Drug Ther Bull. 2024 Feb 7:dtb-2024-000010. doi: 10.1136/dtb.2024.000010. Online ahead of print.

ABSTRACT

Overview of: Medicines and Healthcare products Regulatory Agency. Omega-3-acid ethyl ester medicines (Omacor/Teromeg 1000 mg capsules): dose-dependent increased risk of atrial fibrillation in patients with established cardiovascular diseases or cardiovascular risk factors. Drug Safety Update 2024;17(6):3.

PMID:38326011 | DOI:10.1136/dtb.2024.000010

Drug Ther Bull. 2024 Feb 7:dtb-2024-000011. doi: 10.1136/dtb.2024.000011. Online ahead of print.

ABSTRACT

Overview of: Li RHW, Lo SST, Gemzell-Danielsson K, et al. Oral emergency contraception with levonorgestrel plus piroxicam: a randomised double-blind placebo-controlled trial [correction appears in Lancet 2023;402:850]. Lancet 2023;402:851-8.

PMID:38326010 | DOI:10.1136/dtb.2024.000011

Expert Opin Drug Saf. 2024 Feb 7. doi: 10.1080/14740338.2024.2315113. Online ahead of print.

ABSTRACT

Anticancer drug-induced interstitial lung disease (DIILD) has received increasing clinical attention, and the quality of relevant guidance documents has become critical. Our purpose was to assess the quality of documents for anticancer DIILD and summarize the recommendations. Clinical practice guidelines (CPGs) and consensus statements with recommendations for the evaluation, treatment, and monitoring of anticancer DIILD were searched in electronic databases, websites of guideline organizations, and professional societies. The quality of documents was assessed using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) methodology, and the specific recommendations were aggregated and compared to analyze the consistency among documents. A total of 11 documents were eligible, including 6 CPGs and 5 consensus statements. The quality of AGREE II assessments differed greatly, both between domains of documents and between documents across domains. The domains of scope and purpose and clarity of presentation received the highest median scores, while the stakeholder involvement domain received the lowest score. Recommendations were inconsistent between documents, particularly regarding the selection of steroid regimens. The methodological quality of the guidance documents needs to be enhanced, especially in the domain of stakeholder involvement. Inconsistencies exist in documents regarding specific recommendations for evaluation, treatment and, monitoring of anticancer DIILD, and further discussions among multidisciplinary experts are needed to reach an agreement. In particular, we have focused our concerns on the differences in steroid regimens, and future research is still needed on the risks of adverse events related to hormone therapy and discovery of precise biomarkers.

PMID:38323333 | DOI:10.1080/14740338.2024.2315113

Nature. 2024 Feb;626(7998):261. doi: 10.1038/d41586-024-00301-7.

NO ABSTRACT

PMID:38321136 | DOI:10.1038/d41586-024-00301-7

Elife. 2024 Feb 6;12:RP87318. doi: 10.7554/eLife.87318.

ABSTRACT

BACKGROUND: Primaquine is an 8-aminoquinoline antimalarial. It is the only widely available treatment to prevent relapses of Plasmodium vivax malaria. The 8-aminoquinolines cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase deficiency (G6PDd). G6PDd is common in malaria endemic areas but testing is often not available. As a consequence primaquine is underused.

METHODS: We conducted an adaptive pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer primaquine radical cure regimens compared to the currently recommended 8-weekly regimen (0.75 mg/kg once weekly), potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai and Burmese male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15-20 days. In Part 2 conducted at least 6 months later, a single primaquine 45 mg dose was given.

RESULTS: 24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers, the ascending dose regimen was stopped because of haemolysis (n=1) and asymptomatic increases in transaminases (n=2; one was hepatitis E positive). Otherwise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, the median haemoglobin concentration decline was 3.7 g/dL (range: 2.1-5.9; relative decline of 26% [range: 15-40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the median haemoglobin concentration decline was 1.7 g/dL (range 0.9-4.1; relative fall of 12% [range: 7-30% decrease]). The ascending dose primaquine regimens gave seven times more drug but resulted in only double the haemoglobin decline.

