Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative advanced and metastatic breast cancer in Japan (KBCSG-TR-1316).

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative advanced/metastatic breast cancer (HR+/HER2- mBC). However, some cancers show resistance to CDK4/6i and have a poor prognosis. The non-luminal disease score (NOLUS) was developed to predict non-luminal disease using immunohistochemical analysis. METHODS: The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including real-world progression-free survival (rw-PFS) and overall survival (OS). Real-world data of patients with HR+/HER2- mBC who received CDK4/6i therapy [palbociclib or abemaciclib] as first- or second-line endocrine treatments was obtained. NOLUS was calculated using the formula: NOLUS (0-100) = - 0.45 × estrogen receptor (ER) (%) - 0.28 × progesterone receptor (PR) (%) + 0.27 × Ki67(%) + 73, and the patients were divided into two groups: NOLUS-positive (≥ 51.38) and NOLUS-negative (< 51.38). RESULTS: Of the 300 patients, 28 (9.3%) were NOLUS-positive, and 272 (90.7%) were NOLUS-negative. The expression rates (%) of ER and PgR in NOLUS-positive patients were lower than those in NOLUS-negative patients (p < 0.001). Ki67 expression was higher in NOLUS-positive patients. There were statistically significant differences in prognosis (rw-PFS and OS) between the two groups. Moreover, NOLUS-negative patients showed statistically better rw-PFS with first-line therapy than second-line therapy. However, NOLUS-positive patients showed poor prognoses with both the first and second therapeutic lines, suggesting CDK4/6i inefficacy for NOLUS-positive patients. CONCLUSIONS: The efficacy and prognosis of CDK4/6i significantly differed between the NOLUS-positive and NOLUS-negative patients. This feasible method can predict patients with HR+/HER2- mBC resistant to CDK4/6i and help select a better therapeutic approach to overcome resistance.

The therapeutic strategy for advanced gastric cancer with pyloric stenosis and liver metastasis; successfully treated by gastro-jejunal bypass and chemotherapy first, followed by curative R0 resection.

BACKGROUND: The indication of surgical resection for liver metastasis from gastric cancer (GC) is still limited and controversial because of its more aggressive oncological characteristics than liver metastasis from colorectal cancer. Pyloric stenosis causes an inadequate oral intake and malnutrition in GC patients. We herein report a case of GC with these two factors that was successfully treated by the combination of gastro-jejunal bypass and chemotherapy, followed by curative R0 resection. CASE PRESENTATION: A 60-year-old man was diagnosed with type 2 GC with liver metastasis and pyloric stenosis, which was confirmed as the HER2-positive type. He underwent gastrojejunostomy and received capecitabine and cisplatin (XP) + trastuzumab chemotherapy. After three courses of the XP + trastuzumab regimen, shrinkage of the primary lesion and liver metastasis was confirmed and his nutritional parameters markedly improved with a stable oral intake after bypass surgery. He underwent curative R0 resection by distal gastrectomy with D2 lymphadenectomy and partial hepatectomy. Histologically, viable tumor cells were observed in less than one-third of the primary lesion, and only scar tissue without viable cancer cells was noted in the resected liver specimen. His postoperative course was uneventful, and recurrence has not been detected in the 30 months after surgery without adjuvant chemotherapy. CONCLUSION: The present case report describes a successful strategy for advanced GC with pyloric stenosis and liver metastasis.

[Preoperative Esophageal Decompression and Enteral Nutrition Using a W-ED Tube in Patients with Esophagogastric Junction Cancer-A Case Report].

The patient was a 67-year-old male diagnosed with adenocarcinoma of the esophagogastric junction. The esophagus was markedly dilated due to severe stenosis, and aspiration pneumonia was observed. Therefore, he was treated with a W- ED tube for simultaneous esophageal decompression and enteral nutrition. Two weeks of W-ED tube placement improved esophageal dilatation and pneumonia while maintaining nutritional status; thus, he underwent proximal gastrectomy, lower esophagectomy and combined resection of distal pancreas, spleen and left crus of diaphragm with jejunal interposition reconstruction. His postoperative course was uneventful, and he was discharged 16 days after surgery without any postoperative infectious complications such as pneumonia, anastomotic leakage, pancreatic fistula and enterocolitis. In the preoperative management for patients with esophagogastric junction cancer with severe stenosis, simultaneous esophageal decompression and enteral nutrition using a W-ED tube is very useful because it can improve aspiration pneumonia, reduce the risk of anastomotic leakage by improving esophageal edema, and prevent disuse atrophy of small intestinal villi.

