A Japanese Patient with Gastric Cancer and Dihydropyrimidine Dehydrogenase Deficiency Presenting with DPYD Variants.

A 63-year-old Japanese male with stomach adenocarcinoma received oral 5-fluorouracil derivative, cisplatin and trastuzumab chemotherapy. On day 8, severe diarrhea and mucositis developed; chemotherapy was stopped. On day 14, the patient developed renal dysfunction and febrile neutropenia. He also suffered from pneumonia due to Candida albicans. Systemic symptoms improved after intensive conservative treatment. Best supportive care was continued until the patient died from gastric cancer. The dihydropyrimidine dehydroge-nase protein level was low at 3.18 U/mg protein. The result of DPYD genotyping revealed three variants at posi-tions 1615 (G > A), 1627 (A > G), and 1896 (T > C) in exons 13, 13, and 14, respectively.

Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency.

The effectiveness of vandetanib, an agent that targets RET, VEGFR and EGFR signaling, against EGFR-mutant lung cancer cells with PTEN loss was investigated. Two EGFR mutant non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN null), were used. We transfected an intact PTEN gene into H1650 cells and knocked down PTEN expression in PC-9 cells using shRNA. The effectiveness of gefitinib and vandetanib was assessed using a xenograft model. While PC-9 cells were more resistant to vandetanib than gefitinib, H1650 cells were more sensitive to vandetanib than gefitinib. Both gefitinib and vandetanib suppressed the activation of EGFR and MAPK in H1650 cells, although phosphorylated AKT levels were not affected. In an H1650 cell xenograft model, vandetanib was also more effective than gefitinib. Although PTEN-transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro, the xenograft tumors responded to gefitinib and vandetanib. Knockdown of PTEN in PC-9 cells caused resistance to gefitinib. In conclusion, vandetanib might be effective in NSCLC with EGFR mutations that lack PTEN expression. The contribution of PTEN absence to vandetanib activity in NSCLC cells harboring EGFR mutations should be further examined.

Sutimlimab suppresses SARS-CoV-2 mRNA vaccine-induced hemolytic crisis in a patient with cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare form of acquired autoimmune hemolytic anemia driven mainly by antibodies that activate the classical complement pathway. Several patients with CAD experience its development or exacerbation of hemolysis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or after receiving the SARS-CoV-2 mRNA vaccine. Therefore, these patients cannot receive an additional SARS-CoV-2 mRNA vaccination and have a higher risk of severe SARS-CoV-2 infection. Sutimlimab is a monoclonal antibody that inhibits the classical complement pathway of the C1s protein and shows rapid and sustained inhibition of hemolysis in patients with CAD. However, whether sutimlimab could also inhibit hemolysis caused by SARS-CoV-2 mRNA vaccination is uncertain. Here, we present the case of a 70-year-old man with CAD who repeatedly experienced a hemolytic crisis after receiving SARS-CoV-2 mRNA vaccines. The patient eventually underwent SARS-CoV-2 mRNA vaccination safely, without hemolytic attack, under classical pathway inhibition therapy with sutimlimab. This report suggests that appropriate sutimlimab administration can suppress SARS-CoV-2 mRNA vaccination-induced CAD exacerbation, and that it could be a preventive strategy to minimize hemolytic attacks in susceptible populations.

JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 6-12 months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 3-12 h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.

[A case of primary adenocarcinoma of small intestine responding to XELOX chemotherapy and leading to a partial metabolic response].

We report a case of adenocarcinoma of the small intestine responding to XELOX chemotherapy, leading to a partial metabolic response(PMR). The patient was a 58-year-old male with multiple peritoneal dissemination of adenocarcinoma of the small intestine. Chemotherapy with XELOX(L-OHP 130 mg/m² on day 1 , and capecitabine 1,000 mg/m2 on days 1-14)was performed. After 4 courses, a significant tumor reduction was obtained. This case suggests that chemotherapy with XELOX is a potential regimen for small intestinal adenocarcinoma.

[Successfully resected stage IIIA non-small cell lung cancer with mediastinal lymphnode metastasis after chemotherapy of cisplatin and docetaxel combined with concurrent radiation].

A 47-year-old man with no symptoms was admitted to our hospital for the treatment of NSCLC, which was incidentally detected by an X-ray examination at the mass screening. Computed tomography (CT) of the chest and FDG-PET revealed a 3.6 cm tumor in the right upper lobe with multiple lymphadenopathy in the right mediastinum. Based on these clinical findings, we classified this case as a T2N2M0, stage IIIA NSCLC. The patient consented to and received 2 courses of systemic chemotherapy consisting of cisplatin (CDDP 40 mg/m(2); day 1, 8) and docetaxel (DOC 40 mg/m(2); day 1, 8) combined with concurrent radiation (2 Gy/day; total 46 Gy) with no severe adverse events. His tumors responded well to the treatment, and restaging chest CT showed marked regression of mediastinal lymphadenopathy, and partial response to the lung tumor. Then, acurative surgical resection was performed. Finally, the case was diagnosed as a T1N1M0, stage IIA NSCLC pathologically. Our chemotherapy regimen consisting of CDDP and DOC combined with concurrent radiation might be as potent as neo-adjuvant therapy for clinical stage III NSCLC.

