Nivolumab has been approved for treating ≥ 10 cancer types. However, there is limited information on the incidence of rare, but potentially serious, treatment-related adverse events (TRAEs), as well as notable TRAEs in patients with certain medical disorders or older patients in Japan. We performed pooled analyses of data from published post-marketing surveillance in Japan of nivolumab monotherapy for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and gastric cancer to determine the frequencies of 20 categories of TRAEs of special interest overall and in patient groups with higher perceived safety risks (history of autoimmune disease, interstitial lung disease, tuberculosis, or hepatitis B/C; patients vaccinated during nivolumab treatment; and older patients [≥ 75 years]). The overall population comprised 7421 patients treated with nivolumab. TRAEs were reported in 49.1

Introduction: Testosterone replacement therapy (TRT) is a standard treatment for men with hypogonadism, characterized by low testosterone levels and associated symptoms. Methods: To identify the impact of TRT on hypogonadism, a systematic review and meta-analysis of studies were performed. Three major databases (PubMed, CHAHL, and Web of Science) were searched for publications from May 1, 2010 to May 1, 2024. Results: Twelve articles, including 5,198 patients, were enrolled in the final analysis, with the duration of TRT ranging from 6 to 36 months. TRT increased total, free, and bioavailable testosterone by 7.81 nmol/l (95% CI: 5.77, 9.85; P < 0.001; I2 = 92%), 0.18 nmol/l (95% CI: 0.15, 0.20; P < 0.001; I2 = 0%), and 3.57 nmol/l (95% CI: 2.87, 4.27; P < 0.001; I2 = 0%), respectively. Body mass index (BMI) increased by 1.17 kg/m2 (95% CI: 0.15, 2.19; P = 0.03; I2 = 5%) with an increase in lean body mass (LBM) of 1.58 kg (95% CI: 0.16, 3.00; P = 0.03; I2 = 0%) and a trend of reducing fat mass by 0.82 kg (95% CI: −2.53, 0.88; P = 0.34; I2 = 0%). There were no statistical differences in fracture risk, handgrip strength, or forearm bone mineral density (BMD). Additionally, there was no significant difference in lipid metabolism or homeostatic model assessment for insulin resistance. The odds ratio of any grade adverse events of TRT compared with placebo was 1.08 (95% CI: 0.75, 1.56; P = 0.67; I2 = 59%). Conclusion: TRT is a safe and effective treatment for men with hypogonadism. Long-term use of TRT can improve BMI and LBM, though it does not appear to enhance handgrip strength or BMD. A combined approach of TRT and exercise may be an important strategy for optimizing outcomes.

Background: Central venous catheters (CVCs) are sometimes superior to peripheral vascular access for chemotherapy. Central line-associated bloodstream infections (CLABSIs) are an important complication of CVCs in chemotherapy.Methods: A retrospective, observational study was conducted to investigate patients with implanted venous access ports (PORTs) from July 2010 to June 2021 in a teaching hospital. General conditions of the PORTs, backgrounds, and characteristics of patients were compared between CLABSI cases and uninfected cases to identify predictors of CLABSI.Results: A total of 566 patients with PORTs who underwent chemotherapy were enrolled in this study, with CLABSI identified in 41 patients, for a total of 436,597 catheter-days. The median duration of PORT use was 26 vs. 494 days (P<0.001) in the CLABSI and uninfected groups, respectively. There were no lymphocyte proportion, albumin, C-reactive protein (CRP), and performance status between the CLABSI and uninfected groups. Multivariable analysis showed that antibiotic usage within the previous week, total protein (TP), and immediate PORT use were independently associated with CLABSI, and their odds ratios (ORs) were 4.89 [95% confidence interval (CI): 1.67, 14.35], 1.95 (95% CI: 1.14, 3.53), and 3.13 (95% CI: 1.18, 8.30), respectively. The area under the curve (AUC) of the receiver-operating characteristic curve for TP was 0.63, and the cutoff value was 5.9 g/dL.Conclusions: PORT implantation should be avoided in patients who had antibiotic treatment episodes within 1 week, especially for those with low serum TP levels.

