The prognosis of patients with B-cell non-Hodgkin lymphoma (B-NHL) has improved with the use of anti-CD20 based immunochemotherapy. However, management of relapsed or refractory disease remains a challenge, indicating a high unmet need for novel treatments. Epcoritamab (recombinant) is a humanized immunoglobulin G1 (IgG1) bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on B cells or tumor cells inducing T-cell mediated cytotoxicity against CD20-positive B cells. It demonstrated consistent cytotoxic effects in B-cell lymphoma cell line-derived xenograft models, patient-derived xenograft models, and cynomolgus monkey studies. Pharmacological studies in cynomolgus monkeys showed peak plasma concentrations of cytokines were lower with subcutaneous versus intravenous administration. To reduce the risk of cytokine release syndrome (CRS) and improve convenience, Epcoritamab has been developed as a subcutaneous formulation.To further reduce the risk of CRS, clinical trials utilized a priming dose and incremental dose increases. In Phase I/II overseas trials with relapsed, progressive, or refractory B-NHL patients, the recommended Phase II trial dose was determined based on safety, efficacy, and pharmacokinetic model simulation results. The Phase II dose-expansion part demonstrated the efficacy and high tolerability of epcoritamab monotherapy at the recommended dose. Similar efficacy and tolerability were observed in Japanese Phase I/II trials in relapsed or refractory B-NHL patients. Based on these results, epcoritamab received the approval in September 2023 for the treatment of "relapsed or refractory large B-cell lymphoma (DLBCL, HGBCL, PMBCL)" and "relapsed or refractory follicular lymphoma (Grade 3B)" in Japan.

Recent evidence suggests that the targeting of membrane transporters specifically activated in cancer stem cells (CSCs) is an important strategy for cancer therapy. The objectives of the present study were to investigate the ion channel expression profiles in digestive CSCs. Cells strongly expressing CSC markers, such as ALDH1A1 and CD44, were separated from the human esophageal squamous cell carcinoma, gastric cancer, and pancreatic cancer cell lines using fluorescence-activated cell sorting, and CSCs were identified based on tumorsphere formation. Messenger RNA levels of CSC markers were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to anticancer agents. The microarray analysis revealed that the expression of transient receptor potential vanilloid 2 (TRPV2), voltage-gated calcium channels (VGCCs), and voltage-gated potassium channels (VGKCs) were upregulated in esophageal, gastric, and pancreatic CSCs, respectively, compared with non-CSCs. The TRPV2 inhibitor tranilast, VGCCs inhibitors amlodipine and verapamil, and VGKC inhibitor 4-aminopyridine exhibited greater cytotoxicity in CSCs compared with non-CSCs, and their inhibitory effects were also confirmed in a xenograft model in nude mice. Taking these results, phase I/II study to investigate clinical safety and efficacy of neoadjuvant combination chemotherapy of tranilast in advanced esophageal squamous cell carcinoma (TNAC study) is ongoing. These researches identified a role of ion channels in the persistence of CSCs and suggested that their inhibitors may have potential as a therapeutic agent for digestive cancers.

On March 28th, 2022, asciminib hydrochloride (Scemblix® Tablets 20 ‍mg/40 ‍mg), the world's first tyrosine kinase inhibitor (TKI) specifically targeting the ABL myristoyl pocket (STAMP inhibitor), was approved for chronic myeloid leukemia (CML) resistant or intolerant to prior therapy. Asciminib specifically binds to the myristoyl pocket, an allosteric site of BCR::ABL1, and inhibits the ABL1 family molecules. In vitro and in vivo pharmacology studies demonstrated cell growth inhibition and antitumor effects of asciminib. The international phase I study for patients with chronic or accelerated phase CML investigated the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of asciminib monotherapy. However, the MTD was not reached, so and RDE was determined based on tolerability, safety, pharmacokinetics (PK) and preliminary efficacy data obtained by the time of the study. RDE was determined to be 40 ‍mg twice daily in chronic or accelerated phase CML without T315I mutation, and 200 ‍mg twice daily in chronic or accelerated phase CML with T315I mutation. The international phase III study for patients with chronic phase CML who were previously treated with ≥2 TKIs and resistant or intolerant to the recent treatment demonstrated the superiority of asciminib over bosutinib in achieving the primary endpoint of a major molecular response (MMR) at week 24. Regarding safety, the most common treatment-related adverse event in asciminib arm was thrombocytopenia, and others included neutropenia. Asciminib is expected to be a new treatment option for CML patients who have limited choices due to resistance or intolerance to previous therapies.

