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Background Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the standard treatment for advanced hormone receptor-positive breast cancer. Although interstitial lung disease is a rare (1–3.3%) but serious adverse event associated with CDK4/6 inhibitors, the incidence of interstitial lung disease in Japanese patients in the real world and the risk factors of interstitial lung disease are not clear. Methods We retrospectively investigated the incidence of interstitial lung disease in 224 patients with advanced breast cancer who received CDK4/6 inhibitors at our hospital between 31 January 2017 and 31 January 2021. The correlation of age (>50 vs ≤50 years), presence or absence of previous history of interstitial lung disease, lung metastasis, smoking history and chest radiation with the development of interstitial lung disease was evaluated. Results In total, 177 cases received palbociclib, 39 cases received abemaciclib and 8 cases received both palbociclib and abemaciclib, constituting a palbociclib group (n = 185) and an abemaciclib group (n = 47). At a median observation period of 607 days, 8.0% (18/224) cases (13 definite and 5 probable cases) had interstitial lung disease; 6.5% (12/185) of palbociclib-treated and 13% (6/47) of abemaciclib-treated cases. The median time to interstitial lung disease onset was 178 (range, 14–750) days. There was no significant correlation between the background factors studied and the development of interstitial lung disease. Conclusion The frequency of CDK4/6 inhibitor-induced interstitial lung disease was higher than that reported in clinical trials. We did not identify any risk factors for the development of interstitial lung disease in this study, and thus, larger studies that include patient predisposition are required.

Somatic mutations in human epidermal growth factor receptor 2 (HER2) are present in approximately 3% of breast cancers. Some HER2 mutations are activating, and they represent a mechanism of resistance to conventional anti-HER2 therapies such as trastuzumab and lapatinib. Consistently, in patients with HER2-amplified breast cancer, these mutations are predominantly observed in metastatic tumors obtained after exposure to anti-HER2 systemic therapies, possibly after clonal selection. Therefore, it is rare to find coexistent HER2 mutation and amplification in the early clinical course, and thus, the clinical relevance of HER2 mutation to the sensitivity to HER2-targeted drugs, particularly antibody-drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and the recently approved fam-trastuzumab deruxtecan (T-DXd), remains unclear. In this article, we describe a patient with de novo metastatic breast cancer who exhibited both HER2 amplification and the L755S mutation in the untreated primary breast tumor obtained at the initial diagnosis, and the lesion responded to T-DM1 and T-DXd after exhibiting clinical resistance to other HER2-targeted drugs. Our current case findings suggested that anti-HER2 ADCs should be prioritized over conventional trastuzumab- or lapatinib-based therapies for patients with HER2-amplified and comutated tumors. Key Points Although HER2 mutations were implicated in resistance to anti-HER2 monoclonal antibodies or HER2 tyrosine kinase inhibitors in preclinical studies, their clinical impact on sensitivity to anti-HER2 drugs is unclear owing to the rarity of concomitant HER2 mutation and HER2 amplification. A case of de novo metastatic breast cancer harboring both HER2 amplification and the L755S mutation in an untreated breast primary tumor displayed clinical resistance to standard trastuzumab- or lapatinib-based therapies but good responses to ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd). Anti-HER2 antibody-drug conjugates such as T-DM1 and T-DXd may be prioritized over conventional trastuzumab- or lapatinib-containing therapies for patients with HER2-amplified and comutated tumors.

Although clinicians are expected to set a higher threshold for administering adjuvant chemotherapy to older than younger patients with breast cancer, the extent to which older patients are less likely to be offered adjuvant chemotherapy and the medico-social factors that influence decision-making are unclear.We retrospectively evaluated the correlations of clinicopathological factors, including age (≥75 years vs.75 years), for all candidates for adjuvant chemotherapy, and of additional medico-social factors, including the number of family members living together, for older patients, with the rate of referral from breast surgeons to medical oncologists.Among 872 candidates for adjuvant chemotherapy, age ≥75 years was significantly correlated with a lower referral rate (24 % vs. 44%, p0.001). In the analysis by age group, we did not identify specific medicosocial factors that were differentially emphasized, but older patients who lived with ≥2 other family members tended not to be referred to a medical oncologist compared to those who lived alone or with one family member (1/23 vs. 15/47). Although 5 of 22 older patients (23%) who were referred to a medical oncologist actually received adjuvant chemotherapy (vs. 60% of younger patients), all needed treatment modifications.Breast surgeons regard age ≥75 years as a key factor for avoiding adjuvant chemotherapy but they also consider similar medico-social factors irrespective of the patient's age regarding the decision to refer patients to medical oncologists.

