Currently, a variety of anticancer agents are used in the treatment of cancer. Since anticancer agents are used continuously over a long time, they carry the risk of side effects. One of the major side effects is cardiac dysfunction. For example, doxorubicin, an anthracycline-type anticancer agent, is clinically restricted because of its dose-dependent cardiotoxicity. Cardiotoxicity includes decreased ejection fraction, arrhythmias, and congestive heart failure, all of which are associated with high mortality rates. Therefore, it is important to assess the risk of cardiotoxicity of anticancer agents in advance. Cardiomyocytes require energy to beat and retain an abundance of mitochondria. We established quantitative measurements of mitochondrial length and respiratory activities using cardiomyocytes. We found that exposure of human iPS cell-derived cardiomyocytes (hiPSC-CMs) to anticancer agents with reported cardiotoxicity enhanced mitochondrial hyperfission and the oxygen consumption rate was significantly reduced. Knockdown of dynamin-related protein 1 (Drp1), mitochondrial fission-accelerating GTP-binding protein, suppressed mitochondrial hyperfission in hiPSC-CMs. This indicates that visualizing mitochondrial functions in hiPSC-CMs will be helpful in assessing the risk of cardiotoxicity caused by anticancer agents and that maintaining mitochondrial quality will become a new strategy to reduce anticancer agents-induced cardiotoxicity. In this review, we present the evaluation of cardiotoxicity targeting mitochondrial quality in anticancer agents, using osimertinib, a non-small cell lung cancer drug, as an example.

This is a personal review of my chemistry research on retirement from Teikyo University. Under the guidance of Prof. Masaji Ohno of the Faculty of Pharmaceutical Sciences, The University of Tokyo, my research career started with the synthesis of water-soluble basic natural compounds, including the first artificial bleomycin showing potent molecular-oxygen activation effects and DNA binding abilities. While studying abroad at Eidgenössische Technische Hochschule (ETH) under the guidance of Prof. Albert Eschenmoser, I studied the formation of ribose under prebiotic conditions. The condensation reaction between formaldehyde and glycolaldehyde phosphate produced ribose in far greater yield than the formose reaction. In the School of Pharmacy, Showa University, I conducted research in nucleic acid chemistry to synthesize, for example, anomeric spiro-nucleosides using radical chemistry and oligonucleotides that interacted with the κB motif. After moving to Teikyo University in 1999, I engaged in studies on the synthesis of vitamin D derivatives, included in fat-soluble vitamins, with selective biological activities without calcemic side-effects, and discovered, for example, 2α-(3-hydroxypropyl)-19-nor-1α,25-dihydroxyvitamin D3 (MART-10), which exhibits potent anticancer activity in vivo, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 (AH-1), which shows greater bone-forming effects than natural active vitamin D3 in vivo, and the A-ring-converted vitamin D derivative KK-052, which is an in vivo selective inhibitor of sterol regulatory-element binding protein (SREBP), a master transcription factor of lipogenesis, independent of the vitamin D canonical activity through a vitamin D receptor.

A 75-year-old female who was referred to our hospital with dizziness as the main complaint. Computed tomographic (CT) and positron emission tomography-CT scans indicated the presence of generalized lymphadenopathy and a 10 cm tumor in her left kidney. Further evaluation led to a diagnosis of Hodgkin’s lymphoma and left renal cell carcinoma. Due to her poor general condition secondary to the lymphoma, she was referred to our institution where chemotherapy was promptly initiated. After one year, metastases to the sternum and right hilar lymph nodes from the renal cancer were detected. Therefore, treatment for the lymphoma was discontinued, and combination therapy with Pembrolizumab and Axitinib for the renal carcinoma was started. Eight months after starting treatment for kidney cancer, the patient developed gastritis as an immune-related adverse event (irAE), which improved with high-dose steroid therapy. Subsequently, severe thrombocytopenia developed following the initiation of steroid therapy but improved upon discontinuation of Axitinib. Currently, treatment is ongoing with Cabozantinib without recurrence of either gastritis or thrombocytopenia.