The effect of denosumab in breast cancer patients receiving adjuvant aromatase inhibitors: 36-month results.

INTRODUCTION: Aromatase inhibitor (AI)-associated bone loss increases the risk of bone fracture and reduces patients' quality of life, making it a critical issue worldwide. We conducted a prospective non-randomized clinical trial (UMIN-CTR, UMIN 000016173) to assess the effect of denosumab on bone loss in patients treated with adjuvant AI and have previously reported the results at 12 and 24 months. This study aimed to present the results at 36 months of treatment with denosumab for osteopenia in breast cancer patients who were undergoing treatment with adjuvant AI; 36 months is the longest denosumab treatment period reported so far. MATERIALS AND METHODS: Patients received 60-mg denosumab subcutaneously every 6 months. Daily supplements containing 500-mg elemental calcium and at least 400 international units of vitamin D were highly recommended throughout the study period. The levels of bone mineral density (BMD) and bone turnover markers, serum tartrate-resistant acid phosphatase isoform 5b, and bone alkaline phosphatase were determined at baseline and 6, 12, 18, 24, and 36 months. RESULTS: At 36 months, the bone mineral density of the lumbar spine, right femoral neck, and left femoral neck were found to increase by 8.8% (95% confidence interval CI 7.6-10.1), 4.3% (95% CI 3.0-5.5), and 3.1% (95% CI 2.1-4.1), respectively. No non-traumatic clinical fractures occurred in patients receiving AI and denosumab. CONCLUSION: Twice-yearly administration of denosumab to the breast cancer patients treated with adjuvant AI, regardless of the skeletal site, resulted in consistent increases in BMD without severe adverse events at 36 months.

[A Case of Synchronous Bilateral Male Breast Cancer].

A 71-year-old man with right and left mammary tumor came to our hospital. Using needle biopsy, we diagnosed both tumors as ER-positive, PgR-positive, and HER2(1+)invasive ductalcarcinoma. We performed radicalmastectomy and axillary dissection. After surgery, the patient received postoperative chemotherapy, radiotherapy, and hormone therapy. The incidence of male breast cancer has been reported to be<1% of all breast cancer cases; only a few cases of simultaneous bilateral male breast cancer has been reported. Here, we report a rare case of synchronous bilateral male breast cancer.

Predictive factors for the development of proteinuria in cancer patients treated with bevacizumab, ramucirumab, and aflibercept: a single-institution retrospective analysis.

The development of proteinuria restricts the dose of anti-angiogenic agents, thereby reducing their efficacy. Thus, this retrospective study was undertaken to identify predictive factors of the development of angiogenesis inhibitor-induced proteinuria, and to elucidate if there is a difference in the likelihood of proteinuria among anti-angiogenic agents or cancer types, to help guide future strategies to improve the safety, efficacy, and quality of life of patients receiving chemotherapy. Between April 2014 and February 2019, 124 cancer patients at our outpatient chemotherapy center who were receiving chemotherapy with bevacizumab, ramucirumab, or aflibercept were enrolled. Variables related to the development of proteinuria were extracted from the patients' clinical records and used for regression analysis. The level of the proteinuria was evaluated based on CTCAE version 5. Multivariate ordered logistic regression analysis was performed to identify predictive factors for the development of proteinuria. The Wilcoxon/Kruskal-Wallis test was used to identify significant differences between groups. Significant factors identified included systolic blood pressure (SBP) [odds ratio (OR) = 1.031, 95% confidence interval (CI) = 1.005-1.058; P = 0.0197], number of cycles (OR = 1.049, 95% CI = 1.018-1.082; P = 0.0019), and calcium channel blocker use (OR = 2.589, 95% CI = 1.090-6.146; P = 0.0311). There was no difference among the three anti-angiogenic agents (P = 0.4969) or among cancer types (P = 0.2726) in the likelihood of proteinuria. In conclusion, SBP, number of cycles, and calcium channel blocker use were identified as significant predictors of the development of angiogenesis inhibitor-induced proteinuria. There was no difference among the three anti-angiogenic agents or among cancer types.

Comparison of the efficacy of cryotherapy and compression therapy for preventing nanoparticle albumin-bound paclitaxel-induced peripheral neuropathy: A prospective self-controlled trial.

