Phase II trial of biweekly administration with eribulin after three cycles of induction therapy in hormone receptor-positive, HER2-negative metastatic breast cancer (JACCRO BC-03).

PURPOSE: Metastatic breast cancer (MBC) is usually incurable; treatment aims to maximize patients' function and quality of life (QOL). Eribulin is a standard treatment in patients with MBC pretreated with anthracycline and taxane; however, the best administration schedule is unknown. METHODS: In this prospective phase II trial of patients with luminal MBC, we administered biweekly eribulin to patients who completed a three-cycle induction treatment. RESULTS: Sixty patients with hormone-receptor-positive and HER2-negative MBC were enrolled; 40 obtained stable disease (SD) or better efficacy after induction therapy, after which they were switched to biweekly maintenance administration. The median progression-free survival (PFS) in patients who switched to maintenance therapy was 15.21 weeks (95% CI 9.71-22.14), starting on the first day of maintenance therapy. Overall survival (OS) in patients who switched to maintenance therapy was 21.39 months (95% CI 18.89-32.89). PFS and OS in the whole population starting from the registration date were 19.00 weeks (95% CI 17.00-25.00) and 21.52 months (95% CI 16.23-24.25), respectively. PFS from the enrollment date for patients who received maintenance therapy was 25.29 weeks (95% CI 19.14-32.14). Patients who achieved complete response or partial response during induction therapy had significantly longer PFS compared to patients with SD. CONCLUSION: The efficacy of biweekly administration of eribulin at maintenance was nonsignificant. However, less frequent visits are convenient, and reduced dose intensity improves safety. Biweekly administration, besides dose reduction, could be an acceptable option for patients who are unable to maintain a standard regimen.

[Interstitial Lung Disease after OK-432 Pleurodesis for Malignant Pleural Effusion in Breast Cancer-A Case Report].

The patient was a 42-year-old woman. After 4 courses of capecitabine therapy for right chest wall recurrence of breast cancer, ER(+, 10-15%), PgR(-), HER2(-), she underwent pleurodesis using OK-432 for increased right pleural effusion. On the 12th day after pleurodesis diffuse infiltrative shadows in the right lung, and frosted shadows in both lungs, were observed, and she was diagnosed with drug-induced lung injury. About 3 weeks after administration of prednisolone 1 mg/ kg a tendency for improvement in lung injury was observed, but the patient died of breast cancer progression. Drug- induced lung injury by pleurodesis carries the risk of delaying resumption of chemotherapy. We report this case with a review of the literature.

Ki-67 response-guided preoperative chemotherapy for HER2-positive breast cancer: results of a randomised Phase 2 study.

BACKGROUND: The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated. METHODS: Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: A total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4-56.7; P = 0.025). CONCLUSIONS: The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: UMIN-CTR as UMIN000007074.

First-in-human phase I clinical trial of the NY-ESO-1 protein cancer vaccine with NOD2 and TLR9 stimulants in patients with NY-ESO-1-expressing refractory solid tumors.

Cholesteryl pullulan (CHP) is a novel antigen delivery system. CHP and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen complexes (CHP-NY-ESO-1) present multiple epitope peptides to the MHC class I and II pathways. Adjuvants are essential for cancer vaccines. MIS416 is a non-toxic microparticle that activates immunity via the nucleotide-binding oligomerization domain 2 (NOD2) and TLR9 pathways. However, no reports have explored MIS416 as a cancer vaccine adjuvant. We conducted a first-in-human clinical trial of CHP-NY-ESO-1 with MIS416 in patients with NY-ESO-1-expressing refractory solid tumors. CHP-NY-ESO-1/MIS416 (µg/µg) was administered at 100/200, 200/200, 200/400 or 200/600 (cohorts 1, 2, 3 and 4, respectively) every 2 weeks for a total of 6 doses (treatment phase) followed by one vaccination every 4 weeks until disease progression or unacceptable toxicity (maintenance phase). The primary endpoints were safety and tolerability, and the secondary endpoint was the immune response. In total, 26 patients were enrolled. Seven patients (38%) continued vaccination in the maintenance phase. Grade 3 drug-related adverse events (AEs) were observed in six patients (23%): anorexia and hypertension were observed in one and five patients, respectively. No grade 4-5 drug-related AEs were observed. Eight patients (31%) had stable disease (SD). Neither augmentation of the NY-ESO-1-specific IFN-γ-secreting CD8+ T cell response nor an increase in the level of anti-NY-ESO-1 IgG1 was observed as the dose of MIS416 was increased. In a preclinical study, adding anti-PD-1 monoclonal antibody to CHP-NY-ESO-1 and MIS416 induced significant tumor suppression. This combination therapy is a promising next step.