To the Editor Opioidinduced nausea and vomiting (OINV) is an important side effect of opioids, causing interruption of opioid therapy and inadequate pain control. There is currently no standard of care for OINV; the first randomised controlled trial for the prevention of OINV found no significant preventive effect of prochlorperazine on OINV. OINV has similar mechanisms to chemotherapyinduced nausea and vomiting (CINV), and dexamethasone is shown to be effective for preventing CINV. Dexamethasone is also effective for preventing postoperative nausea and vomiting, which is also known to have similar aetiologies to OINV. Considering overall usefulness of dexamethasone, we conducted a prospective study to investigate the feasibility of a randomised controlled trial of a single dose of dexamethasone for OINV. This study is a multicentre, prospective clinical trial. The registration number for this study is UMIN000031741. Adult cancer patients who were scheduled to start oral opioids at a dose of at least 15 mg/day of oral morphine equivalent, and had adequate major organ function, were enrolled. Patients who had received any opioids or highly/ moderately emetogenic anticancer drugs within 3 weeks, mildly emetogenic anticancer drugs within 1 week, patients with nausea or vomiting within 1 week, patients with diabetes requiring regular insulin administration and history of delirium within 1 year were excluded. Enrolled patients received a single oral dose of 8 mg dexamethasone 0–12 hours before the first opioid dose. The patients recorded their symptoms and medication use during observation period (120 hours) in the patient diary. Symptoms during the observation period were assessed retrospectively by the attending physician, checking against the patient diary at the visit. The primary endpoint of the study was the percentage of complete response (CR), defined as the absence of emesis and use of antiemetic drugs during the observation period. The expected CR rate for this study was 85%, and the threshold CR rate was set to 60%, considering the results of a randomised controlled trial in a similar population. Since this study is a feasibility study, the α was 10% onesided, the power was 80% and the expected number of enrolled patients was set at 15. The ttest was used for group comparisons of continuous variables, and the χ test was used for group comparisons of categorical variables. Between May 2018 and April 2019, 15 cancer patients were enrolled. The mean age was 71 years (range: 55–83 years), 73% were male and 73% were lung cancer patients. The breakdown of opioids was 73% oxycodone, 20% hydromorphone and 7% morphine. No patient experienced vomiting during the observation period. Nausea occurred in 3 patients (20%) within 24 hours and in 4 patients (27%) within 96 hours. The severity of nausea was Grade 1 in 1 patient and Grade 2 in 3 patients. Although antiemetic medication was recommended for Grade 3 or higher nausea, 3 patients actually took antiemetics. Therefore, the percentage of CR was 80% (80% CI: 60.7%–92.4%) at both 72 hours and 120 hours. The lower limit of the 80% CI of CR rate was above 60%, indicating that the study met its primary endpoint. A comparison of the endpoints observed in this study with the historical control is shown in table 1. During the 120hour observation period, the percentage of patients who experienced vomiting and nausea was 0% and 26.7% in this study, and 26.7% and 51.7% in the historical control, respectively. The percentage of patients who used antiemetic agents was 20% in the study and 26.7% in the historical control. In other words, 75% of patients with nausea used antiemetic agents in the study, compared with only 52% in the historical control. Adverse events of dexamethasone observed in this study were Grade 1 constipation in 2 patients (13%). None of the patients with constipation developed nausea, and constipation resolved during management of opioidinduced constipation. No other adverse events for which information was routinely collected in this study (confusion, insomnia, gastric bleeding, duodenal bleeding, anorexia, facial oedema, trunk oedema, limb oedema, fatigue and hiccups) occurred, and no other adverse events were reported. This prospective clinical trial of a single oral dose of 8 mg dexamethasone for OINV met the primary endpoint. Compared with data from a previous study in which placebo was given to a similar patient population with similar background, which was set as a historical control in advance, the incidence of vomiting (0% vs 26.7%) and Table 1 Comparison with historical control