BACKGROUND: Recently, the efficacy of cryotherapy and compression therapy to prevent taxane-induced peripheral neuropathy has been reported. We prospectively compared the efficacy of cryotherapy using a frozen glove (FG) and compression therapy using a surgical glove (SG) to prevent nanoparticle albumin-bound paclitaxel (nab-PTX)-induced peripheral neuropathy. PATIENTS AND METHODS: Breast cancer patients who received 260 mg/m2 of nab-PTX were eligible to participate in this trial. Patients wore a FG on one hand (60 min) without changing and two SGs of the same size (i.e., one size smaller than the size that best fit their hand) on the other hand (90 min) during chemotherapy. Peripheral neuropathy was evaluated at each treatment cycle using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, the Patient Neurotoxicity Questionnaire (PNQ), and the Functional Assessment of Cancer Therapy-Taxane subscale. Temperatures at each fingertip in both groups were measured thermographically. RESULTS: Between August 2017 and March 2019, 43 patients were enrolled and 38 were evaluated. No cases showed discordance of peripheral neuropathy between each gloved group in cases of CTCAE ≥ grade 2. In cases of PNQ ≥ grade D, using the Nam equivalence test, the upper test (P = 0.0329) and lower test (P = 0.0052) both showed negative results in comparisons between each gloved group. Fingertip temperature was significantly lower in the FG group than in the SG group after treatment (P < 0.0001). CONCLUSIONS: It seems to be no difference in incidence of nab-PTX-induced peripheral neuropathy using either cryotherapy or compression therapy.

[A Case of Small Cell Carcinoma of the Breast].

A 67-year-old woman with a mass in the right breast was admitted to our hospital. The tumor measured 35mm in diameter in the right breast, and the lymph node measured 30mm in diameter in the right axilla. The mass was diagnosed as malignant based on core needle biopsy. Immunohistochemistry staining for synaptophysin, chromogranin A, and CD56 was positive, suggesting that the tumor was small cell carcinoma. Positron emission tomography-computed tomography imaging excluded any other primary disease. Thus, the patient was diagnosed as having primary small cell carcinoma of the breast. Modified radical mastectomy with axillary lymph node dissection was performed. The pathological diagnosis of the surgical material confirmed small cell carcinoma. The expression of estrogen, progesterone, and human epidermal growth factor receptors was negative. After surgery, chemotherapy- and radiotherapy-based breast cancer treatment were performed. The patient was relapse free 9 months after surgery.

Predictive factors for the efficacy of denosumab in postmenopausal Japanese women with non-metastatic breast cancer receiving adjuvant aromatase inhibitors: a combined analysis of two prospective clinical trials.

Aromatase inhibitors (AIs) are the gold standard therapy for breast cancer in postmenopausal women. AI suppresses the conversion of androgens to estrogens; however, this results in osteopenia, osteoporosis, and bone fracture, thus reducing the patient's quality of life. The use of adjuvant denosumab reduces the risk of clinical fractures in postmenopausal patients with breast cancer receiving AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss has not been prospectively evaluated in Japan. In this study, we aimed to investigate the predictive factors for the efficacy of denosumab in postmenopausal patients with breast cancer treated with AI by analyzing the results of two prospective trials. The patients received 60 mg denosumab subcutaneously every 6 months. The primary endpoint was percentage change in lumbar spine bone mineral density (BMD) from baseline to month 12 in lumbar spine. Post hoc analysis and T tests were performed. A total of 205 patients were enrolled. At 12 and 24 months, the lumbar spine BMD increased by 5.6% [95% confidence interval (CI) 4.9-6.3] and 8.3% (95% CI 7.5-9.1), respectively. Subgroup analysis was conducted according to the time of AI therapy initiation, type of AI therapy, age, time since menopause, baseline body mass index, and BMD. The results showed that baseline lumbar and left femoral BMD was significantly associated with a percentage change in these sites, respectively. In addition, baseline left femoral BMD was also associated with a change in lumbar BMD. In conclusion, the baseline BMD in the lumbar spine was a predictive indicator for the efficacy of denosumab in this site and the baseline BMD in left femoral neck was a predictive indicator in lumbar spine and left femur.

Effects of denosumab on bone mineral density in Japanese women with osteoporosis treated with aromatase inhibitors for breast cancer.