Esophageal squamous cell neoplasia is an independent negative prognostic factor for head and neck cancer patients.

BACKGROUND: Patients with head and neck cancer (HNC) have a high incidence of esophageal squamous cell neoplasms (ESCN). ESCN also has a negative impact on the survival of HNC patients. However, recent endoscopic advances enable the early detection of ESCN, and novel treatments may lead to improving survival rates for HNC patients with ESCN. METHODS: HNC patients who underwent magnifying esophagogastroduodenoscopy (EGDS) from 2005 to 2012 were included in this study (n = 226). We analyzed the prevalence and prognostic value of ESCN in HNC patients and the difference in overall survival between HNC patients with and without ESCN. RESULTS: Thirty-four patients (15%) developed an ESCN during their clinical course. Of the 34 patients, 10 patients underwent endoscopic resection for ESCN and 10 patients underwent simultaneous chemoradiation therapy for HNC and ESCN. The 3-year survival rates in HNC patients with and without ESCN were 53% and 70%, respectively. Multivariate analysis identified the advanced clinical stage of the HNC [hazard ratio (HR) = 2.15; 95% confidence interval (CI) = 1.18-3.93; p = 0.012] and the presence of ESCN (HR = 1.73; 95% CI = 1.00-2.97; p = 0.049) as significant and independent determinants of overall survival. CONCLUSIONS: Our study suggests that although the survival of HNC patients with ESCN may be improved by routine EGDS during tumor surveys and by advances in endoscopy, the presence of ESCN still remains an independent negative prognostic factor for HNC patients.

[A Case of Poorly Differentiated Carcinoma of Unknown Primary Site with Risk of Choriocarcinoma Syndrome Effectively Treated with Reduced Bleomycin,Cisplatin ,Etoposide Combination Regimen(BEP Regimen)].

A 64-year-old man visited his physician complaining of bilateral gynecomastia and left shoulder pain. Chest X-ray showed multiple bilateral masses in the lung, and he was referred to our hospital. Radiographical findings, elevation of serum total hCG, and histological findings of the cervical lymph node revealed multiple pulmonary, nodal, and brain metastases of poorly differentiated carcinoma of an unknown primary site with choriocarcinoma components. He was administered a regimen of reduced bleomycin, cisplatin, etoposide combination(reduced BEP regimen)to reduce the risk of acute respiratory failure with intra-alveolar hemorrhage related to post-chemotherapy early tumor necrosis. After chemotherapy, the tumor marker hCG levels were almost restored to normal levels, and radiography showed he had achieved a clinical partial response.

[A case report of a well-differentiated neuroendocrine tumor in which sunitinib treatment resulted in stable disease].

A 52-year-old woman had a primary neuroendocrine tumor, Grade 2(NET G2)with multiple liver metastases and a mesenteric tumor. Since no drugs were approved for NET at that time in Japan, we treated her with sunitinib after approval by the Ethics Committee of Mie University Hospital and obtaining informed consent. Sunitinib was administered at a daily dose of 37.5mg/day, but the dose was reduced to 12.5mg/day because of thrombocytopenia(G3)and neutropenia(G3). CT revealed stable disease after 3 months of treatment, but disease progression was observed after 11 months. The non-hematological toxicity was hypertension(G3), which was controlled with antihypertensive agents. Although there are no previous reports of the treatment of well-differentiated NET with sunitinib in Japan, sunitinib may be effective against this disease.

Ganglioside GD2 Expression Is Associated With Unfavorable Prognosis in Early Triple-negative Breast Cancer.