Nivolumab, a monoclonal antibody against human programmed death 1, was approved for the treatment of melanoma in July 2014 in Japan. Because the Japanese phase II studies (ONO-4538-02, ONO-4538-08) enrolled small numbers of melanoma patients, post-marketing surveillance (PMS; JapicCTI-163 272) was conducted to collect safety data in a larger patient population. We report data for melanoma patients who received nivolumab between July 4, 2014 and February 28, 2017. Data collected included baseline characteristics, laboratory tests, treatment-related adverse events (TRAE), and overall survival (OS). Of 2069 enrolled patients, 2008 patients were included in the safety analysis population. There were 1030 (51.3%) males, the median age was 69 years, and 269 patients (13.4%) had a performance status of >= 2. The primary tumor sites were cutaneous (34.4%), mucosal (34.2%), acral lentiginous (18.6%), others (6.8%), and unknown (6.3%). TRAE occurred in 62.1% of patients, the most common being hypothyroidism (14.0%), increased aspartate aminotransferase (8.5%), and increased alanine aminotransferase (6.9%). TRAE of special interest in >= 5% of patients were thyroid dysfunction (24.9%), hepatic dysfunction (20.6%), infusion reactions (11.4%), colitis/severe diarrhea (6.3%), and interstitial lung disease (ILD; 5.0%). Several types of TRAE of special interest, which included myasthenia gravis/myocarditis/myositis/rhabdomyolysis (0.9%), venous thromboembolism (0.2%), immune thrombocytopenic purpura (0.1%), and encephalitis (0.0%), were observed in this PMS. Although these TRAE were not reported in previous studies (ONO-4538-02, ONO-4538-08, CheckMate 066, and CheckMate 037), they have been listed in the current Risk Management Plan. History of ILD and male sex were risk factors for ILD in a multivariable analysis. Age <75 years was a risk factor for hepatic dysfunction. At 12 months, median OS was not reached. In conclusion, these results suggested that there was no concern requiring additional precautions for the safety of nivolumab in Japanese patients with melanoma other than the safety information in the Risk Management Plan.

Background Neutrophil-to-lymphocyte ratio (NLR) has recently attracted attention as a prognostic predictor in patients with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors (ICIs). However, the utility of NLR in relation to cytotoxic anticancer drugs or molecular targeted drugs remains unclear. We determined if NLR could predict the treatment efficacy and prognosis in NSCLC patients who receive cytotoxic anticancer drugs or molecular targeted drugs, as well as ICIs, in a cross-sectional manner. Methods Of 658 patients with advanced NSCLC who received first-line systemic treatment in our hospital between 2008 and 2019, 312 who met the analytical criteria were included in the study. We retrospectively analyzed the ability of NLR with a cut-off value of 5 to predict time to treatment failure (TTF) and overall survival (OS) in patients who received the following treatments: first-line treatment with molecular targeted drugs (mt group, n=100); first-line treatment with cytotoxic anticancer drugs (wt group, n=212); and first-line treatment with cytotoxic anticancer drugs followed by ICIs (ICI group, n=58). Results In the high- and low-NLR mt subgroups, median TTFs were 6.7 and 14.9 months (P<0.01), respectively, and median survival times (MSTs) were 17.8 and 39.1 months (P<0.01), respectively. In the high- and low-NLR wt subgroups, median TTFs were 1.5 and 5.8 months (P<0.01), and MSTs were 6.3 and 20.7 months (P<0.01), respectively. In the high- and low-NLR ICI subgroups, median TTFs were 1.3 and 6.8 months (P<0.01), and MSTs were 9.2 and 25.8 months (P<0.01), respectively. Multivariate analysis identified NLR as a significant independent predictor of TTF [hazard ratio (HR) 1.89, P=0.01; HR 2.51, P<0.01; and HR 5.06, P<0.01 in the mt, wt, and ICI groups, respectively) and OS (HR 3.81, P<0.01; HR 2.59, P<0.01; and HR 2.48, P<0.01, respectively). Conclusions This study showed that NLR might be a predictor of treatment efficacy and prognosis in advanced NSCLC patients who receive various systemic treatments. This finding of consistent applicability of NLR to a wide variety of systemic treatments is of great significance.