Adjuvant aromatase inhibitor (AI) therapy, for hormone receptor-positive breast cancer, in postmenopausal women is associated with bone loss, leading to an increased risk of fractures. Denosumab, an antibody raised against the receptor activator of nuclear factor-κB ligand, has been proven to protect against AI-induced bone loss. Hence, we aimed to determine whether denosumab is effective in postmenopausal Japanese women with osteoporosis, treated with AI. We prospectively evaluated the bone mineral density (BMD) in the lumbar spine and the bilateral femoral neck in 102 postmenopausal women with clinical hormone receptor-positive breast cancer, stages I-IIIA, during a postoperative period of 12 months. The other inclusion criteria for this study were: women that should receive AIs as adjuvant therapy and those with evidence of osteoporosis (lumbar spine or bilateral femoral neck BMD, equivalent to T-score classification of ≤ - 2.5) upon enrollment. The patients received supplemental calcium, vitamin D, and 60 mg of subcutaneous denosumab every 6 months. The BMD of the lumber spine increased by 4.9 and 6.6% at 6 and 12 months, respectively. An increase in BMD was observed at the femoral neck, bilaterally. Hypocalcemia ≥ grade 2, osteonecrosis of the jaw, and non-traumatic clinical fracture were not observed in this study. Our findings revealed that biannual treatment with denosumab is associated with a great increase of BMD in Japanese women receiving adjuvant AI therapy, irrespective of their previous history of AI therapy.

Predictive factors for taxane acute pain syndrome determined by ordered logistic regression analysis.

This retrospective study was undertaken to identify predictive factors for developing taxane acute pain syndrome (TAPS) and to determine new strategies for improving QoL in patients undergoing chemotherapy. Between November 2010 and May 2018, we enrolled 121 breast cancer patients at our outpatient chemotherapy center who were undergoing chemotherapy with nanoparticle albumin-bound paclitaxel (nab-PTX) every 3 weeks. Variables related to the development of TAPS were extracted from the patients' clinical records and used for regression analysis. The degree of TAPS was classified as grade 0 = not developed; grade 1 = developed but did not require analgesics; grade 2 = developed but alleviated by analgesics such as acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs); or grade 3 = syndrome developed, causing sleep problems or interfering with daily living activities, but not alleviated by analgesics such as acetaminophen or NSAIDs thus requiring opioids. Multivariate ordered logistic regression analysis was performed to identify predictive factors for the development of TAPS. Significant factors identified for the development of TAPS included dose of nab-PTX (odds ratio (OR) = 11.717, 95% confidence interval (CI) = 11.6161-11.8182; P = 0.0421) and the administration of dexamethasone for up to 3 days (OR = 0.133, 95% CI = 0.0235-0.7450; P = 0.0223). In conclusion, a high dose of nab-PTX and the lack of dexamethasone administration for up to 3 days were identified as significant predictors of the development of TAPS.

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.

Dynamic Contrast-enhanced Magnetic Resonance Imaging for Patients with Breast Cancer Receiving First-line Bevacizumab and Paclitaxel.

BACKGROUND: Bevacizumab plus paclitaxel shows promise for metastatic disease; however, there is no predictive biomarker. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) is widely used to evaluate the efficacy of anti-angiogenic therapies. PATIENTS AND METHODS: Patients with locally advanced/metastatic breast cancer who had not received any prior chemotherapy or hormone therapy were included. DCE-MRI was conducted at baseline and after one and two cycles of bevacizumab and paclitaxel. The percentage change in the volume transfer constant (ΔKtrans) and the correlation of ΔKtrans with tumour regression and time to progression (TTP) were evaluated. RESULTS: The mean ΔKtrans from baseline after one and two cycles was -51.4% and -55.1%, respectively. Patients with ΔKtrans ≥50% displayed more tumour regression than those with ΔKtrans <50%; TTP was not significantly different. CONCLUSION: We demonstrate a decrease in blood permeability following bevacizumab and paclitaxel using DCE-MRI and a correlation between ΔKtrans and tumour regression.

Effect of denosumab on bone mineral density in Japanese women with osteopenia treated with aromatase inhibitors for breast cancer: subgroup analyses of a Phase II study.

