[History and Perspective of Chemotherapy in Advanced Esophageal Cancer].

Advanced esophageal carcinoma is one of the diseases with a poor prognosis. CF(cisplatin plus 5-FU)therapy and taxanes( paclitaxel or docetaxel)were considered standard treatments for first- and second-line treatment of advanced esophageal carcinoma based on the results of phase Ⅱ trials, although no randomized controlled trials were conducted. Subsequently, anti-epidermal growth factor receptor(EGFR)inhibitors, which had shown efficacy in head and neck cancer and colorectal cancer, were developed but failed to prolong survival both first- and second-line treatment. Immune checkpoint inhibitors have shown efficacy as single agents or in combination with chemotherapy in a variety of cancers, including esophageal cancer, where the KEYNOTE-181 trial and the ATTRACTION-3 trial demonstrated that single-agent pembrolizumab and nivolumab extended survival versus chemotherapy, respectively. In addition, the KEYNOTE-590 trial and the CheckMate 648 trial showed that pembrolizumab plus CF therapy was superior to CF, and nivolumab plus CF therapy and nivolumab plus ipilimumab were superior to CF in advanced esophageal carcinoma. These combinations have become the standard of care for the first-line treatment of advanced esophageal cancer. Immune checkpoint inhibitors had prolonged survival, but the results are still unsatisfactory, and CF therapy combined with immune checkpoint inhibitors and novel agents is being investigated. This article reviews the history of chemotherapy in advanced or recurrent esophageal cancer and discusses future prospects.

Immunotherapy for Unresectable Small Bowel Adenocarcinoma: A Case Series.

BACKGROUND/AIM: The efficacy of systemic therapy for unresectable small bowel adenocarcinoma that is refractory to fluoropyrimidines and oxaliplatin has not yet been established because of the rarity of this cancer. Although immunotherapy with anti-PD-1 antibodies has shown robust efficacy in the treatment of esophagogastric adenocarcinoma, its effectiveness in small bowel adenocarcinoma remains unclear. CASE REPORT: In the first case, a 75-year-old man was diagnosed with metastatic moderately differentiated adenocarcinoma of the jejunum with stable microsatellite instability. After receiving multiple lines of therapy, including fluoropyrimidines plus oxaliplatin, irinotecan, and paclitaxel, the patient was treated with nivolumab and achieved a partial response that lasted for 12 months. In the second case, a 65-year-old man was diagnosed with an unresectable locally advanced duodenal adenocarcinoma. High microsatellite instability was confirmed by polymerase chain reaction-based testing. After showing resistance to 5-fluorouracil and oxaliplatin, the patient received nivolumab and ipilimumab therapy. Although therapy was discontinued because of immune-related colitis and skin rash, a partial response was achieved. CONCLUSION: Treatment with immune checkpoint inhibitors is effective for refractory small bowel adenocarcinoma, irrespective of the microsatellite status.

Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM).

Therapeutic options for breast cancer patients with brain metastases (BM)/leptomeningeal carcinomatosis (LMC) are limited. Here, we report on the effectiveness and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2-positive breast cancer patients with BM. Data were analyzed for 104 patients administered T-DXd. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), intracranial (IC)-ORR, and IC-PFS were evaluated. ORR by investigator assessment was 55.7% (total population). Median PFS was 16.1 months; 12-month OS rate was 74.9% (total population). Median time-to-treatment failure was 9.7 months. In 51 patients with BM imaging, IC-ORR and median IC-PFS by independent central review were 62.7% and 16.1 months, respectively. In 19 LMC patients, 12-month PFS and OS rates were 60.7% and 87.1%, respectively. T-DXd showed effectiveness regarding IC-ORR, IC-PFS, PFS, and OS in breast cancer patients with BM/active BM, and sustained systemic and central nervous system disease control in LMC patients.Trial Registration: UMIN000044995.

The Impact of Nutritional Support on Survival Outcomes in Patients with Advanced Gastric Adenocarcinoma Treated with Chemotherapy.

Malnutrition and cachexia occur commonly in patients with advanced gastric cancer (AGC). This study elucidated the effect of nutritional support (NS) on survival outcomes among patients with AGC undergoing chemotherapy. We retrospectively evaluated new AGC cases at our institute between January 2015 and January 2021. Inclusion criteria were unresectable or recurrent chemotherapy-treated gastric adenocarcinoma, ECOG performance status (PS) 0-2, and adequate organ function. Time to treatment failure (TTF) and overall survival (OS) were evaluated, and univariate and multivariate analyses identified prognostic factors. A total of 103 eligible patients were separated into groups: 69 patients (67%) into NS and 34 (33%) into routine care (RC). The median follow-up time was 11.0 mo, (0.5-92). NS was offered to patients with poorer PS (p = 0.03), Glasgow prognostic score (GPS) positivity (p = 0.001), and high neutrophil-to-lymphocyte ratios (cut-off ≤ 3, p = 0.02). Median OS and TTF in the RC and NS groups were 11.6 and 10.4 mo, (p = 0.99) and 4.2 and 5.5 mo, (p = 0.07), respectively. Multivariate analyses identified NS (hazard ratio [HR] = 0.53, p = 0.01) and GPS positivity for TTF, and low body mass index (HR = 2.03, p = 0.007) and GPS positivity (HR = 2.25, p = 0.001) for OS as significant prognostic factors. Thus, NS with chemotherapy is a potentially effective intervention for AGC.