Novel TSC1 and TSC2 mutations in Japanese patients with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome characterized by development of unusual tumor-like growths. Involvement of the brain is associated with the most problematic clinical manifestations of TSC, including intellectual retardation, epilepsy and abnormal behaviors. Until now, over 300 mutations of TSC1 and TSC2 were reported. Here, we report one novel mutation of TSC1 (Q897X) and five novel mutations of TSC2 (c.336+1 G>A, L345R, E700K, R905G, K914K) identified in Japanese patients with TSC. We also identified three new polymorphisms in TSC2 (N331N, A431A, S802G). The TSC1 mutation was predicted to cause a nonsense substitution whereas all of the five TSC2 mutations were predicted to cause either a splicing error or a missense substitution. In accordance with previous findings, the patients with TSC1 mutations had milder clinical manifestations than those with TSC2 mutations.

Synergistic effect of olaparib with combination of cisplatin on PTEN-deficient lung cancer cells.

PARP enzyme plays a key role in the cellular machinery responsible for DNA damage repair. PTEN is a tumor-suppressor gene deactivating PI3K downstream of EGFR signaling. We hypothesize that PTEN-deficient lung cancer cells suppressed DNA damage signaling and that the absence of PTEN can sensitize these cells to a concurrent treatment of a DNA-damaging agent (cisplatin) and a PARP inhibitor (olaparib). To investigate the effect of olaparib and cisplatin on PTEN-deficient lung tumors, two EGFR-mutant (deletion in exon19) non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild-type) and H1650 (PTEN loss), were used. We transfected intact PTEN gene into H1650 cells (H1650(PTEN+)) and knocked down PTEN expression in the PC-9 cells (PC-9(PTEN-)) using short hairpin RNA (shRNA). Combination of cisplatin with olaparib showed a synergistic effect in vitro according to the combination index in H1650 cells. Restoration of PTEN in the H1650 cells decreased sensitivity to the combination. Ablation of PTEN in PC-9 cells increased sensitivity to olaparib and cisplatin. We also examined the effectiveness of cisplatin and olaparib in a xenograft model using H1650 and PC-9(PTEN-) cells. The combination of cisplatin with olaparib was more effective than each agent individually. This effect was not observed in a xenograft model using H1650(PTEN+) and PC-9 cells. Mechanistic investigations revealed that PTEN deficiency caused reductions in nuclear RAD51 and RPA focus formation and phosphorylated Chk1 and Mre11. Thus, genetic inactivation of PTEN led to the suppression of DNA repair.

Benefits and adverse events among elderly patients receiving concurrent chemoradiotherapy for locally advanced non-small cell lung cancer: analysis of the Okayama Lung Cancer Study Group trial 0007.

INTRODUCTION: Thoracic radiotherapy (RT) with concurrent chemotherapy may be offered to selected elderly patients with locally advanced non-small cell lung cancer. The Okayama Lung Cancer Study Group (OLCSG) 0007 trial with patients up to 75 years showed that with concurrent RT, docetaxel and cisplatin (DP) chemotherapy was an alternative to mitomycin C, vindesine, and cisplatin (MVP) chemotherapy. METHODS: Of the 99 patients in the DP arm, 73 were younger than 70 years and 26 were 70 years or older. Of the 101 patients in the MVP arm, 75 were younger than 70 years and 26 were 70 years or older. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method and were compared using an early period weighted log-rank test. Toxicities and treatment intensities were compared by χ(2) and t tests, respectively. RESULTS: OS and PFS tended to be longer in the DP arm versus MVP arm: median OS (months), 27.5 versus 22.9 (p = 0.109) and 25.6 versus 23.4 (p = 0.064) in the ≥70-year and <70-year groups, respectively; median PFS (months), 19.0 versus 11.5 (p = 0.175) and 12.0 versus 9.3 (p = 0.132) in the ≥70-year and less than 70-year groups, respectively. Severe toxicity (neutropenia, esophagitis, and pneumonitis) rates did not differ between age groups. Nevertheless, the absence of statistically significant differences in this retrospective analysis might be due to the small number of patients. Radiation intensity was similar between the groups, but chemotherapy intensity was lower in the ≥70-year group. CONCLUSION: Chemotherapy with concurrent RT may be effective and tolerable in elderly patients with locally advanced non-small cell lung cancer.

Chemopreventive effects of gefitinib on nonsmoking-related lung tumorigenesis in activating epidermal growth factor receptor transgenic mice.

Twenty-five percent of all lung cancer cases are not attributable to smoking. Epidermal growth factor receptor (EGFR) mutations, which are involved in approximately 50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history. Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer. To investigate the chemopreventive effects of gefitinib on nonsmoking-related lung cancer, we generated transgenic mice expressing EGFR L858R in type II pneumocytes constitutively using the surfactant protein-C promoter. The transgenic mice invariably developed atypical adenomatous hyperplasia at age 4 weeks and multifocal adenocarcinoma of varying sizes at age 7 weeks. Notably, the expression levels of phosphorylated and total ErbB2, ErbB3, and thyroid transcription factor-1 were elevated in the transgenic mice compared with wild-type controls at age 3 weeks. Administration of gefitinib to 3-week-old transgenic mice for 1 week before carcinogenesis reduced the amount of phosphorylated EGFR in the lungs of the mice to the baseline level. Gefitinib (5 mg/kg/d; n = 5, 5, and 15) or vehicle (n = 5, 5, and 15) was administered to transgenic mice from age 3 to 8, 13, and 18 weeks, respectively. The numbers of lung tumors in the control and gefitinib-treated groups were 1.75, 5.8, 10.2, and 0 (P < 0.05), respectively. No fatal toxic events occurred in either group, and gefitinib inhibited tumorigenesis completely in this mouse model. These results suggest the utility of molecular targeted chemoprevention against nonsmoking-related lung cancer.