A 58-year-old man was treated with radical excision for rectal cancer. Pathological findings were pT3N1M0, Stage ⅢB, RAS: mutant, BRAF: mutant, MSS. The patient was followed up without adjuvant chemotherapy. Eight months after surgery, a CT scan showed recurrence of liver metastases, and chemotherapy was started. The patient was started on regorafenib as the fourth-line therapy for multiple liver metastases, distant lymph node metastases, and peritoneal dissemination. Twenty-three days after the first course, he developed severe abdominal pain and visited the emergency department on day 25. Suspecting generalized peritonitis due to perforation of the upper gastrointestinal tract, he was treated with emergency laparotomy and drainage. A perforation was found in the anterior wall of the lower gastrointestinal body and was sutured closed. There were no adverse events, and the patient was discharged on the 21st postoperative day. regorafenib is a multi-kinase inhibitor, and gastrointestinal perforation has been reported as a serious adverse event, although it is rare. We report a case of upper gastrointestinal perforation during regorafenib administration, with some discussion of the literature.

Due to supply difficulties and other factors associated with COVID-19, oral dexamethasone became less readily available. To address this limitation, we investigated the effect of adjusting prophylactic antiemetic therapy on the efficacy of anticancer drug treatment. This study included patients in the gastrointestinal oncology unit of our hospital who received a regimen containing moderately emetogenic risk anticancer drugs between September 2021 and August 2022. We retrospectively analyzed medical records to assess the treatment regimen, prophylactic antiemetic therapy, oral dexamethasone dose reduction, presence of emetic events during the first course, use of additional antiemetic agents for prominent nausea and vomiting, and the complete response(CR)rate. The study included 98 patients with a median age of 71 years. The overall CR rate was 95% in the standard-dose dexamethasone group and 92.3% in the dexamethasone-reduced group(p=0.68). The CR rates for oxaliplatin- and irinotecan-based regimens were 92.9% and 100% in the dexamethasone-reduced group and 91.5% and 94.7% in the standard-dose dexamethasone group. In this study, the CR rates were not significantly different between the dexamethasone reduction and standard-dose groups. This may be due to the use of steroid-sparing or triple therapy by physicians, depending on the patient's risk factors. Therefore, the prophylactic antiemetic therapies for individual patients must be continued to examine.

The adverse chapter of cancer chemotherapy negatively impact QOL, and pharmacists play a key role in improving QOL by providing optimal drug therapy through pharmaceutical interventions. Although outpatient cancer chemotherapy is now common, the impact of pharmaceutical interventions from a QOL perspective has not been thoroughly studied. Therefore, this study investigated the impact and cost-effectiveness of pharmaceutical interventions on QOL using the EuroQol 5 Dimension (EQ-5D) and Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD). The study was conducted between 2013 and 2015 on 39 patients who underwent their first outpatient chemotherapy for breast cancer at Gifu Municipal Hospital. The results showed that pharmaceutical interventions improved social relationship QOL in patients experiencing fatigue during the first cycle and enhanced psychological QOL in patients with adverse events of nausea during the second cycle. Furthermore, the maximum incremental cost-effectiveness ratio (ICER) was found to be 1.3 million yen per quality-adjusted life years (QALY) according to cost utility analysis. The pharmaceutical interventions by pharmacists in outpatient cancer chemotherapy improve QOL, and the ICER remains well below the Japanese threshold, signifying clear medical and economic benefits.

We report the case of a 46-year-old Japanese woman diagnosed with Stage Ⅳ right breast cancer, cT1cN1M1(ovarian and peritoneal metastases). We administered bevacizumab+paclitaxel as the first-line treatment. In the 13th course, the peritoneal dissemination progressed, and the regimen was changed to eribulin(1.4 mg/m2)as the second-line treatment. During the second course, abdominal distension developed and was resolved during follow-up. However, abdominal distension and pain were observed from day 9 of the fourth course. Based on the results of blood chemistry and CT scans, she was diagnosed with acute pancreatitis(CT Grade 1)and was admitted to the hospital. After fasting and fluid replacement therapy, her clinical symptoms and laboratory data improved, and was discharged from the hospital 8 days later. She had no history of excessive alcohol consumption and no evidence of biliary disease, and was considered having eribulin-induced pancreatitis.