BACKGROUND/AIM: Gangliosides (acidic glycosphingolipids) have crucial regulatory roles in normal physiological processes, as well as in pathological conditions, including tumor onset and progression. GD2 is highly expressed in triple-negative breast cancer (TNBC), particularly in cancer stem cells. However, little is known on the clinical impact of GD2 expression on the prognosis of TNBC. Consequently, we aimed to investigate the association between GD2 expression in TNBC and the prognosis of TNBC. PATIENTS AND METHODS: We assessed GD2 expression in 76 patients with primary TNBC who had undergone surgery at our Institute between 2012 and 2015 using immunohistochemical analysis with a tissue microarray technique. We investigated the relationship between GD2 expression and clinicopathological factors in TNBC, recurrence-free survival (RFS), and overall survival (OS). RESULTS: Increased GD2 expression was observed in 45% of TNBC patients. There was no significant association between GD2 expression and clinicopathological factors in TNBC. The 5-year RFS rate among patients with GD2-positive TNBCs was significantly worse than that among patients with GD2-negative TNBCs (75.4% and 94.9%; HR=4.931; 95%CI=1.024-23.752; p=0.027). The OS in patients with GD2-positive TNBCs tended to be inferior to that of patients with GD2-negative TNBCs (HR=5.357; 95%CI=0.599-47.939; p=0.092). Interestingly, in patients with GD2-positive TNBCs, a higher grade of tumor-infiltrating lymphocytes (TILs) displayed a significantly better impact on OS (TILs-high vs. TILs-low; p=0.04). Both univariate and multivariate analyses showed that GD2 expression negatively affected RFS (p=0.027, p=0.021, respectively). CONCLUSION: GD2 expression is an independent unfavorable prognostic factor for TNBC.

Repositioning of Lansoprazole as a Protective Agent Against Cisplatin-Induced Ototoxicity.

Cisplatin (CDDP) is a well-known chemotherapeutic drug approved for various cancers. However, CDDP accumulates in the inner ear cochlea via organic cation transporter 2 (OCT2) and causes ototoxicity, which is a major clinical limitation. Since lansoprazole (LPZ), a proton pump inhibitor, is known to inhibit OCT2-mediated transport of CDDP, we hypothesized that LPZ might ameliorate CDDP-induced ototoxicity (CIO). To test this hypothesis, we utilized in vivo fluorescence imaging of zebrafish sensory hair cells. The fluorescence signals in hair cells in zebrafish treated with CDDP dose-dependently decreased. Co-treatment with LPZ significantly suppressed the decrease of fluorescence signals in zebrafish treated with CDDP. Knockout of a zebrafish homolog of OCT2 also ameliorated the reduction of fluorescence signals in hair cells in zebrafish treated with CDDP. These in vivo studies suggest that CDDP damages the hair cells of zebrafish through oct2-mediated accumulation and that LPZ protects against CIO, possibly inhibiting the entry of CDDP into the hair cells via oct2. We also evaluated the otoprotective effect of LPZ using a public database containing adverse event reports. The analysis revealed that the incidence rate of CIO was significantly decreased in patients treated with LPZ. We then retrospectively analyzed the medical records of Mie University Hospital to examine the otoprotective effect of LPZ. The incidence rate of ototoxicity was significantly lower in patients co-treated with LPZ compared to those without LPZ. These retrospective findings suggest that LPZ is also protective against CIO in humans. Taken together, co-treatment with LPZ may reduce the risk of CIO.

SMARCA2/BRM-Deficient Undifferentiated/Rhabdoid Carcinoma of Unknown Primary Site.