CONCLUSIONS: In patients with Southeast Asian G6PDd variants, full radical cure treatment can be given in under 3 weeks compared with the current 8-week regimen.

FUNDING: Medical Research Council of the United Kingdom (MR/R015252/1) and Wellcome (093956/Z/10/C, 223253/Z/21/Z).

CLINICAL TRIAL NUMBER: Thai Clinical Trial Registry: TCTR20170830002 and TCTR20220317004.

PMID:38319064 | DOI:10.7554/eLife.87318

Lab Chip. 2024 Feb 6. doi: 10.1039/d3lc00829k. Online ahead of print.

ABSTRACT

Cardiovascular disease (CVD) is the leading cause of death worldwide, casting a substantial economic footprint and burdening the global healthcare system. Historically, pre-clinical CVD modeling and therapeutic screening have been performed using animal models. Unfortunately, animal models oftentimes fail to adequately mimic human physiology, leading to a poor translation of therapeutics from pre-clinical trials to consumers. Even those that make it to market can be removed due to unforeseen side effects. As such, there exists a clinical, technological, and economical need for systems that faithfully capture human (patho)physiology for modeling CVD, assessing cardiotoxicity, and evaluating drug efficacy. Heart-on-a-chip (HoC) systems are a part of the broader organ-on-a-chip paradigm that leverages microfluidics, tissue engineering, microfabrication, electronics, and gene editing to create human-relevant models for studying disease, drug-induced side effects, and therapeutic efficacy. These compact systems can be capable of real-time measurements and on-demand characterization of tissue behavior and could revolutionize the drug development process. In this review, we highlight the key components that comprise a HoC system followed by a review of contemporary reports of their use in disease modeling, drug toxicity and efficacy assessment, and as part of multi-organ-on-a-chip platforms. We also discuss future perspectives and challenges facing the field, including a discussion on the role that standardization is expected to play in accelerating the widespread adoption of these platforms.

PMID:38318723 | DOI:10.1039/d3lc00829k

BMJ Case Rep. 2024 Feb 5;17(2):e256956. doi: 10.1136/bcr-2023-256956.

ABSTRACT

A large percentage of the US population is either receiving or should be considered for statin therapy. Whether through primary or secondary prevention for atherosclerotic disease, statins remain one of the mainstay options available to physicians. Myalgias are the most commonly reported side effects, though largely self-limited and subjective in nature. Here, we report a case of drug-related myonecrosis following long-term use of atorvastatin. Prompt recognition of the condition and initiation of treatment is paramount to control the disease's progression. While high-dose steroids are first line, quick escalation to methotrexate, IVIG or rituximab should be considered in refractory cases. This decision is guided by monitoring of serum markers such as CK and transaminases. The goal is quick normalisation of these enzymes, signalling cessation of underlying muscle necrosis. Patients may never regain full function and treatment can last months to years.

PMID:38316487 | PMC:PMC10859973 | DOI:10.1136/bcr-2023-256956

Int J Clin Pharm. 2024 Feb 5. doi: 10.1007/s11096-023-01697-4. Online ahead of print.

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) is a multifactorial condition often induced by drugs commonly used in hospitals. Identifying and staging AKI necessitates frequent monitoring of renal function.

AIM: To assess the impact of real-world hospital practices regarding serum creatinine (SCr) testing on the identification and staging of AKI, and its implications for adjusting drug doses.

METHOD: A historical cohort study utilizing hospital records from all adult patients admitted between 01/06/2018 and 31/12/2020 was conducted. Patients with no SCr assessment during their stay or those with an SCr at admission ≥ 2 mg/dL were excluded. AKI was determined using two criteria, namely AKIN and KDIGO, considering the time intervals between two SCr tests as outlined in the criteria. Additionally, patients with SCr increases exceeding AKI limits, regardless the time interval, were also identified. The estimated glomerular filtration rate (eGFR) and kinetic eGFR (KeGFR) were calculated.