Chemotherapy induced peripheral neuropathy (CIPN) is a numbness or tingling of the hands and feet that occur as a side effect of anticancer drugs including taxanes and platinum drugs. The effective treatments or preventive strategy are not established. Once it develops, symptoms persist for a long time and cause impairment in activity of daily living. Topical cooling is a preventive strategy for side effects of chemotherapy such as hair loss, oral microsites, and skin and nail disorder of the hands and feet. We conducted a clinical trial in breast cancer patients who received paclitaxel treatment to assess the effectiveness of cooling for CIPN prevention. In this study, the individual background factor was standardized using an intra-individual comparison design. In 40 subjects, frozen gloves and socks were applied on the dominant hand and foot from 15 minutes before the anti-cancer drug administration to 15 minutes after the end of administration (total 90 minutes) and compared with non-dominant hand and foot. As a result, clinically and statistically significant differences were observed for changes in tactile threshold evaluated by the monofilament test, subjective symptoms, and changes in dexterity evaluated by functional test. The current cooling system has not been well implemented in oncology field due to the lack of facility and human resources. To deliver this therapy broadly, it will be urgent to develop a medical cooling device that can provide safe and effective cryotherapy.

Gefitinib anderlotinib, which are epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs), have been usedfor the treatment of inoperable andrecurrent non-small cell lung cancer(NSCLC)patients. These drugs are known to cause a skin rash, one of the major side effects, at a high frequency. Biotin is a water-soluble vitamin, andit belongs to the vitamin B family. It is well known that biotin deficiency increases the risk of skin dermatitis. We administered biotin to four patients with skin rash, all of whom were treatedwith either gefitinib or erlotinib andwere unable to be treatedby a steroid ointment alone. In all patients, administration of biotin reduced the skin rash. Surprisingly, in 2 patients in whom EGFR-TKI therapy was discontinued because of the skin rash, the administration of biotin allowed for long-term gefitinib or erlotinib treatment. Biotin may be considereduseful for the treatment of skin rash causedby EGFR-TKIs. Further trials may be needed to confirm the value of biotin in this setting.

Temsirolimus is an inhibitor of mammalian target of rapamycin, with proven efficacy against advanced renal cell carcinoma (RCC), particularly poor risk and/or non-clear cell RCC, in a randomized first-line phase III trial. In this trial, adverse events (AEs)≥grade 3 occurred in 47.6% of patients treated with temsirolimus alone (n＝208), and the common AEs included asthenia, anemia and hyperglycemia. During the observation period of this trial, drug-related pneumonitis was detected ; 4 patients developed temsirolimus-related pneumonitis, including 2 with ≥grade 3. To date, there have not been any reports analyzing data from a large number of Japanese RCC patients treated with temsirolimus. However, judging from our experience, the severity as well as the frequency of AEs associated with temsirolimus in Japanese patients seem to be similar to those in the Western population. In this study, we summarize our clinical experience with the use of temsirolimus focusing on its AEs and try to clarify the characteristics of temsirolimus-related AEs in Japanese patients, and then present our data relevant to this point from our clinical studies in order to discuss the significance of the management of AEs encountered during treatment with temsirolimus.

A phase I/II study of postoperative chemoradiotherapy with weekly cisplatin for head and neck squamous cell carcinoma was conducted. The eligiblity of patients were the high risk features, i. e., multiple lymph nodes metastasis(2 or more), extracapusular extension of nodal disease(ECE), or the presence of tumor at the surgical section margins(at 5mm or less). The recommended dose of CDDP in a phase I study was 30mg/m2. We performed a phase II study to assess toxicity and tolerability. We assessed 13 patients, 10 of whom were enrolled in a phase II study, and 3 patients in phase I were given the RD. Acute adverse events were rather mild, including grade 1-2 anemia(50%), mucositis(43%)and nausea/vomiting(43%). One patient required administration of CDDP to be discontinued due to grade 1 renal toxicity. The compliance rate was markedly high(85%: 11/13 patients). We consider weekly CDDP of 30mg/m2 to be a safe regimen in the setting of postoperative adjuvant chemoradiotherapy.