To assess the prognostic and predictive ability of early C-reactive protein (CRP) kinetics, dynamic changes in CRP levels, in patients with advanced urothelial cancer treated with pembrolizumab. We retrospectively evaluated 97 patients with advanced urothelial cancer treated with pembrolizumab in second-line or later settings. Patients were divided into three early CRP kinetics groups: non-elevated (baseline CRP

Background: Previous prospective studies have shown that eribulin improves the survival in patients with metastatic breast cancer (MBC). However, the optimal timing of its administration to achieve the longest extended survival and the efficacy of using eribulin monotherapy as earlier-line chemotherapy are yet unclear. Methods: We identified all consecutive female patients with MBC who received any chemotherapeutic intervention for metastatic disease at our institution between July 2012 and December 2017, excluding patients with HER2-positive disease. Those who received eribulin monotherapy for MBC were classified under the eribulin cohort, whereas those who never received eribulin were included in the non-eribulin (Non-E) cohort. Among the patients in the eribulin cohort, those who received eribulin as the first- or second-line chemotherapy for MBC were further classified under the earlier-line eribulin (EE), and otherwise classified under the later-line eribulin (LE) cohorts. The survival of patients was assessed using the log-rank test. A multivariable Cox proportional hazards model was used to assess the independent efficacy and timing of eribulin monotherapy. The inverse probability of treatment weighting (IPTW) estimate was utilized to compare the EE and LE cohorts. Results: Of the 507 patients who were initially screened, 226 were included after an intensive chart review: 93, 49, and 84 patients were included in the Non-E, EE, and LE cohorts, respectively. The eribulin cohort showed significantly longer overall survival than the Non-E cohort (30.3 vs. 22.2 months, p = 0.0217). No significant difference was observed in the progression-free survival of the EE and LE cohorts (3.4 vs. 4.4 months, p = 0.1337) after adjusting for clinically relevant factors using IPTW estimates. LE cohort showed good overall survival (OS) compared with patient group of Non-E and EE by log-rank testing (p = 0.0398), although multivariate analysis did not demonstrate eribulin administration timing as an independent prognostic factor of OS. OS was defined from the initiation of first-line chemotherapy date. Conclusions: Our data provided additional insights regarding the use of eribulin monotherapy as earlier-line chemotherapy. However, the optimal timing of eribulin monotherapy for MBC was not determined in the current study.

BACKGROUND/AIM To maximize the effect of perioperative chemotherapy in breast cancer, it is critical to keep the relative dose intensity (RDI) high. While bi-weekly doxorubicin and cyclophosphamide, dose-dense AC (ddAC), instead of tri-weekly conventional AC (cAC) followed by a taxane has been adopted as standard perioperative chemotherapy, postponement or discontinuation are sometimes experienced during ddAC or subsequent taxane phase. This study aimed at evaluating whether ddAC, compared to cAC, was associated with reduced RDI. PATIENTS AND METHODS We compared ddAC and cAC, both followed by a taxane, for perioperative breast cancer regarding the proportion of completion of planned treatment (%completion), defined as an RDI ≥85% for both AC and taxane phases. RESULTS There was no remarkable difference between the groups in patient characteristics after propensity score matching (n=46 in ddAC, and n=86 in cAC). The %completion was similar between the groups (67.4% vs. 65.1%). Most other endpoints related to RDI were similar between groups. The incidence of pneumonia was higher in the ddAC group (13% vs. 3%) including one Pneumocystis jiroveci pneumonia. CONCLUSION ddAC followed by a taxane can be considered with sufficient supportive measures and precautions for pneumonia.

Background Visceral crisis in metastatic breast cancer (MBC) is defined as severe organ dysfunction requiring rapidly efficacious therapy. Although weekly paclitaxel plus bevacizumab (wPTX + BV) achieves a high response rate in human epidermal growth factor receptor 2 (HER2)-negative MBC, the efficacy and safety of wPTX + BV for visceral crisis is unclear. Methods We retrospectively investigated patients with MBC with visceral crisis who received wPTX + BV. Visceral crisis was defined as follows: liver dysfunction (aspartate or alanine aminotransferase >200 U/L or total bilirubin >1.5 mg/dl), respiratory dysfunction (carcinomatous lymphangiomatosis, SpO2, Highlights • Visceral crisis is a severe organ dysfunction requiring rapidly efficacious therapy. • The efficacy of chemotherapy in visceral crisis is unclear. • Weekly paclitaxel plus bevacizumab (wPTX + BV) achieved favorable efficacy and safety. • wPTX + BV may be considered an option for breast cancer patients with visceral crisis.