Postmarketing surveillance of Japanese patients with unresectable, previously treated, advanced or recurrent non-small-cell lung cancer treated with nivolumab was undertaken during the conditional approval period. The study aim was to evaluate the occurrence of treatment-related adverse events of nivolumab in the real world. Patients were registered between December 2015 and March 2016 at 536 sites. Nivolumab was given intravenously (3 mg/kg every 2 weeks); the observation period was 12 months after the first dose of nivolumab. Patients were evaluated for safety (n = 3601; 18.2% ≥75 years, 22.4% ECOG performance status ≥2) and effectiveness (n = 3570). The frequencies of any grade and grade 3 or higher treatment-related adverse events were 47.1% and 15.9%, respectively. The most frequent treatment-related adverse events (any grade) were interstitial lung disease (6.4%), hypothyroidism (5.7%), and diarrhea (4.4%). Treatment-related adverse events of special interest (priority items) occurring at a frequency of 5% or more were adverse events related to interstitial lung disease, thyroid dysfunction, liver dysfunction, colitis/severe diarrhea, infusion reaction, and infusion reaction within 24 hours. Significant risk factors for these priority items were identified by competing risk analysis: interstitial lung disease (previous/comorbid interstitial lung disease, abnormal findings on chest imaging, and smoking history); liver dysfunction (previous/comorbid liver disease, smoking history, and metastasis); thyroid dysfunction (previous/comorbid thyroid disease and performance status); and colitis/severe diarrhea (treatment line 2 vs ≥3). The 12-month survival rate was 40.7%. In conclusion, the safety profile of nivolumab in this postmarketing surveillance was similar to that in clinical trials, and no new safety signals were identified. The study was registered with the Japan Pharmaceutical Information Center (clinicaltrials.jp: Japic-163271).

Nivolumab, a human monoclonal antibody against programmed death-1, is approved for the treatment of non-small cell lung cancer (NSCLC). Although nivolumab is generally well tolerated, it can cause interstitial lung disease (ILD), a rare but potentially fatal immune-related adverse event. Currently, there are limited data available on the treatment of nivolumab-induced ILD and its outcome. This retrospective cohort study based on a post-marketing study described the treatment of nivolumab-induced ILD and its outcome in NSCLC patients in Japan through the assessment of clinical and chest imaging findings by an expert central review committee. Treatment details for patients who experienced a relapse of ILD were also analyzed. Of the 238 patients identified as having nivolumab-induced ILD, 37 patients died of ILD. Corticosteroids were used in 207 (87.0%) patients. Of those, 172 (83.1%) patients responded well and survived and 35 (16.9%) died (most died during corticosteroid treatment). A total of nine patients experienced a relapse; at the time of relapse, four patients were taking nivolumab. Of those who were receiving corticosteroids at the time of relapse, three of four patients were taking low doses or had nearly completed dose tapering. All patients (except one, whose treatment was unknown) received corticosteroids for the treatment of relapse, but one patient died. Patients with NSCLC who experience nivolumab-induced ILD are treated effectively with corticosteroids, and providing extra care when ceasing or reducing the corticosteroid dose may prevent relapse of ILD.

