A 65-year-old woman was diagnosed with hepatocellular carcinoma (HCC) in February 20XX-1. Following three cycles of transarterial chemoembolization (TACE) for recurrent HCC, combination therapy with atezolizumab and bevacizumab (Atezo+Beva) was initiated in February Y, 20XX. Eight days after treatment initiation (Y+8), the patient developed a fever and generalized malaise. By day 14 (Y+14), her symptoms worsened, prompting a visit to her primary physician, where a fever of 39°C was recorded. However, no hypoxemia was observed, and she was sent home. The following day (Y+15), she developed dyspnea and hypoxemia (SpO2 in the 80% range), and chest computed tomography (CT) revealed a hilar central alveolar infiltration. She was subsequently admitted to her previous hospital. Comprehensive evaluation led to a diagnosis of congestive heart failure associated with thyrotoxicosis. According to the IMbrave150 study, thyroid dysfunction occurs in 13.4% of patients receiving Atezo+Beva therapy;however, cases classified as Common Terminology Criteria for Adverse Events Grade 3 or higher, requiring hospitalization, are extremely rare, with an incidence of only 0.3%.

An 86-year-old man underwent laparoscopic ileocecal resection with lymph node dissection(pT3N0M0, Stage Ⅱa, Ly1a, V1a). The patient did not receive any adjuvant chemotherapy. Two years later, the patient was diagnosed with a recurrence at the anastomotic site(RAS mutant, HER2 negative, MSI-low). After 4 courses of FOLFOX plus bevacizumab, the patient was admitted for ileus. Preoperative echocardiography revealed an ejection fraction(EF)of 35% and BNP level of 562.2 pg/ mL. Therefore, asymptomatic cardiomyopathy was suspected because of bevacizumab administration. Although the last bevacizumab dose was administered within 2 weeks, we performed a laparoscopic tumor resection with lymph node dissection. Histological examination revealed colon cancer recurrence without lymph node metastasis. The patient was discharged on 19 POD without heart failure and had no recurrence of UFT/UZEL for 11 months. Three months after surgery, EF increased to 61% and BNP level was 14 pg/mL. VEGF inhibitors are associated with a very high risk of cardiomyopathy according to the ESC guidelines(2022). These side effects in conversion therapy for cancer should be carefully considered, even though they are rare.

Diterpenoid alkaloids are major pharmaceutically active constituents of Aconitum plants. In phytochemical investigations on Aconitum japonicum subsp. subcuneatum, Aconitum yesoense var. macroyesoens, and Delphinium elatum cv. Pacific Giant (Ranunclaceae), the structures of isolated C19- and C20-diterpenoid alkaloids were elucidated. Three aconitine-type C19-diterpenoid alkaloids, jesaconitine, aconitine, and mesaconitine, which are main components of A. japonicum subsp. subcuneatum, are significantly toxic to the central nervous system. However, lycoctonine-type C19-diterpenoid alkaloids and C20-diterpenoid alkaloids are less toxic. Several diterpenoid alkaloids from the genera Aconitum and Delphinium and their derivatives exhibited slight cytotoxic activity against several human tumor cell lines [A549 (lung carcinoma), DU145 (prostate carcinoma), MDA-MB-231 (triple-negative breast cancer), MCF-7 (estrogen receptor-positive, HER2-negative breast cancer), KB (identical to cervical carcinoma HeLa derived AV-3 cell line), and multidrug-resistant (MDR) subline KB-VIN]. In our course of studies on synthetic derivatives of the C19-diterpenoid alkaloids delcosine and delpheline and the C20-diterpenoid alkaloids lucidusculine, pseudokobusine, and kobusine, we found several derivatives showing significant cytotoxic activity and, thus, providing promising new leads for further development as antitumor agents. Notably, several diterpenoid alkaloids were more potent against MDR subline KB-VIN cells than the parental drug-sensitive KB cells. Among non-cytotoxic synthetic analogues, several lycoctonine-type C19-diterpenoid alkaloid derivatives effectively and significantly sensitized MDR cells to three anticancer drugs, paclitaxel, vincristine, and doxorubicin.