Undifferentiated neoplasms of unknown primary sites are rare. It is difficult to identify their characteristics and determine the appropriate chemotherapy regimen to be used. Undifferentiated/rhabdoid carcinoma is reportedly associated with loss of SWI/SNF chromatin remodeling complexes, such as observed in SMARCA4-deficient tumors. However, little is known about SMARCA2/BRM-deficient tumors. A 48-year-old man presented with low back pain. Computed tomography (CT) revealed intraperitoneal lymph nodes and multiple bone metastases that invaded the thoracic and lumbar spinal canals. The primary tumor was not identified despite the standard diagnostic methods being used. CT-guided needle biopsy of right iliac bone metastasis showed that the tumor had an undifferentiated/rhabdoid morphology. Immunostaining revealed that the tumor was SMARCA2/BRM-deficient despite both SMARCB1/INI1 and SMARCA4/BRG being retained. We found no genomic alterations during domestic next-generation sequencing panel profiling, which can identify 114 genes. Thus, he was diagnosed with SMARCA2/BRM-deficient undifferentiated/rhabdoid carcinoma of an unknown primary site with multiple bone metastases and intraperitoneal lymph node metastasis. We administered radiotherapy to the thoracic and lumbar spine to improve cord compression, and carboplatin (CBDCA) and paclitaxel regimen was chosen as first-line chemotherapy, but this was discontinued due to an anaphylactic shock. We then selected the CBDCA and gemcitabine regimens; however, the patient did not continuously receive the regimen due to myelosuppression. Radiation therapy effectively relieves pain and cord compression. To our knowledge, this is the first reported case of SMARCA2/BRM-deficient undifferentiated/rhabdoid carcinoma of an unknown primary site. Further studies are needed to improve SWI/SNF-deficient tumor identification methods.

A Case of Metaplastic Squamous Cell Carcinoma of the Breast that Showed a Pathological Complete Response After Neoadjuvant Chemotherapy with Weekly Paclitaxel.

BACKGROUND Primary squamous cell carcinoma of the breast is a rare type of metaplastic breast carcinoma, characterized by resistance to conventional chemotherapy agents. We report a case of metaplastic squamous cell carcinoma of the breast in which a pathological complete response was achieved after neoadjuvant chemotherapy with weekly paclitaxel and in which the patient remained disease free for 15 years and 7 months. CASE REPORT A 40-year-old woman had a palpable 5-cm-diameter tumor in the right breast that was diagnosed as metaplastic squamous cell carcinoma of the breast based on core needle biopsy. The patient was initially treated with an adjuvant chemotherapy (AC) regimen consisting of doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) as neoadjuvant chemotherapy. Because the tumor grew rapidly and the skin redness increased after 1 cycle of the AC regimen, 12 cycles of weekly paclitaxel 80 mg/m² were subsequently administered. The tumor responded dramatically to paclitaxel. The patient underwent mastectomy with level II axillary lymph node dissection. No residual tumor cells were found, which indicated pathological complete response. The patient is currently disease free at 15 years and 7 months after the operation. CONCLUSIONS To our knowledge, there are no previous reports of metaplastic squamous cell carcinoma of the breast in which pathological complete response was achieved by treatment with neoadjuvant chemotherapy with weekly paclitaxel (80 mg/m²).

Atezolizumab-Induced Sarcoidosis-Like Reaction in a Patient with Metastatic Breast Cancer.

Tumor-related sarcoidosis-like reactions (SLR) have been reported with the use of immune checkpoint inhibitors (ICIs). We report a case of 50-year-old woman who observed an enlarged lymph node in the right hilar region and the appearance of a subcutaneous mass in the extremities during chemotherapy with atezolizumab plus nab-paclitaxel for metastatic triple-negative breast cancer (TNBC). Skin biopsy revealed the formation of epithelioid granulation species with the Langhans giant cell. After discontinuing atezolizumab in the treatment procedure, the hilar lymph nodes and the subcutaneous mass were reduced. A pathological examination was effective in differentiating tumor exacerbation from SLR. Owing to limited information on ICI-related SLR in breast cancer, future studies are recommended to properly manage immune-related adverse effects during cancer treatment.

Preliminary results of reduced myocardial blood flow in the subacute phase after radiation therapy for thoracic esophageal cancer: A quantitative analysis with stress dynamic myocardial computed tomography perfusion imaging.