BACKGROUND: The aim of the study was to conduct subgroup analyses of therapeutic effects of 12-month denosumab therapy on the percentage change in bone mineral density (BMD) from baseline in the lumber spine and femoral neck. MATERIALS AND METHODS: We prospectively evaluated the BMD of the lumbar spine and femoral neck of 100 hormone receptor-positive, clinical stage I-IIIA postoperative postmenopausal breast cancer patients, for whom treatment with aromatase inhibitors (AIs) as adjuvant endocrine therapy was scheduled. The primary endpoint was the percent change in lumbar spine BMD from baseline to 12 months. Patient subgroups were analyzed according to baseline variables that are known risk factors for bone loss, including previous AI therapy, age, time since menopause, baseline body mass index (BMI), and baseline BMD T-score. RESULTS: At 12 months, lumbar spine BMD increased by 4.7%; the patients who were administered AI therapy prior to denosumab (n=70) demonstrated a 4.7% increase in BMD, and the patients who received denosumab at the start of AI therapy (n=30) demonstrated a 4.5% increase in BMD (p=0.8385). Additionally, 2.4% and 1.4% increases in BMD of the right and left femoral neck, respectively, were observed. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (<65, ≥65 years), time since menopause (≤5, >5 years), BMI (<25, ≥25 kg/m2), and T-score (≤-1.0, >-1.0) of the right femoral neck were as follows: (2.2%, 2.5%, p=0.7773), (2.6%, 0.9%, p=0.1726), (2.5%, 2.3%, p=0.7594), (2.1%, 2.4%, p=0.2034), (2.1%, 2.9%, p=0.2034), and (2.3%, 2.7%, p=0.6823), respectively. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (<65, ≥65 years), time since menopause (≤5, >5 years), BMI (<25, ≥25 kg/m2), and T-score (≤-1.0, >-1.0) of the left femoral neck were as follows: (1.0%, 1.5%, p=0.1972), (1.2%, 2.7%, p=0.2931), (1.4%, 1.3%, p=0.8817), (-0.1%, 1.6%, p=0.1766), (1.3%, 1.9%, p=0.6465), and (1.5%, 1.1%, p=0.6573), respectively. CONCLUSION: Twice-yearly treatment with denosumab was associated with increased BMD among Japanese women receiving adjuvant AI therapy, regardless of the baseline characteristics or skeletal site.

Effect of denosumab administration on low bone mineral density (T-score -1.0 to -2.5) in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer.

Although adjuvant aromatase inhibitor (AI) therapy is widely used in postmenopausal women with hormone receptor-positive breast cancer, it is known to be associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand, has been shown to protect against AI-induced bone loss. However, the efficacy of denosumab in the treatment of AI-associated bone loss has not been prospectively evaluated in Japan. We prospectively monitored bone mineral density (BMD) of the lumbar spine and bilateral femoral necks in 100 postmenopausal women with hormone receptor-positive postoperative breast cancer of clinical stage I-IIIA in whom treatment with AI as adjuvant endocrine therapy was planned or had been ongoing. Study participants received supplemental calcium and vitamin D every day and denosumab (60 mg) subcutaneously every 6 months. At enrollment, patients were required to have evidence of low bone mass without meeting the criteria for osteoporosis. The primary endpoint was percentage change from baseline in lumbar spine BMD at month 12. At 6 and 12 months, lumbar spine BMD increased by 3.3 and 4.7%, respectively. BMD of the femoral necks also increased. Hypocalcemia of grade ≥2, osteonecrosis of the jaw, and non-traumatic clinical fracture did not occur. In conclusion, semi-annual treatment with denosumab was associated with increased BMD in Japanese women receiving adjuvant AI therapy, regardless of prior AI treatment.

An in-house-anti-hepatitis A virus (HAV)-specific immunoglobulin M capture enzyme-linked immunosorbent assay: evaluation and application to an HAV outbreak.

An anti-hepatitis A virus (HAV)-specific immunoglobulin M capture enzyme-linked immunosorbent assay (anti-HAV IgM ELISA) kit was re-designed for laboratory use and compared with a commercial anti-HAV IgM detection system using 58 serum samples collected from patients, vaccines, and healthy individuals. Because concordance between the two systems was high (r = 0.93, P < 0.05), 19 sets of serum and fecal samples obtained from individuals exposed to an HAV outbreak were also examined. Serum levels of anti-HAV IgM were determined using the in-house ELISA kit and the HAV genome in fecal samples was detected using the polymerase chain reaction (PCR). Among the 19 sets of sample, 14 were positive for both anti-HAV IgM and the HAV genome. All of those whose serum samples were anti-HAV IgM negative were also negative for the HAV genome in fecal samples. The results of the in-house IgM ELISA were consistent with those of the HAV genome detected by PCR and with the commercial IgM ELISA. The in-house anti-HAV IgM ELISA kit was therefore proven suitable for laboratory use and applicable to epidemiological studies of HAV infection.