CPX-351 (Vyxeos®), a liposomal formulation used in the treatment of acute myeloid leukemia, has been associated with cutaneous adverse events, particularly purpura, in previous clinical trials. We present the case of a 73-year-old woman with refractory acute monocytic leukemia and leukemia cutis, who was treated with CPX-351 as salvage induction therapy. Following treatment, the extramedullary lesions resolved; however, some skin lesions developed into pustular eruptions. These pustules appeared during the neutropenic phase, and cultures ruled out infection, leading to the diagnosis of sterile pustulosis. Supportive care, including skin care measures and application of antibiotic ointment, allowed for continued treatment, and the pustules resolved after crusting. To our knowledge, this is the first reported case of sterile pustulosis associated with CPX-351 treatment, highlighting the importance of early detection and appropriate management of skin complications for the successful continuation of therapy.

Ixazomib (IXA) is a convenient oral anticancer drug; however, due to its fixed dosage, IXA tolerability among elderly Japanese individuals may be reduced. Therefore, this study aimed to clarify the difference in relative dose intensity (RDI) of IXA in IRd therapy in elderly patients. Between October 2018 and September 2023, patients who underwent IRd therapy (IXA, lenalidomide, and dexamethasone combination treatment) at Ogaki Municipal Hospital were enrolled in the study and categorized into two age groups: ≥75 years (group O, n=16) and <75 years (group Y, n=6). We retrospectively analyzed RDI of IXA, in IRd therapy. In addition, we evaluated the reasons for dose reduction or delayed treatment. The median initial IXA dose was 3 mg (range: 2.3-4 mg) and 4 mg (range: 3-4 mg) in group O and Y, respectively (p=0.122). The median RDI in group O (65.8%, range: 51.1-91.7%) was significantly lower than in group Y (93.3%, range: 80.5-100.0%) (p=0.002). Among them, anorexia was more common in group O than in group Y (p=0.049). In group O, dose adjustments were made due to anorexia (n=10), diarrhea (n=5), nausea (n=2), and fatigue (n=2). In group Y, adjustments were made due to diarrhea (n=2) and thrombocytopenia (n=1). Upon IXA (4 mg) administration, the rate of dose adjustments due to gastrointestinal symptoms were 75% and 17% in group O and Y, respectively (p=0.051). Overall, RDI was lower in group O owing to gastrointestinal symptoms. This suggests that the fixed IXA dosage (4 mg) is less tolerable in older individuals.

Emesis and vomiting are the most common adverse events related to trastuzumab deruxtecan(T-DXd). T-DXd is listed as a moderate emetogenic chemotherapy(MEC)agent in the latest guidelines for the appropriate use of antiemetic drugs in Japan; however, the National Comprehensive Cancer Network Guidelines regard it as a highly emetogenic chemotherapy (HEC)agent. We investigated the risk factors for chemotherapy-induced nausea and vomiting(CINV)associated with T-DXd by analyzing data from 40 patients with advanced breast cancer(median age, 56 years)were receiving T-DXd administration between June 2020 and July 2023. CINV was graded using CTCAE v5.0. All patients were treated with antiemetic therapy consisting of a 5-HT3 receptor antagonist(5-HT3RA)and dexamethasone(DEX); 3 patients also received an NK1 receptor antagonist(NK1RA). Emesis was observed in 23(57.5%)(Grade≥2 in 7), and vomiting in 2 patients(5.0%, Grade 1). Emesis occurred >1 day after T-DXd administration in 78.3% and lasted for ≥7 days in 69.6%. These symptoms may be characteristic of T-DXd-related CINV. Antiemetic therapy for CINV in HEC may be considered to control T-DXd-associated CINV in patients aged<50 years or in those who did not achieve sufficient curative effects with MEC.