The present study was designed to evaluate the preventive effects of elemental diet Elental (ED) on chemotherapy-induced stomatitis in patients with colorectal cancer.

The standard of care for gastric cancer with peritoneal metastasis is chemotherapy. However, there is no chemotherapy regimen with a sufficient level of evidence, and thus S-1 plus cisplatin (CDDP), which is regarded as the standard regimen for advanced metastatic gastric cancer, is widely applied. Meanwhile the efficacy of intraperitoneal (IP) administration of taxanes has been verified, and the novel multidisciplinary treatment combining chemotherapy and surgery is now being tested. We developed a combination chemotherapy regimen of S-1, weekly intravenous and IP paclitaxel (PTX), and determined the recommended dose of IP PTX to be 20 mg/m2 in our phase I study. In our phase II study, the median survival time (MST) of 40 patients enrolled was 23.6 months, and peritoneal cytology turned negative for 86% of 28 patients. Moreover, we performed gastrectomy on 52 patients after disappearance or obvious shrinkage of peritoneal metastasis, and the MST was 34.9 months. The multidisciplinary treatment combining IP-containing chemotherapy and surgery is safe and effective for gastric cancer patients with peritoneal metastasis. We have just started a phase III trial (PHOENIX-GC trial) comparing our IP regimen versus S-1 plus CDDP.

The efficacy and safety of aprepitant(APR)were examined in cancer patients who received chemotherapy including cisplatin(CDDP)at a dose of ≥ 50mg/m2.APR was administered concomitantly with conventional antiemetic therapy to 20 patients(APR group)in a prospective study performed from May to July 2010. In addition, a retrospective study based on medical records of 20 patients(conventional therapy group)from February to April 2010 was performed.These patients received antiemetic therapy with a serotonin receptor antagonist and dexamethasone. Significantly more patients did not vomit in the 5-day study period(days 1-5).Also, severity of vomiting was significantly improved over the 5-day period and in the late phase(days 2-5)in the APR group, compared to the conventional therapy group. Loss of appetite was significantly improved over the 5-day period and the acute(day 1)and late phases, leading to increased food intake during the 5-day period and late phase. There were no adverse events with suspected involvement of APR, and the tolerability was favorable. These results suggest that APR is useful for nausea, vomiting, and appetite loss caused by CDDP, which is a highly emetic drug, and that such guideline-based antiemetic therapy might improve the quality of life of patients.

Rebamipide, a cytoprotective agent, has been suspected to attenuate oral mucositis through anti-inflammatory potentials and induction of endogenous prostaglandin synthesis. This prospective study was designed to assess the clinical efficacy of rebamipide gargle against oral mucositis, which is induced by fluoropyrimidines in patients with stomach and colorectal cancer. We first conducted a pilot study on gargle flavors, because the solution in this agent has a strong and bitter after taste. Nine kinds of flavors were prepared, and six characteristics were evaluated by ten volunteers: sourness, bitterness, sweetness, remain, after taste, and hard to drink. We determined the contents of rebamipide using HPLC, which showed stability in an acidic condition. Finally, we decided that 100% Pokka Lemon should be used as the flavor of the rebamipide solution. A clinical study was then started to compare the preventive effects rebamipide gargle and placebo have on stomatitis, quality of life (QOL), and the therapeutic effects of chemotherapy.

