Managing adverse events is important for optimizing cancer treatment and ensuring high patient satisfaction. Studies have assessed (1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody-induced skin toxicities, (2) development of severe neutropenia by renally excreted anticancer drugs in patients with renal impairment (RI), and (3) pharmaceutical care in the treatment of immune checkpoint inhibitors (ICIs). We identified liver metastasis as a risk factor and preemptive systemic antibiotic administration with anti-inflammatory effect as a preventive factor for grade ≥2 overall skin toxicities in anti-EGFR treatment for metastatic colorectal cancer (mCRC). Additional prophylactic topical steroids to systemic minocycline significantly prevented grade ≥2 rashes, but did not mitigate overall skin toxicities. Patients receiving trifluridine/tipiracil (FTD/TPI)-based chemotherapy for mCRC were assessed, resulting in significantly higher early severe neutropenia development among patients with RI. Additionally, we assessed the impact of RI on severe neutropenia development in carboplatin+pemetrexed-based chemotherapy for thoracic cancer. Consequently, severe neutropenia in the first cycle and all-treatment cycles was significantly more confirmed in patients with RI. We assessed the usefulness of pharmaceutical interventions in ICI treatment, which suggested that pharmaceutical care may improve quality of outpatient ICI treatment, and pharmaceutical intervention during the first three months after initiation of ICI treatment is crucial. Our studies have found clinically important outcomes that support the provision of less onerous chemotherapy.

In recent years, cancer chemotherapy has been administered in an outpatient setting; therefore, patient self-management of adverse events is an important issue. Pharmaceutical interventions were performed by pharmacists at the following 3 time points: before the physician consultation, after the physician consultation, and during multidisciplinary conferences at the Ibaraki Prefectural Central Hospital Cancer Chemotherapy Center. In this study, prescription proposals and their effectiveness for adverse events, were investigated. Of the 338 cases in which pharmaceutical interventions were performed, 280 were accepted by physicians, and the acceptance rates were 77% in conference, 89% before physician consultations, and 85% after physician consultations. Pharmaceutical interventions for the management of nausea and vomiting were most frequently accepted (96 cases), with improvement observed in 58 cases (60%). Improvement rates for hypertension and skin disorders were 76% and 56%, respectively, and improvement rates for peripheral neuropathy and dysgeusia were 33% and 22%, respectively. Of all interventions made by pharmacists, 68% were for the 1st 5 courses, with proposals continuing beyond the 6th course, suggesting that there is demand for long-term intervention. Pharmacists collecting patient information and implementing pharmaceutical interventions may contribute to the management of adverse events. As the degree of improvement varies according to the type of adverse event, it will be necessary to establish optimal pharmaceutical interventions in the future.

Hematologic malignancies have shown improved prognosis in some diseases owing to advanced treatment. Cytarabine (Ara-C) is widely used for treatment; however, ocular symptoms frequently occur as a side effect. In this retrospective study, we investigated the preventive effect of combining corticosteroid eye drops with saline eye wash on ocular symptoms in patients receiving high-dose or intermediate-dose Ara-C therapy without concomitant radiation therapy.

BRAF is a serine/threonine kinase that functions as a key component of the RAS/RAF/MEK/ERK (MAPK) signaling pathway and is recognized as an important oncogenic driver across multiple cancers. BRAF mutations are detected in a variety of malignancies including melanoma, thyroid cancer, colorectal cancer, non-small cell lung cancer, and biliary tract cancer. Among them, the V600 mutation results in constitutive activation of the MAPK pathway and promotes tumor growth and survival. BRAF mutations are currently classified into three functional classes (class 1-3) according to their signaling mechanisms and dependency on RAS activation. The development of BRAF inhibitors and MEK inhibitors has significantly improved outcomes in patients with BRAF V600-mutant melanoma, and combination therapy with these agents has become the standard of care. Clinical activity of BRAF/MEK inhibition has also been demonstrated in other malignancies such as non-small cell lung cancer and thyroid cancer. In contrast, BRAF-mutated colorectal cancer shows limited sensitivity to BRAF inhibitor monotherapy due to feedback activation of EGFR signaling, leading to the development of combination strategies including EGFR inhibitors. In recent years, basket trials such as VE-BASKET, NCI-MATCH, and ROAR have demonstrated the efficacy of BRAF-targeted therapies across tumor types, supporting the concept of tumor-agnostic treatment. Current BRAF inhibitors mainly target the active BRAF monomer; however, resistance mediated by RAF dimerization frequently occurs. Novel therapeutic approaches including pan-RAF inhibitors and ERK inhibitors are under development to overcome these resistance mechanisms.