BACKGROUND AND PURPOSE: Late adverse cardiac events after radiation therapy (RT) for thoracic malignancies are known, but the underlying mechanisms are poorly understood. This study aimed to determine the radiation dose that can cause MBF alterations in the subacute phase after RT for thoracic esophageal cancer using stress dynamic myocardial computed tomography perfusion imaging (CTP). MATERIALS AND METHODS: Twenty-five patients with esophageal cancer scheduled for RT were prospectively enrolled. The quantitative analysis of MBF by CTP was performed before and 3 months after RT. The mean radiation dose and hyperemic MBF in 15 segments of the left ventricular (LV) myocardium were determined. ΔMBF was calculated in each segment as MBFafter RT - MBFbeforeRT. The myocardial segments were classified into the following 5 groups according to the mean radiation dose: group A, <10 Gy; B1, 10-15 Gy; B2, 15-20 Gy; C, 20-30 Gy; and D, >30 Gy. RESULTS: The final cohort included 22 patients who completed pre- and post-RT CTP. A one-way analysis of variance revealed a significant difference (p=0.005) in ΔMBF among the five groups of LV segments classified by the mean radiation dose. ΔMBF was significantly lower in group C (-7.7 ± 28.9 mL/min/100 g, p=0.020) and group D (-8.4 ± 34.8 mL/min/100 g, p=0.004) in comparison to ΔMBF in group A (4.9 ± 26.1 mL/min/100 g). CONCLUSIONS: This study using CTP early after RT demonstrated a significant reduction of the MBF in the LV segments with ≥20 Gy of radiation. The results might provide important insights into preventing radiotherapy-induced cardiac events.

Adjuvant trastuzumab without chemotherapy for treating early HER2-positive breast cancer in older patients: A propensity score-adjusted analysis of a prospective cohort study.

PURPOSE: To gauge the effects of treatment practices on prognosis for older patients with HER2-positive early breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This is a prospective cohort study which accompanies the RESPECT that is a randomized-controlled trial (RCT). METHODS: Patients who declined the RCT were treated based on the physician's discretion. We studied the 1) trastuzumab-plus-chemotherapy group, 2) trastuzumab-monotherapy group, and 3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method. Relapse-free survival (RFS) and health-related quality of life (HRQoL) were assessed. RESULTS: We enrolled 123 patients aged over 70 years (median: 74.5). Treatment categories were: trastuzumab-plus-chemotherapy group (n = 36, 30%), trastuzumab-monotherapy group (n = 52, 43%), and non-trastuzumab group (n = 32, 27%). The 3-year DFS was 96.7% in trastuzumab-plus-chemotherapy group, 89.2% in trastuzumab-monotherapy group, and 82.5% in non-trastuzumab group. DFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted hazard ratio; HR: 3.29; 95% CI: 1.15-9.39; P = 0.026). The RFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32-26.2, P < 0.0001). There were no significant intergroup differences in the proportions of patients showing HRQoL deterioration at 36 months (P = 0.717). CONCLUSION: Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Trastuzumab monotherapy could be considered for older patients who reject chemotherapy.

A multicenter phase-II study of 5-FU, leucovorin and oxaliplatin (FOLFOX6) in patients with pretreated metastatic colorectal cancer.

OBJECTIVE: Infusional 5-fluorouracil and leucovorin with oxaliplatin is one of the standard regimens for patients with pretreated metastatic colorectal cancer, as well as for first-line chemotherapy. FOLFOX4 has shown its efficacy in pivotal trials, but patients must make twice-weekly hospital visits. FOLFOX6 is a more convenient regimen, requiring a visit once every two weeks. The objective of this study was to evaluate the efficacy and safety profile of FOLFOX6 in Japanese patients with pretreated colorectal cancer. METHOD: Fifty-one metastatic colorectal cancer patients who failed to respond to first-line chemotherapy were enrolled in the study from April to July 2005. Oxaliplatin, 5-fluorouracil and l-leucovorin were administered every two weeks. Oxaliplatin (100 mg/m(2)) and l-leucovorin (200 mg/m(2)) were given intravenously over 2 h followed by 5-fluorouracil bolus 400 mg/m(2) i.v. and 46-h infusion of 2400 mg/m(2). The primary endpoint was the response rate. RESULTS: Two patients had no measurable lesions and were excluded from the efficacy analysis. Of the 49 eligible patients, one complete response and 6 partial responses were observed, resulting in a response rate (RR) of 14.3% (95% confidence interval: 5.9-27.2%). Median time to treatment failure and progression-free survival was 4.4 and 5.3 months, respectively. Overall survival was 11.4 months. The incidence of grade 2/3 (Debiopharm neurotoxicity criteria) peripheral neuropathy was 41.2%, whereas the overall incidence of grade 3/4 neutropenia was 43.2%. CONCLUSION: The results of our study suggest that FOLFOX6 had an acceptable profile in terms of both efficacy and safety in previously treated colorectal cancer patients.