RESULTS: During the study period, 17,269 hospitalizations and 62,255 SCr tests were recorded. Among the 17,032 hospitalizations with a length of stay > 48 h, 46.8% experienced periods with no SCr tests performed for more than 48 h. Any stage of AKI was identified in 7.0% of patients and in 9.1% using AKI and KDIGO criteria, respectively. Ignoring time limits in both criteria revealed potential AKI in 1942 patients (11.2%), indicating a potential underdiagnosis of AKI by 37.5% or 19.1%, depending on the criteria used. A total of 76 drugs requiring dose adjustment in patients with eGFR ≤ 50 ml/min were prescribed in 78.5% admissions. These drugs were prescribed in 87.9% of patients potentially underdiagnosed with AKIN and in 88.9% with KDIGO.

CONCLUSION: There is a need for changes in the established hospital procedures to ensure more frequent testing of SCr levels. Implementing an advanced scope of practice for clinical pharmacists could support these changes.

PMID:38315304 | DOI:10.1007/s11096-023-01697-4

Drug Des Devel Ther. 2024 Jan 30;18:165-192. doi: 10.2147/DDDT.S445555. eCollection 2024.

ABSTRACT

Cardiovascular diseases (CVDs) are the most common cause of death worldwide and has been the focus of research in the medical community. Curcumin is a polyphenolic compound extracted from the root of turmeric. Curcumin has been shown to have a variety of pharmacological properties over the past decades. Curcumin can significantly protect cardiomyocyte injury after ischemia and hypoxia, inhibit myocardial hypertrophy and fibrosis, improve ventricular remodeling, reduce drug-induced myocardial injury, improve diabetic cardiomyopathy(DCM), alleviate vascular endothelial dysfunction, inhibit foam cell formation, and reduce vascular smooth muscle cells(VSMCs) proliferation. Clinical studies have shown that curcumin has a protective effect on blood vessels. Toxicological studies have shown that curcumin is safe. But high doses of curcumin also have some side effects, such as liver damage and defects in embryonic heart development. This article reviews the mechanism of curcumin intervention on CVDs in recent years, in order to provide reference for the development of new drugs in the future.

PMID:38312990 | PMC:PMC10838105 | DOI:10.2147/DDDT.S445555

Clin Pharmacol Drug Dev. 2024 Feb 4. doi: 10.1002/cpdd.1371. Online ahead of print.

ABSTRACT

Baxdrostat is a selective small-molecule aldosterone synthase inhibitor in development for treatment of hypertension and chronic kidney disease. This phase 1, open-label, parallel-group study assessed the safety and pharmacokinetics (PK) of baxdrostat in participants with varying degrees of renal function. Participants were enrolled into control (estimated glomerular filtration rate [eGFR] ≥60 mL/min), moderate to severe renal impairment (eGFR 15-59 mL/min), or kidney failure (eGFR <15 mL/min) groups and received a single 10-mg baxdrostat dose followed by 7 days of inpatient PK blood and urine sampling. Safety was assessed by adverse events, clinical laboratory evaluations, vital signs, physical examinations, and electrocardiograms (ECGs). Thirty-2 participants completed the study. There were no deaths and only 1 mild drug-related adverse event (diarrhea). No clinically meaningful changes in laboratory values, vital signs, physical examinations, or ECGs occurred. Plasma concentration-time curves of baxdrostat were similar among all groups. Urine PK parameters were similar (approximately 12% excreted) in the moderate to severe renal impairment and control groups. Inadequate urine production in the kidney failure group resulted in minimal urinary baxdrostat excretion. Renal impairment had no significant impact on systemic exposure or clearance of baxdrostat, suggesting that dose adjustment due to PK differences in patients with kidney disease is unnecessary.

PMID:38311833 | DOI:10.1002/cpdd.1371

Drug Metab Rev. 2024 Feb 4:1-38. doi: 10.1080/03602532.2024.2313967. Online ahead of print.