Immune checkpoint inhibitors (ICIs), a widely adopted therapeutic option for metastatic renal cell carcinoma, are also associated with a range of immune-related adverse events, some of which can be severe and life-threatening. Here, we describe the case of a 70-year-old man with renal cell carcinoma and brain, lung, and bone metastases who developed ICI-associated encephalitis, which was fatal. Initial computed tomography imaging revealed a 9.8 cm mass in the right kidney, multiple pulmonary nodules, and an osteolytic lesion in the left fifth rib. Brain magnetic resonance imaging revealed metastatic lesions in the right parietal lobe and left lateral ventricle. The patient underwent therapy with pembrolizumab and lenvatinib in combination with stereotactic radiotherapy targeting the brain metastases. On day 20 of treatment, the patient developed a generalized seizure, followed by a rapid deterioration in consciousness. He died the following day. Post-mortem examination revealed widespread lymphocytic infiltration of the brain parenchyma, which was consistent with the diagnosis of ICI-associated encephalitis.

Rash caused by lenalidomide, a key therapeutic agent for multiple myeloma (MM), often interferes with treatment continuation. This study investigated whether thymus and activation-regulated chemokine (TARC), a Th2-related chemokine, could serve as a biomarker for lenalidomide-induced rash. We evaluated patients treated with lenalidomide for MM at Takarazuka Municipal Hospital between January 2016 and October 2023. TARC levels were measured in patients who developed grade ≥2 rash. Clinical information, including blood test results, management of rash, and subsequent clinical course, was collected from medical records. Each episode was defined as one event consisting of three time points: before lenalidomide initiation, at rash onset (when TARC was measured), and at rash resolution. Fourteen events in eleven patients were analyzed. In all events, TARC levels were elevated at rash onset. In contrast, elevations in general inflammatory markers (white blood cell count, eosinophils, and C-reactive protein) or in lactate dehydrogenase, an indicator of atopic dermatitis, were observed in only a minority of events. These findings suggest that TARC may be a useful biomarker for identifying lenalidomide-induced rash and may aid in optimizing clinical management while maintaining treatment continuity.

Immune checkpoint inhibitors (ICIs) are increasingly used as adjuvant therapy in high-risk renal cell carcinoma (RCC), but may cause serious immune-related adverse events, such as myocarditis. We report a rare case of myocarditis followed by steroid-induced myopathy during adjuvant pembrolizumab therapy. A 74-year-old man underwent partial and radical nephrectomy for bilateral clear cell RCC (pT1b and pT3a). Pembrolizumab was initiated postoperatively. On day 22, he developed exertional fatigue and cardiac enzyme levels were elevated. Myocardial biopsy confirmed myocarditis, and corticosteroid pulse therapy was started. Although cardiac markers improved initially, they rose again, requiring a second steroid pulse and higher maintenance doses. After 27 days of steroid therapy, the patient developed severe proximal muscle weakness. Myasthenia gravis and other autoimmune diseases were excluded. Steroid-induced myopathy was diagnosed, and steroid tapering plus rehabilitation led to functional recovery. He was later discharged without recurrence of myocarditis. This case highlights the importance of early detection and treatment of ICI-related myocarditis and awareness of secondary complications such as steroid myopathy. Multidisciplinary care is essential in managing these rare but serious conditions.

All-trans retinoic acid (ATRA) is essential in treating acute promyelocytic leukemia (APL), but has been linked to adverse events such as differentiation syndrome and intracranial hypertension. Hearing impairment associated with intracranial hypertension is rare but clinically relevant. We report the case of a 6-year-old girl with APL who developed transient low-frequency sensorineural hearing impairment during ATRA/arsenic trioxide therapy. No headache or neurologic signs suggesting intracranial hypertension were observed, and both hearing symptoms and low-frequency audiometric changes resolved spontaneously without corticosteroids or treatment modification. This case suggests that ATRA-related hearing impairment may occur even without intracranial hypertension, and careful monitoring may enable continuation of therapy.