Futibatinib (Lytgobi® Tablets 4 ‍mg), a novel fibroblast growth factor receptor (FGFR) inhibitor developed by Taiho Pharmaceutical using the Cysteinomix Drug Discovery Platform, was approved in Japan in June 2023 for the treatment of patients with unresectable biliary tract cancer with FGFR2 fusion or rearrangement that had progressed after at least one prior chemotherapy. Futibatinib covalently binds to the cysteine residue in the FGFR kinase domain P-loop structure and is believed to exert antitumor activity by selectively and irreversibly inhibiting FGFR1-4. Many FGFR inhibitors under development are ATP-competitive; however, futibatinib is the first approved covalently-binding irreversible FGFR inhibitor. It inhibits cell proliferation by inhibiting FGFR phosphorylation and its downstream signaling pathways in cancer cell lines. Futibatinib showed inhibitory activity against a wider range of FGFR mutants than ATP-competitive, reversible FGFR inhibitors and inhibited cell proliferation without significantly deviating from the inhibitory effect on wild-type FGFR. Futibatinib showed antitumor efficacy in mice subcutaneously transplanted with human tumor cell lines driven by FGFR. The international phase 2 study (TAS-120-101) was conducted in patients with refractory intrahepatic cholangiocarcinoma with FGFR2 fusion or rearrangement. The overall response rate was 41.7%, showing consistent efficacy regardless of co-occurring genomic alterations. Although some typical FGFR inhibitor-related side effects were observed, they were manageable and futibatinib had a good safety profile. Futibatinib is an important drug for biliary tract cancer, which has limited treatment options; its development is underway for other types of cancer, and it is expected to benefit more patients.

Many patients with chronic myeloid leukemia (CML) can now maintain response thanks to the advent of tyrosine kinase inhibitors (TKIs) and STAMP inhibitors, but adverse events associated with prolonged TKI therapy have become a problem. Adequate management of adverse events is key to successful treatment, as some can significantly impact the patient's prognosis. The goal of CML treatment was once to prevent acute transformation, but now that many patients achieve deep remission and long-term survival, the goal has shifted to achieving long-term treatment free remission (TFR). It is essential to carefully consider disease risk, patient background, and adverse events of each therapeutic agent in order to make the appropriate choice. This article reviews the treatment of chronic phase CML (CML-CP) as described in the 2023 edition of the Guidelines for Hematopoietic Tumors, focusing on treatment options for first-line CML-CP, dose optimization of ponatinib, outcomes with the new CML drug asciminib, and TFR.

This survey aimed to reveal the actual preventing exposure for handling of clothing and sweat of patients treated with anticancer drugs, following the publication of "Guideline for Preventing Occupational Exposure in Cancer Chemotherapy Drugs, 2019 Edition" (Guideline 2019). A survey was conducted among nurses working at 95 hematopoietic stem cell transplantation promotion base hospitals from September 1, 2023 to October 31, 2023. The response rate was 84.2% (80 facilities). Of the respondents, 45% wore gloves when touching patients' skin to administer anticancer drugs. Almost the nurses identified "urine" and "feces" as fluids on contaminated linen, while 14.1% also identified "sweat." For new staff, the results for preventing exposure education on "if touching the patients' skin" and "if handling clothing and linen" were 23.8% and 34.9%, respectively. This survey shows that nurses may not be following the Guideline 2019 for use of personal protective equipment and handling of clothes. Medical institutions handling anticancer drugs need to educate their staff for preventing occupational exposure.