Evaluation of trastuzumab without chemotherapy as a post-operative adjuvant therapy in HER2-positive elderly breast cancer patients: randomized controlled trial [RESPECT (N-SAS BC07)].

OBJECTIVE: This trial is conducted to investigate the benefit of trastuzumab monotherapy compared with a combination therapy of trastuzumab and chemotherapy in women over 70 years with human epidermal growth factor receptor type-2-positive primary breast cancer. METHODS: Inclusion criteria are the following: histologically diagnosed as invasive breast cancer and received curative operation for primary breast cancer; Stage I, IIA, IIB or IIIA/M0; and baseline left ventricular ejection fraction is ≥55%. Patients are randomized to receive either trastuzumab (8 mg/kg loading dose, 6 mg/kg every 3 weeks for 1 year) plus chemotherapy selected from regimens specified on the protocol or trastuzumab monotherapy. The primary endpoint is disease-free survival. Secondary endpoints are overall survival, relapse-free survival, safety, health-related quality of life, comprehensive geriatric assessment and cost effectiveness. RESULTS: Patients recruitment has been commenced in October 2009. Enrollment of 300 patients is planned during the 4-year recruitment period. CONCLUSIONS: We hereby report the study concept.

[Irinotecan as second-line chemotherapy for 5-FU-resistant gastric cancer with disseminated intravascular coagulation: a case report].

A 60-year-old female was diagnosed as advanced gastric cancer with multiple bone, neck and mediastinal lymph node metastases. As a primary chemotherapy, she was treated with S-1(50 m g/body, twice daily for 4 weeks, followed by a 2- week rest). After 3 courses of S-1, she developed a disease progression with pulmonary lymphangitic carcinomatosis and disseminated intravascular coagulation(DIC). Therefore, she received second-line chemotherapy of irinotecan(CPT-11 150 mg/m2, biweekly). Within 3 weeks of starting the treatment, the clinical and laboratory signs of DIC were dramatically resolved. There have been no previous reports of irinotecan alone showing such remarkable effectiveness in a patient with 5- FU-resistant gastric cancer with DIC.

CD204-positive macrophages accumulate in breast cancer tumors with high levels of infiltrating lymphocytes and programmed death ligand-1 expression.

Although immunotherapy has been demonstrated to be promising in triple-negative (TN) breast cancer (BC), most BC cases are classified as non-TN. To enrich the responders for immunotherapy regardless of their subtypes, classification based on tumor-infiltrating lymphocyte (TIL) levels and programmed death ligand-1 (PD-L1) status may be useful. However, this classification has not been fully applied to BC. Furthermore, suppressive subsets in the local tumor microenvironment, such as tumor-associated macrophages (TAMs), which promote tumor progression, cannot be ignored to overcome immunotherapy resistance. The aims of the present study were to classify primary BC cases based on the TIL levels and PD-L1 status, and to identify suppressive immune subsets in each categorized group. A retrospective analysis of 73 patients with invasive BC was performed. The frequency of TILs was evaluated in HE-stained slides (10% cutoff), and PD-L1 levels (SP142; 1% cutoff), as well as immune subsets (CD3+, CD8+, FOXP3+, CD20+, CD68+ and CD204+ cells) were assessed using immunohistochemistry. It was revealed that 22% (16/73) of the tumors were categorized as TIL+PD-L1+, of which 69% (11/16) were TN type. By contrast, 66% (48/73) of the tumors were categorized as TIL-PD-L1-, of which 77% (37/48) were HR+ and HER2- types. The number of CD204+ M2-type macrophages was significantly associated with high histological grade (P=0.0246) and high Ki-67 (P=0.0152), whereas CD68+ macrophages were not associated with these factors. Furthermore, CD204+ macrophages and FOXP3+ Tregs accumulated in 88% (14/16) and 63% (10/16) of TIL+PD-L1+ tumors, respectively, compared with 20.8% (10/48) and 27.1% (13/48) of TIL-PD-L1- tumors. In conclusion, 22% of BC tumors were classified as TIL+PD-L1+ (69% were TN), which were enriched with suppressive immune subsets. These cell types may serve as potential novel immunotherapeutic targets.