ABSTRACT

Many drugs that serve as first-line medications for the treatment of depression are associated with severe side effects, including liver injury. Of the 34 antidepressants discussed in this review, four have been withdrawn from the market due to severe hepatotoxicity, and others carry boxed warnings for idiosyncratic liver toxicity. The clinical and economic implications of antidepressant-induced liver injury are substantial, but the underlying mechanisms remain elusive. Drug-induced liver injury may involve the host immune system, the parent drug, or its metabolites, and reactive drug metabolites are one of the most commonly referenced risk factors. Although the precise mechanism by which toxicity is induced may be difficult to determine, identifying reactive metabolites that cause toxicity can offer valuable insights for decreasing the bioactivation potential of candidates during the drug discovery process. A comprehensive understanding of drug metabolic pathways can mitigate adverse drug-drug interactions that may be caused by elevated formation of reactive metabolites. This review provides a comprehensive overview of the current state of knowledge on antidepressant bioactivation, the metabolizing enzymes responsible for the formation of reactive metabolites, and their potential implication in hepatotoxicity. This information can be a valuable resource for medicinal chemists, toxicologists, and clinicians engaged in the fields of antidepressant development, toxicity, and depression treatment.

PMID:38311829 | DOI:10.1080/03602532.2024.2313967

Urol Int. 2024 Feb 2. doi: 10.1159/000536563. Online ahead of print.

ABSTRACT

INTRODUCTION: We evaluated the effectiveness and safety profile of the tyrosine kinase inhibitor Sunitinib in patients with advanced or metastatic renal cell carcinoma (a/mRCC) in a real-world setting.

METHODS: We analyzed data of adult a/mRCC patients treated with Sunitinib. Data was derived from the German non-interventional post-approval multicenter STAR-TOR registry (NCT00700258). Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated using descriptive statistics and survival analyses for the entire cohort and patient subgroups.

RESULTS: A total of 116 study sites recruited 702 patients treated with Sunitinib (73.1% male; median age 68.0 years; median Karnofsky Index 90%) between November 2010 and May 2020. The most frequent histological subtype was clear cell RCC (ccRCC) (81.6%). Sunitinib was administered as first-line treatment in 83.5%, as second line in 11.7%, and as third line or beyond in 4.8% of the patients. Drug related AEs and serious AEs were reported in 66.3% and 13.9% of the patients, respectively (most common AE: gastrointestinal disorders; 39.7% of all patients).

CONCLUSIONS: This study adds further real-world evidence of the persisting relevance of Sunitinib for patients with a/mRCC who cannot receive or tolerate immune checkpoint inhibitors. The study population includes a high proportion of patients with unfavorable MSKCC poor-risk score, but shows still good PFS and OS results, while the drug demonstrates a favorable safety profile.

PMID:38310863 | DOI:10.1159/000536563

Int J Clin Oncol. 2024 Feb 4. doi: 10.1007/s10147-023-02460-5. Online ahead of print.

ABSTRACT

INTRODUCTION: Male breast cancer, comprising approximately 1% of all breast cancer cases, often leads to the exclusion of male patients as a criterion in clinical trials. While the efficacy of Cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors has been established in metastatic hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-negative (HER2 -) breast cancer in women, limited data exist on their effectiveness in male patients. We aimed to evaluate the efficacy and safety of palbociclib or ribociclib in male patients with breast cancer.

METHODS: This study is a multicenter, retrospective study. We included male patients with HR + and HER2-metastatic breast cancer who received palbociclib or ribociclib as first-line treatment. Our primary endpoints were progression-free survival (PFS), overall response rates (ORR), and drug-related adverse effects.

RESULTS: A total of 46 male patients from 27 institutions were enrolled. The median age at initiation of CDK 4/6 inhibitors was 63.64 ± 13.69 years, with a median follow-up of 21.33 (95% CI 14.92-27.74) months. The ORR were 84% for palbociclib and 76.2% for ribociclib. The mPFS for the entire cohort was 28.06 months (95% CI 18.70-37.42). No significant difference in PFS was observed between palbociclib and ribociclib (mPFS: 24.46 months (95% CI 11.51-37.42) vs 28.33 months (95% CI 14.77-41.88), respectively, p = 0.211). No new adverse events were reported.

DISCUSSION: This study demonstrates that palbociclib and ribociclib are effective and safe options for first-line treatment in male patients with HR + /HER2 - metastatic breast cancer. However, further prospective studies are warranted to establish their efficacy in this population.