Patients undergoing outpatient cancer chemotherapy are prescribed"as-needed"medication(antiemetics, laxatives, and antibiotics)as a form of self-care for early response to side effects. We conducted a questionnaire survey to clarify whether prescribed"as-needed"medication contributes to the relief of patients' anxiety about cancer chemotherapy. We obtained responses from 80 breast cancer patients who received neoadjuvant or adjuvant chemotherapy from 2019-2021". As- needed"medication was used by 68(85.0%)of patients. Fifty patients(73.5%)who used"as-needed"medication experienced relief of anxiety associated with chemotherapy. Also, 10 patients(83.3%)who did not use"as-needed"medication experienced relief of anxiety associated with chemotherapy". As-needed"medication may contribute to the relief of anxiety associated with chemotherapy in breast cancer patients.

Pseudocirrhosis, which is radiologically and clinically similar to liver cirrhosis, may develop following chemotherapy for breast cancer with liver metastasis. There are few reports of eribulin treatment. We report 5 patients with metastatic or recurrent breast cancer who developed pseudocirrhosis during eribulin treatment. All patients had diffuse liver metastasis, and the liver metastases significantly reduced in size during the early phase of eribulin treatment, when they developed pseudocirrhosis. Subsequently, the patients had poor prognoses.

The efficacy of antibody-drug conjugates(ADCs)has been well-established in clinical use, prompting ongoing research and development efforts to advance the field of ADCs further. This chapter provides overview of the structure and mechanism of action of ADCs, detailing the roles of its components: the antibody, the payload, and the linker. ADCs leak from cancer vessels to bind to specific antigens on the surface of tumor cells. Upon binding and internalization, the drug is released by metabolic enzymes, such as peptidases in the lysosome. The therapeutic window of the conjugated drug is therefore expanded. To enhance the efficacy of ADCs, the chapter will also explore the development of methodologies for generating homogeneous ADCs and the concept of bystander effects, which are particularly relevant in the tumor microenvironment. Additionally, innovative approaches such as radioimmunotherapy, utilizing alpha-ray emitting radionuclides, and photoimmunotherapy, are discussed as promising next-generation ADC strategies. The integration of ADCs with immunotherapy may offer amplified effectiveness through synergistic actions. The chapter underscores that the prolonged therapeutic impact of ADCs cannot be solely attributed to the targeted delivery and controlled release of the payload. A comprehensive understanding from the perspective of cancer immunology is imperative for elucidating the underlying mechanisms contributing to their sustained efficacy.

Hypersensitivity reactions are an adverse effect of anticancer drug therapy. Prophylactic administration of antiallergic drugs and steroids is recommended when administering drugs associated with a high hypersensitivity reaction incidence. First-generation antihistamines are generally used in this setting. These medications, however, induce drowsiness and sedation due to their inhibitory effects on the central nervous system. They are contraindicated in patients with angle-closure glaucoma and prostatic hyperplasia. Second-generation antihistamines are used as alternative drugs for such cases in our hospital. This study investigated the use of second-generation antihistamines at our hospital and examined their efficacy and safety. A total of 7 second-generation antihistamines were used at our hospital. Approximately 90% of the target patients were shifted from first-generation antihistamines to bilastine or desloratadine. The most frequent reasons for changing to second- generation antihistamines were drowsiness(32.3%)and car driving(24.2%). No central inhibitory side effects were observed upon consumption of second-generation antihistamines. Only 2 patients(3.2%)developed hypersensitivity reactions after changing to second-generation antihistamines. Our findings suggest that second-generation antihistamines are effective in preventing hypersensitivity reactions. These medications may be used in patients who have concerns regarding the central inhibitory side effects of first-generation antihistamines or their potential to exacerbate comorbidities. Their use can help improve the safety of anticancer drug therapy.