Health-Related Quality of Life With Trastuzumab Monotherapy Versus Trastuzumab Plus Standard Chemotherapy as Adjuvant Therapy in Older Patients With HER2-Positive Breast Cancer.

PURPOSE: We report findings on quality of life (QoL) in the RESPECT trial, which compared adjuvant trastuzumab monotherapy with trastuzumab plus chemotherapy in older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). PATIENTS AND METHODS: Patients age 70-80 years with human epidermal growth factor receptor 2-positive surgically treated breast cancer were randomly assigned to receive trastuzumab (T) or trastuzumab plus chemotherapy (T + C). QoL was assessed using the Functional Assessment of Cancer Therapy-General (FACT-G), Philadelphia Geriatric Center Morale Scale, Hospital Anxiety and Depression Scale, Patient Neurotoxicity Questionnaire, and Tokyo Metropolitan Institute of Gerontology Index of Competence at baseline and after 2, 12, and 36 months. Comparisons were based on individual changes from baseline and were performed by Fisher's test or mixed-model repeated-measures. RESULTS: Among 275 patients in the parent study, 231 (84%) (average age: 74 years) were included in the analysis. At 2, 12, and 36 months, 198, 177, and 178 patients completed surveys, and the mean FACT-G scores at each survey point were 78.9, 80.4, 82.7, and 79.1 in group T and 79.5, 74.5, 78.4, and 78.5 in group T + C. Compared with group T + C, the proportion of patients showing QoL deterioration (≥ 5 points decrease from baseline in FACT-G) was significantly lower at 2 months (31% v 48%; P = .016) and 12 months (19% v 38%; P = .009). In group T, the Hospital Anxiety and Depression Scale score (P = .003) and the proportion of severe sensory peripheral neuropathy (P = .001) were significantly lower at 2 months, and Philadelphia Geriatric Center Morale Scale and Tokyo Metropolitan Institute of Gerontology Index of Competence scores were significantly higher (P = .024, .042) at 12 months. At 36 months, there were no significant differences in any QoL items. CONCLUSION: Detrimental effects of adjuvant chemotherapy on global QoL, morale, and activity capacity lasted for at least 12 months but were not observed at 36 months.

An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity.

Cisplatin is widely used to treat various types of cancers, but it is often limited by nephrotoxicity. Here, we employed an integrated in silico and in vivo approach to identify potential treatments for cisplatin-induced nephrotoxicity (CIN). Using publicly available mouse kidney and human kidney organoid transcriptome datasets, we first identified a 208-gene expression signature for CIN and then used the bioinformatics database Cmap and Lincs Unified Environment (CLUE) to identify drugs expected to counter the expression signature for CIN. We also searched the adverse event database, Food and Drug Administration. Adverse Event Reporting System (FAERS), to identify drugs that reduce the reporting odds ratio of developing cisplatin-induced acute kidney injury. Palonosetron, a serotonin type 3 receptor (5-hydroxytryptamine receptor 3 (5-HT3R)) antagonist, was identified by both CLUE and FAERS analyses. Notably, clinical data from 103 patients treated with cisplatin for head and neck cancer revealed that palonosetron was superior to ramosetron in suppressing cisplatin-induced increases in serum creatinine and blood urea nitrogen levels. Moreover, palonosetron significantly increased the survival rate of zebrafish exposed to cisplatin but not to other 5-HT3R antagonists. These results not only suggest that palonosetron can suppress CIN but also support the use of in silico and in vivo approaches in drug repositioning studies.