Transl Cancer Res 2019;8(6):2223-2229 | http://dx.doi.org/10.21037/tcr.2019.08.18 Currently, three strategies for primary treatment of advanced non-small cell lung cancer (NSCLC) with EGFR gene mutations are being investigated: epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) monotherapy, EGFR-TKI + vascular endothelial growth factor (VEGF) inhibitor combination, and EGFR-TKI + cytotoxic anticancer agent combination (Tables 1,2). At the ASCO 2018 meeting, the results from a phase 3 study comparing erlotinib monotherapy for standard primary treatment versus erlotinib + bevacizumab combination were reported (NEJ026) (1). NEJ026 was based on a similarly designed phase 2 study (JO25567), which previously showed that erlotinib + bevacizumab combination significantly increased the primary endpoint, progression-free survival (PFS), compared with erlotinib monotherapy [16.4 vs. 9.8 months; hazard ratio (HR), 0.52; 95% CI, 0.35–0.76] (2). Both were Japanese multicenter studies. NEJ026 was an open-label randomized phase 3 study comparing erlotinib + bevacizumab combination with erlotinib monotherapy in 224 advanced-non-squamous NSCLC patients with EGFR gene mutations (Ex19 del/ Ex21 L858R) in performance status 0–2, with an interim analysis performed with PFS as the primary endpoint when 117 events had occurred. Since PFS (independent central judgment) was significantly higher in the combination group (16.9 vs. 13.3 months; HR, 0.61; 95% CI, 0.42–0.88), the study was ended prematurely. By type of EGFR gene mutation, PFS was 16.6 vs. 12.4 months for Ex19 del (HR, 0.69; 95% CI, 0.41–1.16) and 17.4 vs. 13.7 months for Ex21 L858R (HR, 0.57; 95% CI, 0.33–0.97): for both types of mutation, PFS was better in the combination group. Reported adverse events (AEs) included hypertension (45.5% vs. 8.8%), proteinuria (32.1% vs. 2.6%), and hemorrhage (25.0% vs. 2.6%), which were all noted at higher incidences in the combination group than in the monotherapy group; however, the treatment discontinuation rate due to AEs was similar between the two groups (18.8% vs. 15.2%). Overall survival (OS) data remain immature, with no final analysis results reported to date. Another subgroup analysis showed the PFS to be 16.9 vs. 12.6 months in the group with malignant pleural effusions (HR, 0.58; 95% CI, 0.34–1.02) and 16.6 vs. 14.2 months in the group without (HR, 0.67; 95% CI, 0.41–1.10): even in the population with pleural effusion, PFS increased in the combination group. In the group without cerebral metastases, PFS was higher in the combination group (18.0 vs .15.1 months; HR, 0.56; 95% CI, 0.35–0.90). However, in the group with cerebral metastases, PFS did not differ between the two groups (12.7 vs. 11.2 months; HR, 0.78; 95% CI, 0.42–1.43). As stated above, erlotinib + bevacizumab combination is advantageous not only with increased PFS for any type of EGFR gene mutation, but also with expected increases in PFS even in patients with pleural effusion; however, some issues remain to be resolved, including unknown OS-increasing effect, necessity for further investigations of effects on cerebral metastases, and definitely increased incidences of AEs. Potentials of combinations of EGFR-TKI and VEGF inhibitors are discussed below in view of preclinical study results. The first to discuss is a crosstalk between EGFR and VEGF, both key factors in tumor growth and metastases. When binding to EGFR, EGF and TGF-α activate EGFR to increase VEGF expressions. The crosstalk has 2229

Background: Malignancy-related ascites (MRA) is one of the symptoms causing discomfort in advanced cancer patients. Cell-free and concentrated ascites reinfusion therapy (CART) is one of the palliative treatments widely conducted in Japan only. Methods: A systematic review following a meta-analysis of CART was performed. The efficiency and adverse events were evaluated. Results: A total of 2567 patients and 6013 procedures of CART were identified in this study. The mean volume of MRA collected was 4.29 (95% confidence interval (CI) 3.47–5.11) L, and the volume reinfused after concentrating was 0.49 (95% CI 0.39–0.60) L. A total of 86.1 (95% CI 77.1–95.2) g protein and 42.9 (95% CI 36.0–50.0) g albumin was reinfused. The mean time to the next paracentesis was 20.7 (95% CI 15.6–25.8) days. The body weight was reduced by 3.38 (95% CI 1.90–4.86; p < 0.01) kg, and abdominal circumference was reduced by 7.86 (95% CI 6.58–9.14; p < 0.001) cm. Serum albumin increased an average of 0.14 (95% CI −0.01–0.28; p = 0.07) mg/dL the day after CART. Abdominal distension, dyspnea, and fatigue were alleviated by 6.0 (95% CI 5.59–6.51), 2.66 (95% CI 2.05–3.28), and 2.64 (95% CI 1.86–3.42) points using a numerical rating scale system ranging from 0 to 10. Overall, 17% (95% CI 0.03–0.31%) of patients had improved performance status after CART. Significant body temperature elevation was observed, at an average of 0.4 °C (95% CI 0.18–0.62 °C). Conclusions: CART might be a safe and effective palliative therapy in MRA and further clinical trials are necessary.