Tumor necrosis (TN) is one of the unfavorable prognostic factors in renal cell carcinoma (RCC). We identified two patterns of TN according to their morphology: dirty necrosis and ghost necrosis. We aimed to elucidate the morphological features and unfavorable prognostic impact of dirty necrosis in RCC. A total of 261 tumors collected after nephrectomy, which were pathologically identified as RCC, were analyzed in this study. We classified TN as dirty necrosis or ghost necrosis and compared their clinicopathological features. We also assessed their morphological features using digitally analyzed slides. The correlation between tumor size and necrosis area or the number of necrotic foci was calculated. There were 77 tumors (30%) with TN, and the presence of TN was significantly associated with unfavorable clinicopathological factors. Thirty tumors (39%) had dirty necrosis, and 47 tumors (61%) had ghost necrosis. There were significantly higher numbers of unfavorable factors associated with dirty necrosis than with ghost necrosis. In dirty necrosis, both the TN area and the number of necrotic foci were correlated with tumor size (p

An association between the development of overall or specific immune-related adverse events (irAEs) and outcomes of immune checkpoint inhibitors has recently been suggested. To address this emerging association in patients with urothelial cancer receiving pembrolizumab, we conducted a multicenter retrospective analysis, which is the first and largest in an Asian cohort as well as a systematic literature review. We retrospectively evaluated 97 patients with advanced urothelial cancer treated with pembrolizumab as second- or later-line treatment between January 2018 and March 2019. irAEs were categorized by the involved organs and graded using Common Terminology Criteria for Adverse Events version 5.0. Associations between irAEs and pembrolizumab efficacy, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. In our review of the literature, 28 studies, including 9 studies involving patients with urothelial cancer and 19 studies reporting the association between outcomes and spectrum of irAEs, were analyzed. Patients with irAEs had significantly higher ORR (52% vs. 16%, P .01), longer PFS (11.0 months vs. 3.6 months, P .01) and OS (median not reached vs. 13.1 months, P = .12) than in patients without irAEs. Endocrine (P = .02), pneumological (P = .06), and other (gastrointestinal, hematological, hepatic) (P = .04) irAEs were associated with increased ORR, whereas skin irAEs were not. Endocrine irAEs (P = .04) was associated with improved OS, whereas pneumological and skin irAEs were not. The association between the occurrence of irAEs and clinical efficacy of immune checkpoint inhibitors was consistently supported by the multiple studies we reviewed. The association between clinical outcomes and the spectrum of organs/systems affected by irAEs seems to be inconsistent and could be dependent on tumor type. irAEs were associated with a higher ORR and better survival of patients with advanced urothelial cancer treated with pembrolizumab.

Background Eribulin demonstrated longer overall survival for pretreated metastatic breast cancer. Several factors are reported to be associated with their survival outcomes of breast cancer patients, and scarce of predictors are determined for each agent. Previous reports have demonstrated that high neutrophil to lymphocyte ratio (NLR) is related to poor survival outcomes of cancer. We hypothesized that low NLR is predictor of longer survival of breast cancer patients. We investigated whether baseline NLR before chemotherapy is associated with overall survival, and explored possible mechanism of better survival in patients with metastatic breast cancer. Methods We extracted female patients with metastatic breast cancer who received Eribulin for metastatic disease at NCCHE. We included HER2-negative disease, and those treated with standard chemotherapy including eribulin. We retrieved patient and disease characteristics; age, disease location, de novo stage IV or recurrent disease, hormone receptor status. Result We identified 135 patients between July 2012 and December 2018 with a median age of 57.9 (34-77), of which 106 (78.5%) had HR positive disease, 104 (77.0%) had recurrent disease, and 114 (84.4%) had visceral disease. Log rank test showed hormone receptor status and visceral disease were significant variable for candidate for multivariate analysis. COX regression model demonstrated that decreasing of NLR was associated with better OS [HR = 1.145, 95% confidence interval (95% CI)=1.073-1.223]. We showed low NLR at the administration of eribulin was independent predictor of OS [HR = 1.048, 95% confidence interval (95% CI)=1.004-1.093]. Conclusion We showed low NLR is better prognostic factor of any chemotherapy for metastatic breast cancer. Our exploratory research also showed low NLR at eribulin administraton was suspected to be better OS indicator regardless of pretreated chemotherapy.