PMID:38310597 | DOI:10.1007/s10147-023-02460-5

Adv Ther. 2024 Feb 4. doi: 10.1007/s12325-024-02780-6. Online ahead of print.

ABSTRACT

INTRODUCTION: In contrast to the antihypertensive effect of esaxerenone, there is little evidence of its cardioprotective effect. We investigated the efficacy and safety of esaxerenone in patients with uncontrolled hypertension and left ventricular hypertrophy taking a renin-angiotensin system inhibitor (RASi) or calcium-channel blocker (CCB).

METHODS: This was a multicenter, open-label, exploratory study with a 24-week treatment period. Esaxerenone was orally administered at an initial dose of 2.5 mg/day (maximum dose: 5 mg/day). The primary endpoints were the change in morning home systolic blood pressure (BP)/diastolic BP and change and percentage change in left ventricular mass index (LVMI) from baseline to end of treatment (EOT). Key secondary endpoints included change from baseline in bedtime home and office BP, achievement rate of target BP, and safety.

RESULTS: In total, 60 patients were enrolled. Morning home systolic/diastolic BP was significantly decreased from baseline to EOT in the total population (- 11.5/ - 4.7 mmHg, p < 0.001) and in both the RASi and CCB subcohorts (all p < 0.01). Significant reductions in bedtime home and office BP were shown in the total population and both subcohorts. LVMI was also significantly decreased from baseline to EOT in the total population (- 9.9 g/m2, - 8.5%, both p < 0.001) and both subcohorts (all p < 0.05). The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 35.0% and 3.3%, respectively; most were mild or moderate. No new safety concerns were identified.

CONCLUSION: Esaxerenone showed favorable antihypertensive and cardioprotective effects and safety in hypertensive patients with cardiac hypertrophy.

TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs071190043).

PMID:38310194 | DOI:10.1007/s12325-024-02780-6

Comput Biol Med. 2024 Jan 28;170:108040. doi: 10.1016/j.compbiomed.2024.108040. Online ahead of print.

ABSTRACT

Tyrosine kinase inhibitors (TKIs) are highly efficient small-molecule anticancer drugs. Despite the specificity and efficacy of TKIs, they can produce off-target effects, leading to severe liver toxicity, and even some of them are labeled as black box hepatotoxicity. Thus, we focused on representative TKIs associated with severe hepatic adverse events, namely lapatinib, pazopanib, regorafenib, and sunitinib as objections of study, then integrated drug side-effect data from United State Food and Drug Administration (U.S. FDA) and network pharmacology to elucidate mechanism underlying TKI-induced liver injury. Based on network pharmacology, we constructed a specific comorbidity module of high risk of serious adverse effects and created drug-disease networks. Enrichment analysis of the networks revealed the depletion of all-trans-retinoic acid and the involvement of down-regulation of the HSP70 family-mediated endoplasmic reticulum (ER) stress as key factors in TKI-induced liver injury. These results were further verified by transcription data. Based on the target prediction results of drugs and reactive metabolites, we also shed light on the association between toxic metabolites and severe hepatic adverse reactions, and thinking HSPA8, HSPA1A, CYP1A1, CYP1A2 and CYP3A4 were potential therapeutic or preventive targets against TKI-induced liver injury. In conclusion, our research provides comprehensive insights into the mechanism underlying severe liver injury caused by TKIs, offering a better understanding of how to enhance patient safety and treatment efficacy.

PMID:38308871 | DOI:10.1016/j.compbiomed.2024.108040

Pharmacogenomics. 2024 Jan;25(2):97-111. doi: 10.2217/pgs-2023-0173. Epub 2024 Feb 2.

ABSTRACT

HLA alleles, part of the major histocompatibility complex, are strongly associated with adverse drug reactions (ADRs). This review focuses on HLA-B*15:02 and explores its association with ADRs in various ethnic populations and with different drugs, aiming to provide insights into the safe clinical use of drugs and minimize the occurrence of ADRs. Furthermore, the review explores the potential mechanisms by which HLA-B*15:02 may be associated with ADRs, aiming to gain new insights into drug modification and identification of haptens. In addition, it analyzes the frequency of the HLA-B*15:02, genotyping methods, cost-effectiveness and treatment measures for adverse reactions, thereby providing a theoretical basis for formulating clinical treatment plans.