The patient was a 70-year-old man who underwent distal gastrectomy for gastric carcinoma of the antrum. One year after surgery, the patient developed a recurrence in the cardia lymph nodes. Following chemotherapy, the patient underwent a total resection of the remnant stomach and recurrent lymph nodes 2 years and 10 months after the resection of the primary tumor. The patient was re-treated with chemotherapy following surgery; however, he relapsed again, and pembrolizumab was initiated. After the administration of the 10th round of chemotherapy, the patient suddenly developed thirst and polydipsia. Marked hyperglycemia(BS level, 900 mg/dL)and ketoacidosis were observed; therefore, the patient was diagnosed with fulminant type 1 diabetes mellitus. The patient's symptoms improved after insulin administration, and self-injection was initiated. The patient was treated with pembrolizumab for 2 years with no apparent recurrence. The incidence of type 1 diabetes mellitus as an irAE is approximately 0.5% in patients on pembrolizumab. Although this is a rare complication, early detection and therapeutic intervention are desirable, and attention in daily practice is necessary.

We report a case of retroperitoneal abscess due to penetration of colonic diverticulosis during chemotherapy for sigmoid colon cancer. The patient was a 56-year-old man who was outpatient for chronic rheumatoid arthritis and was diagnosed sigmoid colon cancer with multiple simultaneous liver and lung metastases. The antitumor drugs were effective and the primary tumor was resected, and chemotherapy was continued due to progression of liver metastasis. After the molecular targeted drug was changed to bevacizumab, the patient was hospitalized with a diagnosis of colonic diverticulitis and was discharged with conservative therapy. Two months after discharge, the patient was hospitalized due to fever and gait disorder. Abdominal CT scan revealed abscess(12×7 cm)around the right kidney extended to abscess(15×4 cm)along the right iliopsoas muscle to the right hip joint. The retroperitoneal cavity was drained through right lumbar region and right inguinal area, and the retroperitoneal abscess disappeared. The patient improved gait disorder and was discharged from the hospital. The retroperitoneal abscess caused after the administration of bevacizumab, was fortunately possible to eliminate the retroperitoneal abscess by performing incision and drainage from extraperitoneal cavity.

A 76-year-old man with advanced colorectal cancer was started on oral S-1 monotherapy as postoperative chemotherapy. He had dyspnea on exertion, and imaging studies revealed frosted shadows in the bilateral lower lung fields. Transbronchial lung biopsy showed thickening of the alveolar wall, infiltration of inflammatory cells. Based on clinical history and examination results, he was diagnosed interstitial pneumonia with caused by S-1. His respiratory distress on exertion was markedly improved by oral administration of prednisolone(PSL). Thereafter, S-1 medication was not resumed and the patient was followed up on an outpatient basis while the PSL was gradually reduced. According to the S-1 package insert, the frequency of interstitial pneumonia is 0.3%, regardless of the presence or absence of concomitant chemotherapy, so the incidence of S-1 monotherapy is considered to be even lower. In this study, we report a case of colorectal cancer with interstitial pneumonia during monotherapy with S-1, with a review of the literature.

Despite recent advances in chemotherapy with immune-checkpoint inhibitor(ICI), some patients may have to undergo surgery after the immune-related adverse events(irAE). We report here a case of a 61-year-old man who developed the irAE-related anastomotic stenosis after robotic gastrectomy for gastric cancer. Previously, he was diagnosed as double cancers of far-advanced hung cancer and gastric cancer. He was treated with ICI-based chemotherapy comprising CBDCA, PEM and pembrolizumab for lung cancer, and developed drug-induced pneumonia and dermatomyositis due to severe irAE. Stenosis was improved with steroid therapy. Until now, there has been no recurrence without symptoms in these 2 years.

