ADs. Risks for CINV were analyzed by univariate and multivariate analyses. RESULTS: In the univariate analysis of nausea, BMI was a significant factor, while BMI and combination of ADs were significant in vomiting. In the multivariate analysis concerning nausea, BMI was a significant factor. In the analysis concerning vomiting, the combination of ADs and BMI were significant. CONCLUSION: BMI was the most important risk factor for nausea and vomiting, while the combination of ADs was for vomiting.

Effect of denosumab on low bone mineral density in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: 24-month results.

BACKGROUND: Aromatase inhibitors (AI) have been established as the gold-standard therapy for postmenopausal patients. Worldwide, adjuvant denosumab at a dose of 60 mg twice per year reduces the risk of clinical fractures in postmenopausal patients with breast cancer who received AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss had not been prospectively evaluated in Japan. Previously, we reported the 12-month effect of denosumab in Japanese patients for the first time; the primary endpoint was the change in the percentage of bone mineral density (BMD) of the lumbar spine from baseline to 12 months. METHODS: This secondary follow-up study prospectively evaluated the change in the percentage of BMD of the lumbar spine from baseline to 24 months. Postmenopausal women with early-stage, histologically confirmed, hormone receptor-positive, invasive breast cancer who were receiving or scheduled to receive AI were included. Denosumab was administered subcutaneously on day 1 of the study and then 6, 12, 18, and 24 months. The lumbar spine and bilateral femoral neck BMD was measured at baseline and 6, 12, 18, and 24 months. RESULTS: At 18 and 24 months, the lumbar spine BMD increased by 5.9 and 7.0%, respectively. The femoral neck BMD also increased. Grade ≥ 2 hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures did not occur. CONCLUSIONS: Our prospective study showed that semiannual treatment with denosumab was associated with continuously increased BMD in Japanese women receiving adjuvant AI therapy for up to 24 months, regardless of prior AI treatment.

Rapid detection of papillary thyroid carcinoma by fluorescence imaging using a γ-glutamyltranspeptidase-specific probe: a pilot study.

BACKGROUND: Nodular lesions of the thyroid gland, including papillary thyroid carcinoma (PTC), may be difficult to diagnose by imaging, such as in ultrasonic echo testing, or by needle biopsy. Definitive diagnosis is made by pathological examination but takes several days. A more rapid and simple method to clarify whether thyroid nodular lesions are benign or malignant is needed. Fluorescence imaging with γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) uses γ-glutamyltranspeptidase (GGT), a cell-surface enzyme, to hydrolyze the γ-glutamyl peptide and transfer the γ-glutamyl group. GGT is overexpressed in several cancers, such as breast, lung, and liver cancers. This imaging method is rapid and useful for detecting such cancers. In this study, we tried to develop a rapid fluorescence detection method for clinical samples of thyroid cancer, especially papillary carcinoma. METHODS: Fluorescence imaging with gGlu-HMRG was performed to detect PTC using 23 surgically resected clinical samples. A portable imaging device conveniently captured white-light images and fluorescence images with blue excitation light. Hematoxylin-eosin (HE) staining was used to evaluate which fluorescent regions coincided with cancer, and immunohistochemical examination was used to detect GGT expression. RESULTS: All 16 PTC samples exhibited fluorescence after topical application of gGlu-HMRG, whereas the normal sections of each sample showed no fluorescence. HE staining revealed that each fluorescent region corresponded to a region with carcinoma. The PTC samples also exhibited GGT expression, as confirmed by immunohistochemistry. CONCLUSIONS: All PTC samples were detected by fluorescence imaging with gGlu-HMRG. Thus, fluorescence imaging with gGlu-HMRG is a rapid, simple, and powerful detection tool for PTC.

Anti-CD137 monoclonal antibody enhances trastuzumab-induced, natural killer cell-mediated cytotoxicity against pancreatic cancer cell lines with low human epidermal growth factor-like receptor 2 expression.

Because human epidermal growth factor-like receptor (HER) 2 is expressed on the surface of human pancreatic carcinoma cells to varying degrees, trastuzumab, an anti-HER2 monoclonal antibody (mAb), is expected to exert antibody-dependent, natural killer (NK) cell-mediated cytotoxicity (ADCC) against the cells. However, some reports found that the effect of trastuzumab against human pancreatic carcinoma cells was limited because most express only limited HER2. We examined whether anti-CD137 stimulating mAb could enhance trastuzumab-mediated ADCC against Panc-1, a human pancreatic cancer cell line with low HER2 expression, in vitro. Supplementation of anti-CD137 mAb could improve trastuzumab-mediated ADCC against Panc-1 which was insufficient without this stimulating antibody. The ADCC differed in individual cells, and this was related to the expression of CD137 on the surface of NK cells after trastuzumab stimulation in association with the Fcγ-RIIIA polymorphism. NK cells with Fcγ-RIIIA-VV/VF showed high levels of ADCC against Panc-1, but those with Fcγ-RIIIA-FF did not show optimal ADCC. In addition, trastuzumab-mediated ADCC against the human pancreatic cancer cell line Capan-1 with high HER2 expression was generally high and not affected by the Fcγ-RIIIA polymorphism. These results demonstrated that in Fcγ-RIIIA-VV/VF-carrying healthy individuals, trastuzumab plus αCD137 mAb could induce effective ADCC against HER2-low-expressing pancreatic cancer cell lines, and that such an approach may result in similar findings in patients with pancreatic cancer.