Pembrolizumab is an immune checkpoint inhibitor that has been widely used in cancer treatment, and its approved indications have expanded rapidly in recent years. However, the effects of this increase on immune-related adverse events (irAEs) remain unclear. Using data from the Japanese Adverse Drug Event Report (JADER) database and the National Database of Health Insurance Claims and Specific Health Checkups (NDB Open Data), we analyzed trends in the number and characteristics of spontaneously reported adverse events associated with pembrolizumab from fiscal years 2016 to 2024. The number of adverse event reports in JADER generally increased in parallel with prescription volume. Following the expansion of indications for gynecological cancers (such as breast, uterus, and cervix cancers) around 2021, a marked increase in reports was observed from 2022. During this period, the demographic profile of reported patients shifted from predominantly older males to middle-aged females. Regarding cancer types, the proportion of reports on breast and uterus cancers increased significantly, whereas those on lung cancer declined. In addition to pulmonary disorders, endocrine disorders became increasingly reported and represented the most frequent category in fiscal year 2022. The distribution of irAEs by cancer type suggested potential associations; pulmonary toxicity was more frequent in lung cancer, whereas endocrine toxicity was predominant in breast, uterus, and cervix cancers. Our findings indicate that the expansion of pembrolizumab indications has substantially altered the profile of reported immune-related adverse events in Japan, highlighting the need for ongoing pharmacovigilance tailored to cancer type and patient demographics.

A 77-year-old man with unresectable advanced gastric cancer, complicated by multiple liver and distant lymph node metastases, began drug therapy. As a third-line treatment, nivolumab was administered for two courses;however, the patient developed destructive thyroiditis. Treatment with nivolumab was resumed after clinical improvement, but the patient developed interstitial pneumonia following a total of four courses, leading to discontinuation of treatment. Although nivolumab was discontinued and no further drug therapy was initiated, tumor shrinkage persisted for 15 months. Notably, the metastatic lesions remained stable and the tumor markers had not increased even 29 months later. The patient's clinical course differed from that typically observed in patients treated with conventional cytotoxic agents, as tumor shrinkage continued long after the discontinuation of nivolumab.

In Japan, amrubicin hydrochloride (AMR) is occasionally administered to patients with recurrent small cell lung cancer (SCLC). AMR therapy can induce febrile neutropenia (FN), a complication that may be fatal or compromise therapeutic efficacy due to treatment interruption or dose reduction. Identifying risk factors for FN is therefore critical to ensuring safe and effective AMR administration. Current evidence on this issue remains limited to small case series, underscoring the need for more robust studies. We conducted a multicenter retrospective analysis to examine predictors of FN during AMR treatment for recurrent SCLC. Patients who received AMR between April 1, 2013, and March 31, 2023, were included. The cohort comprised 256 patients, divided into 192 without FN and 64 with FN. Multivariate analysis demonstrated that performance status (PS) >2 (odds ratio: 5.8, 95% confidence interval: 1.70-19.80, p=0.005) and hematocrit (HCT) (odds ratio: 0.93, 95% confidence interval: 0.877-0.994, p=0.033) were significantly associated with FN development. These findings suggest that PS and HCT may serve as key indicators for predicting FN during AMR therapy in patients with recurrent SCLC.

While tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis for patients with chronic myeloid leukemia (CML), lifelong therapy presents challenges such as long-term toxicities and financial burden. Consequently, treatment-free remission (TFR) has become a primary therapeutic goal, with the aim of safely discontinuing TKIs while maintaining remission and enhancing patient quality of life (QoL). The feasibility and safety of TFR have been established through numerous clinical trials worldwide. The large-scale J-SKI observational study confirmed a 5-year TFR rate of 65.2% and demonstrated its safety in clinical practice. A sustained period of deep molecular response (DMR) is the most critical predictive factor for a successful TFR attempt. Current challenges include TKI withdrawal syndrome, the success of second TFR attempts, and the rare risk of blast crisis during TFR. Future strategies aim to increase TFR eligibility by achieving higher DMR rates with newer agents.

Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of chronic myeloid leukemia (CML), bringing the CML patients' fertility to the forefront of survivorship care. This review outlines current evidence and pragmatic guidance for patients with CML who desire pregnancy. Ideally, patients should achieve and sustain a deep molecular response (MR4.5), fulfill eligibility criteria for treatment-free remission (TFR), discontinue TKIs, and pursue planned conception under close molecular monitoring. When pregnancy occurs during therapy, TKI exposure should be avoided in the first trimester; interferon-alpha (IFN-α) is the preferred option for disease control. In the event of molecular relapse, carefully considered use of imatinib or nilotinib at the lowest effective dose may be employed exclusively in the second or third trimester following multidisciplinary counseling, whereas dasatinib should be avoided throughout gestation. Available data suggest there is minimal impact of TKIs on male fertility; treatment interruption is generally unnecessary. We emphasize structured algorithms, explicit intervention thresholds, and monthly BCR-ABL1 (IS) testing, as well as collaboration with obstetrics, neonatology, and reproductive medicine, including assisted reproductive technologies. Finally, we discuss practical pathways applicable to resource-limited settings to balance maternal-fetal safety with patient values and to support informed, preference-concordant decision-making.

Tyrosine kinase inhibitors (TKIs) have markedly improved the prognosis of chronic myeloid leukemia (CML). In Japan, in addition to the four established first-line TKIs, asciminib is now approved as an initial therapy, expanding the treatment options. Nevertheless, more than 10% of patients treated with asciminib over 48 weeks, and approximately 20-30% of those receiving other TKIs over five years, require second-line therapy because of resistance or intolerance. As first-line choices diversify, selecting the optimal second-line regimen has become increasingly complex. For intolerance, switching should be guided by the adverse-event profile with attention to potential cross-intolerance. For resistance, assessment of BCR::ABL1 mutations is essential, and second-line agents should be chosen according to the initial TKI and mutation sensitivity. This article summarizes the criteria and timing for switching to second-line therapy and key considerations for selecting and managing second-line TKIs, and briefly reviews the evidence for asciminib and ponatinib in second-line and later settings.

Chemotherapy-induced peripheral neuropathy (CIPN) frequently develops following treatment of cancer with cytotoxic chemotherapeutics, such as taxanes, platinum-containing agents and vinca alkaloids, and leads to impairment of patients' QOL and dose limitation or cessation of chemotherapy in the worst-case scenario. We have demonstrated that extracellular release of high mobility group box 1 (HMGB1), a nuclear protein, plays a critical role in the developmental process of CIPN, and that thrombomodulin alfa (TMα) capable of degrading HMGB1 in a thrombin-dependent manner prevents CIPN development. Our retrospective cohort study in female patients with breast cancer or gynecological cancer undergoing paclitaxel-based chemotherapy has shown that postmenopausal estrogen decline is a risk factor for the development or aggravation of CIPN. We have also demonstrated that ovariectomy aggravates CIPN in laboratory animals treated with paclitaxel, which is prevented by estrogen supplementation or treatment with TMα. On the other hand, there is evidence from animal studies for inhibition of CIPN by progesterone and of neuropathic pain by androgen. Together, different sex hormones including estrogen may function to limit the development of CIPN, while age-related decline of sex hormones could be a risk for CIPN development. Our study to clarify the effects of sex hormones on HMGB1 behavior during the developmental process of CIPN is still in progress, but we nonetheless propose that TMα capable of inactivating HMGB1 is useful in preventive intervention for cancer patients with high risk of CIPN, e.g., postmenopausal females.

A 74‒year‒old male was diagnosed with advanced rectal cancer with bowel obstruction, and abscess formation. After sigmoid colostomy, FOLFOXIRI plus bevacizumab as preoperative chemotherapy was initiated. On day 3, during continuous administration of 5‒fluorouracil(5‒FU), the patient developed impaired consciousness accompanied by convulsive seizures and conjugate deviation. Electroencephalography(EEG)revealed no epileptic discharges, and imaging studies revealed no abnormality. A blood test showed a high ammonia level of 367μmol/L. In the absence of prior liver disease, the cause was suspected to be due to high‒dose 5‒FU. Administration of lactulose was started. The ammonia level normalized and the consciousness recovered quickly by the following day. It was thought that chemotherapy would be difficult to continue, and 1 month later, robot‒assisted low anterior resection and ileostomy were performed. The patient was discharged home without complication on postoperative day 13. We report this case of advanced rectal cancer in which administration of high‒dose 5‒FU caused hyperammonemia accompanied by impaired consciousness, with a literature review.