The patient, a 70-year-old post-menopausal woman diagnosed with cT2N0M0, Stage ⅡA, triple-negative breast cancer (TNBC), received neoadjuvant chemotherapy consisting of carboplatin, paclitaxel, and pembrolizumab. After 3 courses of chemotherapy, the patient experienced diarrhea over 10 times per day. The stool culture was negative for CD and cytomegalovirus antigens. A histological examination of the sigmoid colon and rectum using needle biopsy revealed lymphocytic infiltration of epithelial cells, apoptosis, and collagen band thickening, consistent with irAE-induced enteritis. We diagnosed diarrhea and colitis due to irAE and treated the patient with high-dose steroids according to the NCCN treatment guidelines. The diarrhea and fever resolved rapidly following steroid administration. Lymphocytic infiltration, apoptosis, and collagen bands in the epithelial cells of the biopsied mucosa are critical for diagnosing irAE-induced enteritis. PD-1-associated enterocolitis is rare, with laboratory findings often revealing only minor changes in the early disease stages. Diarrhea worsens if treatment is delayed, underscoring the importance of early diagnosis and prompt initiation of steroid therapy.

Fluoropyrimidines are one of the key drugs in cancer chemotherapy, but rare adverse events are difficult to diagnose and treat. Here we report a case who developed the relatively rare adverse events of rhabdomyolysis and refractory enteritis during S-1-based chemotherapy for gastric cancer. Because S-1 is frequently used in daily practice of cancer chemotherapy, we should always manage adverse events with detailed knowledge of rare and potentially serious adverse events.

We report a case of phenytoin(PHT)toxicity due to a drug interaction with capecitabine started as postoperative adjuvant chemotherapy for rectal cancer. Nevertheless the patient was able to complete 8 courses with therapeutic drug monitoring (TDM). Case: 42-year-old female, diagnosed with epilepsy at age 15, taking PHT. She started CAPOX therapy as postoperative adjuvant chemotherapy for recto-sigmoid colon cancer. 23 days after starting capecitabine, she presented with dizziness and weakness of the legs. She was diagnosed with PHT intoxication because her serum PHT concentration was elevated at 45.8 μg/mL. CAPOX therapy was continued with frequent serum PHT concentration measurements and dosage adjustment, and the planned 8 courses were completed. During the course of the treatment, there were no epileptic seizures or reappearance of PHT intoxication symptoms. In this case, we were able to safely administer CAPOX therapy with TDM.

Tumor-specific active drug release from macromolecular antitumor drugs after tumor delivery is critical to achieve efficient cellular uptake of the active drug, thereby ensuring therapeutic efficacy. Upon reaching the tumor tissue, protease-facilitated depegylation of pegylated zinc protoporphyrin with ester bonds between PEG and ZnPP (esPEG-ZnPP) occurs, leading to a faster cellular uptake and superior antitumor efficacy compared to PEG-ZnPP with ether bonds (etPEG-ZnPP). This finding provides a viable strategy for achieving efficient tumor-specific drug release by utilizing an ester linkage between PEG and antitumor drugs. Another strategy involves using styrene-maleic acid copolymer (SMA), an amphiphilic polymer. Drug-encapsulating SMA aggregates disintegrate upon interaction with cell membrane components, releasing the encapsulated active drug. The author has demonstrated an improvement in the tumor accumulation of SMA-based macromolecular drugs by conjugating pirarubicin (THP), an anthracycline antitumor drug, with SMA. Furthermore, by conjugating various molecular weights of N-(2-hydroxypropyl)methacrylamide (HPMA) to THP via a hydrazone bond (P-THP, DP-THP, and SP-THP), the author has established a positive correlation between HPMA molecular weight and therapeutic efficacy as well as toxicity. Notably, P-THPs release THP under acidic conditions within tumor tissue; however, this release occurs solely outside tumor cells due to HPMA-mediated inhibition of cellular uptake. The author is currently developing macromolecular anticancer drugs using albumin for the tumor-targeted release of anticancer agents both intra- and extracellularly. The strategic development of tumor-targeting macromolecular antitumor drugs based on a comprehensive understanding of polymer characteristics and the tumor-specific environment is imperative for effective cancer therapy.