PMID:38305022 | DOI:10.2217/pgs-2023-0173

PLoS One. 2024 Feb 2;19(2):e0296511. doi: 10.1371/journal.pone.0296511. eCollection 2024.

ABSTRACT

Breast cancer responds variably to anticancer therapies, often leading to significant off-target effects. This study proposes that the variability in tumour responses and drug-induced adverse events is linked to the transcriptional profiles of cell surface receptors (CSRs) in breast tumours and normal tissues. We analysed multiple datasets to compare CSR expression in breast tumours with that in non-cancerous human tissues. Our findings correlate the drug responses of breast cancer cell lines with the expression levels of their targeted CSRs. Notably, we identified distinct differences in CSR expression between primary breast tumour subtypes and corresponding cell lines, which may influence drug response predictions. Additionally, we used clinical trial data to uncover associations between CSR gene expression in healthy tissues and the incidence of adverse drug reactions. This integrative approach facilitates the selection of optimal CSR targets for therapy, leveraging cell line dose-responses, CSR expression in normal tissues, and patient adverse event profiles.

PMID:38306344 | PMC:PMC10836680 | DOI:10.1371/journal.pone.0296511

Curr Hypertens Rep. 2024 Feb 2. doi: 10.1007/s11906-024-01293-5. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: To summarise the evidence regarding which patients might benefit from deprescribing antihypertensive medications.

RECENT FINDINGS: Older patients with frailty, multi-morbidity and subsequent polypharmacy are at higher risk of adverse events from antihypertensive treatment, and therefore may benefit from antihypertensive deprescribing. It is possible to examine an individual's risk of these adverse events, and use this to identify those people where the benefits of treatment may be outweighed by the harms. While such patients might be considered for deprescribing, the long-term effects of this treatment strategy remain unclear. Evidence now exists to support identification of those who are at risk of adverse events from antihypertensive treatment. These patients could be targeted for deprescribing interventions, although the long-term benefits and harms of this approach are unclear.

PERSPECTIVES: Randomised controlled trials are still needed to examine the long-term effects of deprescribing in high-risk patients with frailty and multi-morbidity.

PMID:38305846 | DOI:10.1007/s11906-024-01293-5

Front Immunol. 2024 Jan 18;14:1272450. doi: 10.3389/fimmu.2023.1272450. eCollection 2023.

ABSTRACT

Chemotherapy combined with immunotherapy has significantly improved survival in patients with extensive-stage small cell lung cancer (ES-SCLC), and neoadjuvant immunotherapy combined with chemotherapy has emerged as the standard treatment for those with resectable non-small cell lung cancer (NSCLC). However, the potential benefits of surgery following neoadjuvant immunotherapy combined with chemotherapy in locally advanced SCLC remain unclear. Herein, we report a patient diagnosed with stage IIIB SCLC, who was administered five cycles of neoadjuvant serplulimab combined with chemotherapy followed by surgery, and subsequently achieved a pathologic complete response (pCR). Within a follow-up duration of six months, the patient displayed neither recurrence nor metastasis and experienced no treatment-related adverse reactions of any grade. Based on this case, for locally advanced SCLC, neoadjuvant serplulimab combined with chemotherapy followed by surgery may present an effective, safe, and potentially curative treatment strategy. Nonetheless, further prospective studies are needed to verify our findings.

PMID:38304254 | PMC:PMC10830647 | DOI:10.3389/fimmu.2023.1272450

Gan To Kagaku Ryoho. 2023 Dec;50(13):1906-1908.

ABSTRACT

A 69-year-old male patient with descending colon cancer with para-aortic lymph node metastasis underwent surgery to resect the primary tumor. After the surgery mFOLFOX6 plus panitumumab was introduced. Because 2 times drug-induced lung disease and Stevens Johnson syndrome were occurred, changes in chemotherapy regimen were required. 18 months after administration, complete response was achieved. The chemotherapy was discontinued 48 months after administration. He is alive without recurrence for 32 months after completion of treatment.

PMID:38303248