Background Palbociclb is an orally available selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that is indicated for patients with hormone receptor-positive HER2-negative advanced or recurrent breast cancer with 3 weeks on/1 week off schedule. Previous report showed that elevated serum creatinine (Scr) was only 2.0% in frequency for all grade, without cases of grade 3 or more. Anecdotal episode of declined eGFR (implying elevated Scr) seems to be more frequent in daily clinical practice; however, the actual frequency of declined eGFR and its impact on severe toxicity has not been determined yet. Objective To investigate the frequency of declined eGFR in patients treated with palbociclib and to determine the association between declined eGFR and severe toxicity. Methods Consecutive patients treated with palbociclib at National Cancer Center Hospital East between December 1 2017 and May 31 2018 were retrospectively investigated. Patient characteristics, eGFR at cycle 1 day1 (C1D1) and C1D15, C2D1, C2D15, and C3D1 of palbociclib, grade 4 neutropenia, treatment discontinuation or interruption caused by toxicity were retrieved from medical records. The frequency of declined eGFR and its correlation with severe toxicity were analyzed. Results A total of 42 patients were included. Median age was 65 years (range 43-80), and 41 cases were female. Median eGFR at the start of palbociclib was 76 mL/min/1.73m2, which declined 12.5 in median (range 3.0-39.0) on C1D15. At C2D1, eGFR was recovered (change in median -3 mL/min/1.73m2; range -17.0 - +19.0). Declined eGFR was not correlated significantly with either grade 4 neutropenia or treatment discontinuation. Conclusions While eGFR was declined by median of 12.5 mL/min/1.73m2 with palbociclib administration on C1D15, eGFR recovered to the baseline by drug interruption. Declined eGFR was not correlated with severe toxicity such as grade 4 neutropenia or toxicities leading to treatment discontinuation.

Many but not all studies have indicated that smoking is inversely associated with Parkinson's disease (PD). Meta-analysis of epidemiological studies on smoking and PD was performed to summarize data from published studies. Fifty-four epidemiological studies (48 case-control and 6 cohort studies, 53 publications) were identified for potential inclusion in meta-analysis. The summary risk estimates for current smokers, former smokers, and ever (current and former) smokers were 0.31 (95% confidence interval (CI) = 0.25-0.38), 0.72 (95% CI = 0.63-0.83) and 0.55 (95% CI = 0. 51-0. 59), respectively. In stratified analysis by study design, smoking had a somewhat greater impact on PD risk in cohort studies than in case-control studies. However, meta-regression indicated that the study design did not significantly contribute to heterogeneity. Additional analyses were restricted to case-control studies because of the sufficient number of studies. Stratified analysis by ethnicity indicated that the summary OR for ever-smokers was nonsignificantly smaller in Asian populations than in Caucasian populations. In stratified analysis by source of controls, former smoking was significantly associated with a decreased risk of PD in hospital-based case-control studies but was marginally associated with a decreased risk in population-based case-control studies. The source of controls did not contribute significantly to heterogeneity. PD risk associated with ever-smoking was significantly lower for a hospital-based approach than a population-based approach. Among current smokers, the association held true to the same extent for both approaches. This meta-analysis indicated that smokers have a lower risk of PD. As PD is a multifactorial disease, further investigation of the smoking-gene interaction on PD risk may lead to a better understanding of the pathogenesis of PD., 喫煙はパーキンソン病リスクを低下させることが多くの研究で認められているが，すべての研究でその関連性が認められているわけではない．本研究の目的は，喫煙とパーキンソン病についての研究結果を統合するために，公表された研究についてのメタ分析を行うことである．54 の疫学研究（48 症例対照研究と６コホート研究，53 論文）がメタ分析の対象としての適格基準をみたしてい た．非喫煙に対する現在喫煙，過去喫煙および喫煙経験（現在喫煙＋過去喫煙）の統合リスクはそ れぞれ0.31（95%信頼区間（95% CI)= 0.25-0.38）, 0.72（95% CI = 0.63-0.83）および0.55（95%CI = 0.51-0.59）であった．次に，研究デザインによる層別解析（症例対照研究あるいはコホート研究）を行った．喫煙のパーキンソン病に対する予防効果はコホート研究において，症例対照研究よりもやや強く認められたが，統計学的な有意差は認められなかった．症例対照研究に限ってさらに層別解析を行った．人種（白人あるいはアジア人）による層別解析では，喫煙経験の統合リスクはややアジア人の方が白人よりも小さかった．対照の種類（住民対照あるいは病院対照）による層別解析では，病院対照を用いた場合は過去喫煙は有意にパーキンソン病のリスクを低下させていたが，住民対照を用いた場合はリスクを有意に低下させていなかった．しかし，両者の間に統計学的な有意差は認められなかった．喫煙経験によるリスク低下は病院対照を用いた症例対照研究の方が住民対照を用いた症例対照研究よりも有意に大きかった．現在喫煙のリスクは両者間で有意差はなかった．パーキンソン病は多因子疾患であるので，今後，喫煙−遺伝子交互作用についての研究を行うことによって，パーキンソン病の病因についてよりよい理解が得られると考えられる．