Many anticancer drugs, including anthracycline drugs, pose a risk of cardiovascular damage as an adverse reaction. This can detrimentally impact the prognosis and quality of life of patients, potentially leading to the interruption of cancer chemotherapy and compromising cancer treatment. Recently, onco-cardiology (or cardio-oncology) has developed as a new interdisciplinary field that focuses on the prevention and treatment of cardiovascular toxicity of anticancer drugs. In this review, we explore the mechanism underlying the cardiotoxicity of anthracyclines and examine pharmacological agents that safeguard the heart from anthracycline-induced damage. Anthracycline-induced cardiotoxicity primarily involves oxidative stress, characterized by radical production in mitochondria and subsequent apoptosis in cardiomyocytes. While various antioxidant agents, such as resveratrol, vitamin E, and melatonin have demonstrated efficacy in reducing anthracycline-induced cardiotoxicity in animal models, their clinical effectiveness remains inconclusive. Alternatively, dexrazoxane, an intracellular iron chelator, along with standard heart failure medications, such as β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers, reduce anthracycline cardiotoxicity and prevent subsequent heart failure in both animal and human studies. Additionally, statins [hydroxymethylglutaryl (HMG)-CoA reductase inhibitors] and ranolazine have emerged as potential candidates for attenuating anthracycline-induced cardiotoxicity in clinical settings. Notably, recent in vitro findings suggest that everolimus, an autophagy/mitophagy-inducing antitumor drug, may protect cardiomyocytes from anthracycline-induced toxicity without reducing the antitumor effects of anthracycline. Although promising, further clinical research is warranted to validate the potential of everolimus as a safer and more effective anthracycline chemotherapeutic strategy.

(Purpose) We performed a clinical retrospective study on the evaluation of pembrolizumab treatment results for advanced urothelial cancer in our hospital. (Materials and Methods) Twenty-seven patients diagnosed with advanced or metastatic urothelial carcinoma who received pembrolizumab between April 2018 and December 2021 were included. We retrospectively reviewed medical records to examine treatment outcomes, immune-related adverse event (irAE), and prognostic factors. (Results) The median age of patients was 76 years, and the median number of pembrolizumab doses was 6. The median overall survival was 8.8 months, and the best treatment response according to RECIST version 1.1 was complete response 1, partial response 7, stable disease 5, and progression disease 14. Pre-pembrolizumab risk factors related to overall survival include the presence of liver metastasis, LDH ≥200 IU/L, and TSH <4 μIU/mL in univariate analysis. Grade 3 irAE was type 1 diabetes in only 1 case, and grade 2 were hypothyroidism in 4 cases, type 1 diabetes in 1 case, interstitial pneumonia in 1 case, and skin disorder in 1 case. Nine patients had a TSH of 4 μIU/mL or higher at the start of pembrolizumab, and four of them had hypothyroidism requiring oral levothyroxine, and none of the patients in the low TSH group required hormone replacement (p =0.013). (Conclusion) High TSH level before pembrolizumab administration for advanced urothelial cancer was associated with hypothyroidism, suggesting the possibility of improved prognosis.

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.

Oral anticancer drugs are standard treatments for many cancers and are expected to remain widely used. Owing to the super-aged nature of the Japanese society, the number of elderly patients with cancer is rapidly increasing. Poor adherence to oral medications owing to physical limitations and swallowing difficulties in elderly patients with cancer is a major problem affecting treatment. Therefore, a survey was conducted on the size of oral anticancer drugs marketed in Japan, and the actual prescription patterns were investigated using receipt data. The total diameter of oral anticancer drugs increased with the year of launch, with a significant increase in the long diameter of tablets. In Japan, oral anticancer drugs in tablet form with a long diameter of ≥7 mm and a total diameter of ≥21 mm accounted for 84.2% and 56.8%, respectively, of all oral anticancer drugs in tablet form. In addition, 96.8% and 42% of oral anticancer drugs in tablet form prescribed to people aged ≥65 years had a long diameter of ≥7 mm and a total diameter of ≥21 mm, respectively. Most drugs were larger than those that can be easily taken by the elderly. Furthermore, information on tablet crushing or simple suspension administration was lacking; these methods are clinically used when elderly patients have difficulty taking their medications. The results of this study suggest that adherence to oral anticancer medications may be reduced in elderly patients. Future studies should evaluate adherence to oral anticancer medicines among elderly patients.

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.