Successful Alectinib Treatment for Carcinoma of Unknown Primary with EML4-ALK Fusion Gene: A Case Report.

Gene alteration in anaplastic lymphoma kinase (ALK) is rare, and the efficacy of ALK inhibitors in the treatment of carcinoma of unknown primary (CUP) with ALK alteration remains unclear. The patient was a 56-year-old woman who presented with cervical lymph node swelling. Computed tomography revealed paraaortic, perigastric, and cervical lymph node swelling; ascites; a liver lesion; and a left adrenal mass. A cervical lymph node biopsy was performed, and pathological diagnosis of an undifferentiated malignant tumor was conducted. Finally, the patient was diagnosed with CUP and treated with chemotherapy. To evaluate actionable mutations, we performed a multigene analysis, using a next-generation sequencer (FoundationOne® CDx). It revealed that the tumor harbored an echinoderm microtubule-associated protein-like 4 (EML4) and ALK fusion gene. Additionally, immunohistochemistry confirmed ALK protein expression. Alectinib, a potent ALK inhibitor, was recommended for the patient at a molecular oncology conference at our institution. Accordingly, alectinib (600 mg/day) was administered, and the multiple lesions and symptoms rapidly diminished without apparent toxicity. The administration of alectinib continued for a period of 10 months without disease progression. Thus, ALK-tyrosine kinase inhibitors should be considered in patients with CUP harboring the EML4-ALK fusion gene.

Efficacy of trastuzumab deruxtecan in an advanced gastric cancer patient with brain metastasis.

BACKGROUND: There is no clinical evidence supporting the effectiveness of trastuzumab deruxtecan (T-DXd) for treating advanced gastric cancer (AGC) with brain metastasis. CASE REPORT: This is a case of a 65-year-old man with human epidermal growth factor-2 (HER2)-positive AGC. He was initially treated with capecitabine, cisplatin, and trastuzumab, followed by paclitaxel and ramucirumab, nivolumab, trifluridine and tipiracil, and irinotecan regimens in addition to radiation therapy for brain metastasis. The patient exhibited refractoriness to the standard regimen used for AGC and developed relapse of the brain metastasis after radiation accompanied by headache, nausea, and dizziness. In August 2020, following the approval of T-DXd for HER2-positive AGC, he received T-DXd therapy. After 5 cycles of T-DXd, contrast-enhanced computed tomography and magnetic resonance imaging demonstrated significant tumor shrinkage and improvement of symptoms. CONCLUSION: T-DXd demonstrated effectiveness for the treatment of brain metastasis arising from HER2-positive AGC.

Salvage Chemotherapy by FOLFIRI Regimen for Poorly Differentiated Gastrointestinal Neuroendocrine Carcinoma.

PURPOSE: Chemotherapy is the mainstay treatment for advanced poorly differentiated gastrointestinal neuroendocrine carcinoma (GI-NEC), with platinum-containing regimens being the optimal first-line regimen. However, the role and efficacy of second-line chemotherapy for GI-NEC are unclear. This study aimed to evaluate the feasibility and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line therapy in patients with relapsed or recurrent GI-NEC after first-line platinum plus etoposide therapy. METHODS: We retrospectively evaluated eight consecutive patients with unresectable GI-NEC treated between 2017 and 2020. The inclusion criteria were pre-treatment with platinum doublet therapy, performance status (PS) 0-2, having measurable lesions, and treatment with FOLFIRI as second-line therapy. The overall response rate, progression-free survival (PFS), overall survival (OS), safety, and relative dose intensity were evaluated. RESULTS: Five patients met the inclusion criteria. Overall, 37 cycles of FOLFIRI were administered. The relative dose intensities for irinotecan, continuous infusion of 5-FU, and a bolus injection of 5-FU were 76%, 72%, and 54%, respectively. Overall, 2 of the 5 patients achieved partial response (40%), and the duration of response (DOR) was 4.0 months. The PFS and OS rates were 5.8 (95% CI, 1.5-NA) and 11 (95% CI, 6.3-NA) months, respectively. Overall, 4 of the 5 patients (80%) proceeded with further chemotherapy. Grade ≥ 3 adverse events except hematological toxicity included febrile neutropenia (n = 2), anorexia (n = 2), and fatigue (n = 1). Treatment discontinuation due to treatment-related adverse events was not observed. CONCLUSIONS: FOLFIRI showed modest efficacy and feasibility for GI-NEC patients and has thus potential for patients who fail the first-line treatment.