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This postmarketing study evaluated the poor prognostic factors of ILD in nivolumab-treated patients with non–small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an expert central review committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground-glass opacity (peritumoral-GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab-induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia–like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia–like (20.2%), diffuse alveolar damage (DAD)-like (10.9%), and nonspecific interstitial pneumonia–like (6.3%). The main poor prognostic factors identified were DAD-like pattern (highest hazard ratio: 10.72), ≤60 days from the start of nivolumab treatment to the onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C-reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD-like radiographic pattern, three had peritumoral-GGO, and five had a change in radiographic pattern from non-DAD at the onset to DAD-like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD-like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels.

We herein report a case of breast cancer in a 74-year-old woman treated with exemestane as fourth-line hormonal therapy and bone-modifying agents for long time. She suddenly developed a right femoral shaft fracture during treatment. Her femoral fracture had a beaking sign on radiogram. Given this finding, her fracture was ultimately diagnosed as atypical femoral fracture (AFF). In this case, it was difficult to recognize the difference between groin pain as a prodromal symptom of AFF and that due to an adverse reaction to hormonal therapy. Therefore, clinicians should recognize the difficulty of this differentiation and consider the situation with caution.

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This postmarketing study evaluated the poor prognostic factors of ILD in nivolumab‐treated patients with non–small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an expert central review committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground‐glass opacity (peritumoral‐GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab‐induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia–like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia–like (20.2%), diffuse alveolar damage (DAD)‐like (10.9%), and nonspecific interstitial pneumonia–like (6.3%). The main poor prognostic factors identified were DAD‐like pattern (highest hazard ratio: 10.72), ≤60 days from the start of nivolumab treatment to the onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C‐reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD‐like radiographic pattern, three had peritumoral‐GGO, and five had a change in radiographic pattern from non‐DAD at the onset to DAD‐like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD‐like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels.

Common dermatological side-effects associated with erlotinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), include pruritus and skin rash, which are mediated by substance P, leading to the occasional discontinuation of cancer treatment. Aprepitant is an antagonist of neurokinin-1 receptor, through which substance P activates the pruritogens. Thus, aprepitant is expected to offer a promising option for the treatment of erlotinib-induced pruritus. However, the appropriate treatment schedule for aprepitant administration is under consideration. Here, we discuss the need for flexible adjustment of the treatment schedule for aprepitant administration against erlotinib-induced refractory pruritus and skin rush. A 71-year-old female smoker presented with stage IV EGFR-mutated lung adenocarcinoma. She was started on erlotinib at 150 mg/day. However, by 28 days, severe pruritus and acneiform skin rush resistant to standard therapies occurred, resulting in the interruption of erlotinib therapy. After recovery, she was restarted on erlotinib at 100 mg/day. However, severe pruritus and skin rush developed again within 2 weeks. Then, we started the first 3-day dose of aprepitant (125 mg on day 1, 80 mg on day 3, and 80 mg on day 5) based on the results of the previous prospective study, which showed the success rate of 100% with at least the second dose of aprepitant. However, the pruritus and skin rush exacerbated again within 4 weeks. Therefore, we started the second 3-day dose of aprepitant, but in vain. At this point, as the patient-centered medicine, bi-weekly schedule of the 3-day dose of aprepitant was considered and, then, adopted. As the results, the pruritus and skin rush remained well-controlled throughout the subsequent treatment with erlotinib.

Aim: To assess the clinical features/imaging characteristics of pneumonitis reported during nationwide nivolumab postmarketing surveillance in Japan. Patients & methods: Clinical and radiological data were collected from pneumonitis cases reported during/after nivolumab treatment for melanoma or non-small-cell lung cancer. The expert central review committee evaluated each case. Results: Among 144 cases analyzed, 91 (63.2%) had radiological patterns considered typical for drug-induced pneumonitis and 53 (36.8%) patients had previously unobserved patterns with one or more atypical features, including 23 cases (16.0%) with ground glass opacity confined to the area around the tumor (peritumoral infiltration). A higher proportion of patients with (vs without) peritumoral infiltration had an antitumor response to nivolumab. Conclusion: Images of nivolumab-induced pneumonitis showed previously unobserved radiological patterns.