The administration of cabazitaxel for patients with castration-resistant prostate cancer (CRPC) requires prior docetaxel therapy. Sequential chemotherapy may have to be discontinued due to docetaxelassociated side effects. This study investigated the relationship between treatment outcome of docetaxel and cabazitaxel and their associated side effects. We retrospectively analyzed 69 patients with CRPC who had been administered docetaxel withand without subsequent cabazitaxel at Toyonaka Municipal Hospital from October 2014 to June 2022. Twenty-eight patients (41%) discontinued docetaxel because of side effects, and the median number of docetaxel cycles at discontinuation was 2 (range : 1-11). Fourteen of these patients received no treatment following docetaxel. A comparison of the 28 patients who had discontinued docetaxel due to side effects with 41 patients who had not revealed a significant difference in the total numbers of chemotherapy cycles (2.5 vs 9 ; P＜0.001) and time to treatment failure (56 days vs 301 days ; P＝ 0.001), with a trend toward shorter overall survival from the start of docetaxel treatment (259 days vs 512 days ; P＝0.06). Multivariate analysis identified discontinuation of docetaxel due to side effects (OR＝0.07 ; P＜0.001) and lower hemoglobin (OR＝0.01 ; P＝0.001) as significant factors inhibiting the introduction of cabazitaxel. Reducing the side effects of docetaxel, including early drug switching, may allow more CRPC patients to be reached with cabazitaxel. Consequently, the resulting taxane-based chemotherapy may contribute to an additional survival advantage.

Neurological immune-related adverse events (irAEs) associated with cancer treatment with immune checkpoint inhibitors (ICI) present diverse clinical characteristics. Neurological irAEs affect the peripheral nervous system and muscles more than they affect the central nervous system. Among the various subsets of peripheral neuropathies, polyradiculoneuropathy, which includes Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, stands out as the most severe form, leading to significant muscle weakness. ICIs can induce dysautonomia, including autoimmune autonomic ganglionopathy. Autonomic neuropathy represents a neurological irAE. Neurological irAEs of neuromuscular junctions include myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). Diagnosing MG or myositis independently can be challenging when they occur as irAEs. Myocarditis is sometimes observed as an irAE in patients with MG and can cause both severe heart failure and lethal arrhythmias, resulting in fatal outcomes. Anti-Kv1.4 antibodies are biomarkers of the severe form of MG and myocarditis. The administration of ICI in patients with small cell lung cancer increases the risk of LEMS. The distinction between LEMS is an irAE or a manifestation of paraneoplastic neurological syndrome is unclear as both conditions share common immunological mechanisms.

A series of antitumor bicyclic hexapeptide RA-VII analogues modified at residue 2, 3, or 6 were prepared by the chemical transformation of the hydroxy, methoxy, or carboxy groups or the aromatic rings of natural peptides RA-II, III, V, VII, and X. Analogues with modified side chains or peptide backbones, which cannot be prepared by the chemical transformation of their natural peptides, and newly isolated peptides from Rubia cordifolia roots were synthesized by using protected cycloisodityrosines prepared by the degradation of bis(thioamide) obtained from RA-VII or the diphenyl ether formation of boronodipeptide under the modified Chan-Lam coupling reaction conditions. Studies of the conformational features of the analogues and the newly isolated peptides and their relationships with cytotoxic activities against the HCT-116, HL-60, KATO-III, KB, L1210, MCF-7, and P-388 cell lines revealed the following: the methoxy group at residue 3 is essential for the potent cytotoxic activity; the methyl group at Ala-2 and Ala-4 but not at D-Ala-1 is required to establish the bioactive conformation; the N-methyl group at Tyr-5 is necessary for the peptides to adopt the active conformation preferentially; and the orientation of Tyr-5 and/or Tyr-6 phenyl rings has a significant effect on the cytotoxic activity.

The novel coronavirus disease(corona virus disease 2019: COVID-19)has calmed down worldwide, and the severity of the disease is decreasing. On the other hand, due to the emergence of strain mutations, the number of infected people shows a wavy course. I have experienced a case of gastric cancer that underwent chemotherapy including an immune checkpoint inhibitors(ICI) early after COVID-19, so I will report it including a discussion.