A standard therapeutic regimen of a 5-HT₃ receptor antagonist antiemetic agent+dexamethasone was administered as antiemetic therapy for 29 patients who received chemotherapy for colorectal cancer in the Department of Surgery at Gunma Saiseikai Maebashi Hospital, from January to March 2010. For 13 patients with delayed nausea, the therapy was changed to an aprepitant regimen (aprepitant+5-HT₃ receptor antagonist antiemetic agent+dexamethasone)to evaluate the preventive effect of aprepitant on acute and delayed nausea and vomiting. This aprepitant regimen produced a significant improvement in the primary endpoint, based on a complete response (CR) of no vomiting and no rescue treatment throughout the administration period, and in the secondary endpoint of CR in the delayed phase, with no delayed nausea. In addition, a tendency for improvement was found in other secondary endpoints: complete protection (CP) based on no vomiting, no rescue treatment, and no significant nausea throughout the observation period; no vomiting; and no significant nausea. These findings suggest that using aprepitant as an antiemetic therapy during chemotherapy for colorectal cancer may be effective for patients with nausea and vomiting that are intractable to standard therapeutic regimens.

To evaluate the effects of intravitreal bevacizumab (IVB) injections for secondary macular edema of branch retinal vein occlusion (BRVO).

It has been thought that there is a possibility that infusion speed generally affects the manifested frequency of infusion reaction and its strength. The infusion prescription time of trastuzumab should be over 90 minutes according to the package insert. In the infusion US, is possible over 30 minutes after the second time. We sought to evaluate the safety and tolerability of trastuzumab administered as a 30-minute infusion.

Recently, postoperative adjuvant chemotherapy is very popular for completely resected non-small-cell lung cancer patients, but cisplatin-based regimens are not safety and tolerable for outpatients. In this study, gemcitabine plus carboplatin regimen is selected as more safety and feasible for outpatient chemotherapy, and scheduled bi-weekly administration to reduce hematological toxity, especially thrombocytopenia. Twenty patients with completely resected non-small-cell lung cancer (pStage IA - IIIB) administered gemcitabine 1,000 mg/m2 and carboplatin area under the curve (AUC) 3 bi-weekly for 8 times at outpatient chemotherapy center except that 1st treatment was done with short stay in hospital. Of 20 patients, 13 (65%) completed the 8 times bi-weekly treatment and 7 patients incompleted because of neutropenia in 2, anemia in 1, liver dysfunction in 3, interstitial pneumonia suspected in 1. Relative dose intensity was 79%. Seven patients had grade 3/4 neutropenia, 2 had grade 3 thrombocytopenia, 2 had grade 3 anemia, and 2 had grade 3 liver dysfunction. Hematological toxity, especially thorombocytopenia are less than standard administration of gemcitabine and carboplatin regimen, so we conclude that this regimen is feasible in outpatient adjuvant chemotherapy for completely resected non-small-cell lung cancer.

We conducted a multicenter postmarketing study to investigate the efficacy and safety of reinduction therapy with a high-dose cytarabine-containing regimen for pediatric patients with relapsed or refractory acute leukemia. Seven of 13 patients (53.8%) with ALL achieved complete or partial remission, and only 1 of 6 patients (16.7%) with AML achieved partial remission. The frequent non-hematologic adverse events were gastrointestinal toxicities, such as vomiting, diarrhea and abdominal pain, as well as pyrexia and headache. Infection appeared in 9 of 20 (45%) patients. There were two death during reinduction therapy. One died of invasive bronchopulmonary aspergillosis, and the other died of intracranial hemorrhage and renal failure. These results indicated that a high-dose cytarabine regimen is effective as reinduction therapy in pediatric patients with relapsed ALL, and supportive care is essential to prevent or control treatment-related adverse events, such as infection.

LH-RH agonist is the key drug in hormonal therapy for premenopausal patients with breast cancer. It is important to reduce the pain related to injecting the LH-RH agonist, because patients must continue the medication for several years. We developed a way to reduce the pain by cooling the needle injecting site with a frozen ice pack. 18 premenopausal postoperated women filled out a questionnaire on the severity of pain upon injecting Goserelin acetate compared with the pain without this cooling method and pretreatment. We estimated the pain by a Numerical Rating Scale(NRS). The NRS scores of this cooling method revealed the pain to be significantly less than by control method(p<0. 005). This cooling method could be useful for the reduction of pain upon injecting the LH-RH agonist.

Intrahepatic cholangiocellular carcinoma after curative surgery was treated with pharmacokinetic modulation chemotherapy (PMC) as adjuvant chemotherapy.