Currently, three strategies for primary treatment of advanced non-small cell lung cancer (NSCLC) with EGFR gene mutations are being investigated: epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) monotherapy, EGFR-TKI + vascular endothelial growth factor (VEGF) inhibitor combination, and EGFR-TKI + cytotoxic anticancer agent combination ( Tables 1,2 ).

Cancer of unknown primary site (CUP) is a heterogeneous group of cancers with widely varying natural histories and biological characteristics for which the anatomical site of origin remains occult after detailed investigations.Several clinicopathological subsets with favorable prognosis have been identified.CUP presents a clinical situation quite difficult to manage due to the absence of a standard of care for the initial therapeutic approach, as well as an impossibility to include these cases in randomized clinical trials.Historically, a "favorable subset" designation was made based on a presentation that overwhelmingly suggested a specific primary origin.Although several clinicopathologic subsets with favorable prognosis have been identified, most patients do not fit into any of these subsets.CUP is often associated with a poor prognosis, as patients are usually treated with a non-selective empirical therapy.During the past 3 decades, some phase II trials of platinum-based combination regimens containing newer cytotoxic agents (taxanes, gemcitabine, irinotecan, etc.) resulted in response rates of 20%-60% and median survivals of 6-11 months.In these trials, taxane-based regimens showed better responses and longer survivals.Therefore, taxane-platinum regimens as empiric chemotherapy are widely used for these patients.In the current paper, we summarize both the therapeutic challenges for patients with CUP as well as the current available therapeutic options, and introduce our trial currently in progress for this population.

For sebaceous carcinoma (SC), a rare malignant tumor, no standard chemotherapy regimen for patients with distant metastasis has been studied. We experienced a case of eyelid SC with multiple lung metastases that responded to combination chemotherapy with carboplatin and paclitaxel with 11-month progression-free survival (PFS). This patient also responded to second-line treatment with docetaxel, another taxane, with 7-month PFS, resulting in at least 18 months of survival at the time of reporting. This report shows that taxane-based chemotherapy may be effective for advanced SC, for which no standard therapy has been established.

We encountered a case of primary lung cancer complicated with membranous nephropathy as primary nephrotic syndrome. Because treatment approaches vary greatly for primary and secondary nephrotic syndrome, a renal biopsy was performed for diagnosis. Much time was required to make a definitive diagnosis of primary nephrotic syndrome, as opposed to paraneoplastic nephrotic syndrome. Consequently, the subsequent chemotherapy was ineffective and caused significant toxicity due to reduced performance status (PS) and progression of hypoalbuminemia. Therefore, it is imperative that a diagnosis be made and treatment be initiated without delay before PS declines and hypoalbuminemia progresses.

In lung cancer, several potential mechanisms of intrinsic and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been explored, including mesenchymal-epithelial transition factor (MET) signaling pathway activation. On the other hand, vascular endothelial growth factor (VEGF) production of EGFR-mutated lung cancer cells is stimulated by predominantly activated MET signaling pathway. Therefore, the inhibition of VEGF axis as the downstream target of MET signaling pathway seems promising. Here, for the first time, we report the potential efficacy of combination therapy with bevacizumab and erlotinib in an EGFR-mutated NSCLC patient with MET amplification who showed intrinsic resistance to initial EGFR-TKI therapy. The patient was a 60-year-old male smoker, showing performance status (PS) 2, who presented with stage IV lung adenocarcinoma (cT4N2M1a) harboring the EGFR exon 19 deletion mutation. He was started on gefitinib at 250 mg/day. However, by 28 days, his symptoms further deteriorated along with the increased tumor size, resulting in PS 3. Then, repeat biopsy was performed, showing the positive MET amplification and the preserved EGFR exon 19 deletion mutation. Therefore, on the basis of the potential efficacy for activated MET signaling pathway as well as the confirmed safety by the known phase II trial for EGFR-mutated patients, the patient was started on combination therapy with bevacizumab at 15 mg/kg every 3 weeks plus erlotinib at 150 mg/day. By 21 days, his symptoms gradually improved along with the decreased tumor size, resulting in better PS with no severe toxicities.