1,25-dihydroxyvitamin D suppresses circulating levels of parathyroid hormone in a patient with primary hyperparathyroidism and coexistent sarcoidosis.

CONTEXT: PTH is excessively secreted to develop hypercalcemia and accelerate bone turnover in patients with primary hyperparathyroidism. PTH stimulates the production of 1,25-dihydroxyvitamin D [1,25(OH)2D] that in turn suppresses the synthesis of PTH in parathyroid cells. OBJECTIVE: The objective of the study was to clarify whether 1,25(OH)2D indeed inhibits circulating levels of PTH and influences bone turnover, even in a patient with primary hyperparathyroidism. DESIGN, SETTING, AND PATIENT: We evaluated PTH levels in a patient with primary hyperparathyroidism and coexistent sarcoidosis whose serum 1,25(OH)2D levels were independent of PTH. INTERVENTIONS AND MAIN OUTCOME MEASURES: The present case was treated with prednisolone before and after surgical resection of parathyroid adenoma, and Ca-regulating hormones and bone markers were measured. RESULTS: Serum Ca and PTH levels significantly decreased after parathyroid surgery, whereas serum 1,25(OH)2D levels remained high. Prednisolone administration promptly decreased serum 1,25(OH)2D levels and reciprocally increased PTH levels despite consistent serum Ca levels either before or after surgery. PTH levels were negatively correlated with serum 1,25(OH)2D levels before and after surgery. Urine N-telopeptides, serum osteocalcin, and bone-type alkaline phosphatase all decreased to physiological ranges after parathyroid surgery. CONCLUSIONS: These results suggest that 1,25(OH)2D indeed inhibits the production of PTH not to exacerbate hypercalcemia in a patient with primary hyperparathyroidism. Furthermore, PTH but not 1,25(OH)2D may primarily be involved in the stimulation of bone turnover.

Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study).

PURPOSE: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT). METHODS: Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug. RESULTS: This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted. TRIAL REGISTRATION: University Hospital Medical Information Network. UMIN000003261.

Chromosomal aberrations by comparative genomic hybridization in hürthle cell thyroid carcinomas are associated with tumor recurrence.

Hürthle cell thyroid neoplasms are classified as variants of follicular neoplasms, but they have distinct clinicopathological features. Chromosomal aberrations by comparative genomic hybridization (CGH) are common in Hürthle cell neoplasms. However, there is currently only limited information concerning the relationship between the chromosomal aberrations by CGH and tumor behavior. We, therefore, investigated chromosomal aberrations in primary Hürthle cell neoplasms (13 carcinomas and 15 adenomas) using CGH and correlated the aberrations identified with tumor node metastasis (TNM) stage, tumor differentiation, capsular invasion, and tumor recurrence. Chromosomal aberrations were found in 62% (8 of 13) of carcinomas and 60% (9 of 15) of adenomas. Overall, common chromosomal gains were found on 5p (29%), 5q (36%), 7 (29%), 12p (14%), 12q (21%), 17p (29%), 17q (32%), 19p (32%), 19q (25%), 20p (21%), 20q (29%), and 22q (18%). Common chromosomal losses were found on 2q (18%) and 9q (18%). Thirty-eight percent (5 of 13) of carcinomas were TNM stage III, 31% (4 of 13) were moderately to poorly differentiated, and 46% (6 of 13) were intermediately to widely invasive. Recurrence occurred in 38% (5 of 13). Carcinomas that subsequently recurred had a greater number of chromosomal gains (9.0 vs. 1.3; <0.005) and had more frequent chromosomal gains on 12q, 19q, and 20p (<0.001), 5p, 7, 19p, and 20q (<0.005), and 12p (<0.01) than those that did not recur. Five of the eight (63%) patients with aberrations developed recurrence, whereas none of the five patients without aberrations developed recurrence. In conclusion, chromosomal gains by CGH on 5p, 7, 12p, 12q, 19p, 19q, 20p, and 20q in Hürthle cell carcinomas are associated with tumor recurrence. Such chromosomal aberrations may be predictive for recurrent disease in patients with Hürthle cell thyroid carcinoma.