In the Guidelines for the Appropriate Use of Antiemetic Drugs published in 2023, antiemetic drugs for regimens containing carboplatin(CBDCA)with an area under the blood concentration time curve(AUC)of ≥4 is recommended for neurokinin 1(NK1)receptor antagonists. However, the antiemetic efficacy of aprepitant(APR)has not been adequately evaluated. Therefore, we investigated whether the addition of APR in gynecological cancer CBDCA/paclitaxel(PAC)therapy (TCb therapy)with or without APR influenced the overall treatment rate of emetic control, nausea control rate, emetic complete response(CR rate)and total control rate of nausea and vomiting(total complete: TC rate)were to be investigated. The results showed that the emesis control rate, nausea control rate, CR rate and TC rate were similar with and without concomitant APR. In other words, the addition of APR was not significant for nausea and vomiting in cancer chemotherapy during the first treatment of regimens including CBDCA in gynecological cancer patients.

Skin-related adverse events(AEs)are a major adverse effect of anti-EGFR antibody therapy in metastatic colorectal cancer.While various preventive skincare strategies have been reported, few studies have examined the relationship between skin-related AEs and seasonal variations.We retrospectively analyzed 73 patients who received anti-EGFR antibody therapy at Hyogo Medical University Hospital from January 2020 to August 2023.The primary endpoint was the incidence of Grade≥2 skin-related AEs at weeks 8 and 12 after treatment initiation in the summer(Su group)and winter(Wi group)groups, compared to the spring/autumn(Control group).At week 12, the Wi group had a significantly higher incidence of skin-related AEs than the Control group(94.4% vs 61.1%, p=0.011).No significant differences were observed for rash acneiform or paronychia, but Grade≥2 dry skin was significantly more frequent in the Wi group(83.3% vs 50.0%, p=0.021).Younger age(<65 years)(HR: 1.94, 95%CI: 1.18-3.21, p=0.009)and treatment initiation in winter(HR: 2.04, 95%CI: 1.11-3.76, p=0.022)were identified as risk factors.These findings suggest that patients initiating treatment in winter may be at increased risk of severe dry skin, necessitating enhanced skincare measures.

Gastrointestinal perforation during chemotherapy for gastric cancer is an infrequent but important adverse event. We report a case of ileal ulcer perforation induced S-1 chemotherapy for gastric cancer. A 73-year-old male underwent total gastrectomy in December 2020(palliative surgery)and S-1 chemotherapy was initiated in January 2021. The treatment was well tolerated until late March, when he presented with sudden abdominal pain and fever. He was diagnosed with perforation of the gastrointestinal tract and acute generalized peritonitis. Emergency laparotomy revealed a 2-mm perforation in the ileum, approximately 30 cm proximal to the terminal ileum. About 7 cm of ileum including the perforated area was partially resected. Histopathological analysis confirmed a Ul-Ⅳ ulcer with granulation tissue and severe inflammation. Based on clinical and pathological findings, the perforation was attributed to S-1-induced small intestinal ulceration. The patient subsequently received up to fourth-line chemotherapy. He survived for 15 months after the initial surgery.

Fluoropyrimidine anticancer agents, exemplified by 5-fluorouracil (5-FU), induce severe adverse effects-such as myelosuppression, emesis, diarrhea, and hand-foot syndrome-in approximately 10-30% of patients. As such toxicities can result in delays or discontinuation of therapy, accurate prediction of drug response prior to treatment initiation is of critical importance. The metabolic degradation of 5-FU is primarily mediated by the drug-metabolizing enzymes dihydropyrimidine dehydrogenase (DPD) and dihydropyrimidinase (DHPase). These enzymes are encoded by the DPYD and DPYS genes, respectively; polymorphisms in these genes that reduce or abolish enzymatic activity lead to elevated systemic concentrations of 5-FU, thereby increasing the risk of severe toxicity. In Caucasian populations, four DPYD polymorphisms have been identified as predictive markers of adverse drug reactions. However, these variants are rarely observed in Japanese individuals, and reliable pharmacogenomic biomarkers remain largely unreported in this population. To address this gap, we conducted a comprehensive in vitro functional analysis of DPD and DHPase activity of DPYD and DPYS variants identified through large-scale whole-genome sequencing databases. This review summarizes our findings and elucidates the underlying mechanisms affecting the function of 5-FU-metabolizing enzymes, as revealed by our prior research.