Early phase 2 trial of TAS-205 in patients with Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is a progressive muscular disease characterized by chronic cycles of inflammatory and necrotic processes. Prostaglandin D2 (PGD2 ) is produced by hematopoietic PGD synthase (HPGDS), which is pathologically implicated in muscle necrosis. This randomized, double-blind, placebo-controlled early phase 2 study (NCT02752048) aimed to assess the efficacy and safety of the novel selective HPGDS inhibitor, TAS-205, with exploratory measures in male DMD patients aged ≥5 years. METHODS: Patients were randomized 1:1:1 to receive low-dose TAS-205 (6.67-13.33 mg/kg/dose), high-dose TAS-205 (13.33-26.67 mg/kg/dose), or placebo. The primary endpoint was the change from baseline in a 6-minute walk distance (6MWD) at Week 24. RESULTS: Thirty-six patients were enrolled, of whom 35 patients were analysed for safety. The mean (standard error) changes from baseline to Week 24 in 6MWD were -17.0 (17.6) m in the placebo group (n = 10), -3.5 (20.3) m in the TAS-205 low-dose group (n = 11), and -7.5 (11.2) m in the TAS-205 high-dose group (n = 11). The mean (95% confidence interval) difference from the placebo group was 13.5 (-43.3 to 70.2) m in the TAS-205 low-dose group and 9.5 (-33.3 to 52.4) m in the TAS-205 high-dose group. No obvious differences were observed in the incidences of adverse events between treatment groups. No adverse drug reactions specific to TAS-205 treatment were observed. INTERPRETATION: The HPGDS inhibitor TAS-205 showed a favorable safety profile in DMD patients. Further research is required to examine the effectiveness of TAS-205 in a larger trial.

Solvent-based paclitaxel or nab-paclitaxel for heavily treated relapsed/refractory small cell lung cancer: Retrospective single-institution observational study.

Treatment options for patients with relapsed/refractory small cell lung cancer (R/R SCLC) are limited, and the efficacy of salvage therapies for heavily treated patients should be assessed. Here, we evaluated the efficacy of paclitaxel (PTX) in R/R SCLC patients.A single-institute retrospective chart review was conducted. The primary endpoint was overall survival (OS), whereas the secondary endpoints were progression-free survival (PFS), overall response rate, disease control rate (DCR), and safety.Thirty-one patients (median age, 69 [range, 56-80] years) were analyzed. The median follow-up period was 122 (range, 28-1121) days. The median OS and PFS were 4.4 and 2.2 months, respectively. Adverse events of grade 3 or higher, other than hematological toxicity, were febrile neutropenia and neuropathy. Multivariate analyses identified the following independent predictors of poor OS: performance status and lactate dehydrogenase at the upper limit of normal.PTX monotherapy showed moderate efficacy with acceptable toxicity in heavily treated patients with R/R SCLC patients.

Primary Mediastinal HER2-positive Apocrine Carcinoma in Mature Teratoma Treated With Anti-HER2 Therapy and Chemoradiation.

BACKGROUND: There are no established guidelines for the management of apocrine carcinomas of the breast; they are treated as a non-specific type of breast cancer. CASE REPORT: We report on the case of a 40-year-old man who developed primary mediastinal apocrine carcinoma overexpressing human epidermal growth factor-2 (HER2). The patient initially underwent complete resection of a mediastinal mature teratoma with a focal apocrine carcinoma component. Two years after surgery, relapse was detected in multiple mediastinal lymph nodes. He received induction chemotherapy including docetaxel, trastuzumab, and pertuzumab; consolidative concurrent chemoradiation was added after six cycles. A complete response was confirmed using computed tomography following this multimodal therapy. After chemoradiation, adjuvant trastuzumab and pertuzumab were administered for 1 year and the patient has since had no evidence of progressive disease. CONCLUSION: A multi-modal regimen that includes an anti-HER2 agent appears to be a promising treatment for patients with HER2-positive extramammary apocrine carcinoma.

Mutations in the C-terminal domain of ColQ in endplate acetylcholinesterase deficiency compromise ColQ-MuSK interaction.

Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is mostly composed of an asymmetric form in which three tetramers of catalytic AChE subunits are linked to a triple helical collagen Q (ColQ). Mutations in COLQ cause endplate AChE deficiency. We report three patients with endplate AChE deficiency with five recessive COLQ mutations. Sedimentation profiles showed that p.Val322Asp and p.Arg227X, but not p.Cys444Tyr, p.Asp447His, or p.Arg452Cys, inhibit formation of triple helical ColQ. In vitro overlay of mutant ColQ-tailed AChE on muscle sections of Colq(-/-) mice revealed that p.Cys444Tyr, p.Asp447His, and p.Arg452Cys in the C-terminal domain (CTD) abrogate anchoring ColQ-tailed AChE to the NMJ. In vitro plate-binding assay similarly demonstrated that the three mutants inhibit binding of ColQ-tailed AChE to MuSK. We also confirmed the pathogenicity of p.Asp447His by treating Colq(-/-) mice with adeno-associated virus serotype 8 carrying mutant COLQ-p.Asp447His. The treated mice showed no improvement in motor functions and no anchoring of ColQ-tailed AChE at the NMJ. Electroporation of mutant COLQ harboring p.Cys444Tyr, p.Asp447His, and p.Arg452Cys into anterior tibial muscles of Colq(-/-) mice similarly failed to anchor ColQ-tailed AChE at the NMJ. We proved that the missense mutations in ColQ-CTD cause endplate AChE deficiency by compromising ColQ-MuSK interaction at the NMJ.

Loss of Borealin/DasraB leads to defective cell proliferation, p53 accumulation and early embryonic lethality.

Borealin/DasraB is a member of the chromosomal passenger protein complex (CPC) required for proper segregation of chromosomes during mitosis. In Drosophila melanogaster, inactivation of Borealin/DasraB results in polyploidy, delayed mitosis and abnormal tissue development, indicating its critical role for cell proliferation. However, the in vivo role of mammalian Borealin/DasraB remains unclear. Here, we analyzed the expression of Borealin/DasraB and found that borealin is widely expressed in embryonic tissues and later restricted to adult tissues which relies on rapid cell proliferation. To determine the role of borealin during mouse development, we generated borealin-null mice through targeted disruption. While heterozygous mice developed normally, disruption of both borealin alleles resulted in early embryonic lethality by 5.5 dpc (days postcoitus) due to mitotic defects and apoptosis in blastocyst cells that showed microtubule disorganization and no CPC enrichment. At 5.5 dpc, borealin-null embryos exhibited excessive apoptosis and elevated expression of p53. However, loss of p53 did not abrogate or delay embryonic lethality, revealing that Borealin/DasraB inactivation triggered impaired mitosis and apoptosis though p53-independent mechanisms. Our data show that Borealin/DasraB is essential for cell proliferation during early embryonic development, and its early embryonic lethality cannot be rescued by the loss of p53.

A neurosphere-derived factor, cystatin C, supports differentiation of ES cells into neural stem cells.

Although embryonic stem (ES) cells are capable of unlimited proliferation and pluripotent differentiation, effective preparation of neural stem cells from ES cells are not achieved. Here, we have directly generated under the coculture with dissociated primary neurosphere cells in serum-free medium and the same effect was observed when ES cells were cultured with conditioned medium of primary neurosphere culture (CMPNC). ES-neural stem cells (NSCs) could proliferate for more than seven times and differentiate into neurons, astrocytes, and oligodendrocytes in vitro and in vivo. The responsible molecule in CMPNC was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, which turned out to be cystatin C. Purified cystatin C in place of the CMPNC could generate ES-NSCs efficiently with self-renewal and multidifferentiation potentials. These results reveal the validity of cystatin C for generating NSCs from ES cells.

[Postoperative complete atrioventricular block induced by carbamazepine in a patient with congenital heart disease].

We report here a boy with epilepsy and congenital heart defect, complicated postoperatively by complete atrioventricular (A-V) block caused by an adverse effect of carbamazepine (CBZ). He had been taking CBZ for 7 years to treat complex partial seizures. He also had endocardial cushion defect and first-degree A-V block, and underwent cardiac surgery at the age of 17 years. The postoperative course was unremarkable except transient complete left bundle branch block occuring one day after the surgery. Oral CBZ (400 mg per day) was continued. Five days after the surgery, bradycardia (20 beats per minute) suddenly developed, and electrocardiography (ECG) showed complete A-V block. Pervenous pacing was begun, and the heart rate gradually recovered. CBZ was discontinued on the suspicion that it caused the arrhythmia, although its serum level was estimated to be within the therapeutic range (4 to 5 microg/ml). He underwent pervenous pacing for 12 days. He was discharged 27 days after the surgery, when ECG returned to first-degree A-V block. In this case, the cardiac conduction system was affected by an adverse effect of CBZ, in combination with the preoperative first-degree A-V block and the effects of cardiac surgery, resulting in complete A-V block. Although reports of similar cases are scarce, caution should be made in prescribing CBZ to patients who either have cardiac conduction abnormalities or undergo cardiac surgery.