CD98 heavy chain protein is overexpressed in non-small cell lung cancer and is a potential target for CAR T-cell therapy.

Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future.

[A Case of Cytomegalovirus Reactivation after Chemoradiotherapy for Esophageal Cancer].

An 80-year-old man visited our hospital because of abdominal distension and epigastralgia. He was diagnosed esophageal cancer(Mt, SCC, T3N0M0, Stage Ⅱ). Because he was elderly, he received chemoradiotherapy(CRT)with S-1. At 54 Gy/27 Fr, he was admitted to the hospital because of cough exacerbation, fever, and food intake loss. A chest and abdominal CT showed a pneumonia pattern. First, antibiotics were started for suspected bacterial pneumonia. Nevertheless, elevation of inflammatory reactions and continuous fever were observed. As interstitial pneumonia was suspected, we started to administer an injection of prednisolone 60 mg. His respiratory symptoms were improved. However, we observed that disseminated erythema of the trunk spread throughout the body and liver enzymes further increased. As blood examination revealed elevated CMV-IgG antibody and C7-HRP positive, we diagnosed cytomegalovirus(CMV)reactivation. Administration of ganciclovir improved liver damage and disseminated erythema. He discharged our hospital while the steroid dose was reduced and valganciclovir continued administrating. The therapeutic effect of esophageal cancer was partial response(PR). We are following his symptoms and CT scan while adjusting the steroid dose. This is a rare case of CMV reactivation due to immunosuppression caused by steroids therapy during CRT against esophageal cancer. We should be aware of CMV infection during CRT and steroid therapy.

[Three Cases of Advanced Gastric Cancer with Peritoneal Dissemination Successfully Treated with S-1 and Docetaxel Combination Chemotherapy].

Case 1: A 74-year-old man underwent total gastrectomy for gastric cancer, but peritoneal dissemination(P1c)was con- firmed intraoperatively in July 2011. Postoperatively, S-1/docetaxel(DTX)combination chemotherapy was administered; after 32 courses of treatment, S-1 was continued as monotherapy. However, in November 2013, CT scan showed a portal vein tumor. We modified the chemotherapy regimen, but he died 3 years and 7 months after the operation. Case 2: A 77-year-old man underwent distal gastrectomy for gastric cancer with peritoneal dissemination(P1b)in September 2013. He was treated with S-1/DTX/trastuzumab(Tmab)combination chemotherapy. After 5 courses of treatment, S-1was continued as monotherapy until October 2015. He has since survived without recurrence. Case 3: A 75-year-old woman was diagnosed with gastric cancer with peritoneal dissemination(P1c)by laparotomy in September 2014. She was treated with S-1/DTX combination chemotherapy. After 23 courses of treatment, chemotherapy was discontinued according to the patient's wish. She died 2 years and 6 months after the surgery. We suggest S-1/DTX combination chemotherapy as an option for advanced gastric cancer with peritoneal dissemination.

[Experience of Perioperative Status for Super Elderly Colorectal Patients in Our Facility].

We examined the perioperative situation according to estimation of physiologic ability and surgical stress(E-PASS)score of 35 colon cancer patients aged 85 years or older who underwent operation in our facility. The incidence of Grade 2 and Grade 3 complications according to Clavien-Dindo classifications increased with age. The preoperative risk score(PRS)also increased with age; however, the surgical stress score(SSS)did not. The comprehensive risk score(CRS)also increased with age. Because the PRS was already high in these elderly patients, since 2016, we implemented methods to lower the SSS to reduce patient risk, including decreasing the operative time and increasing the laparoscope rate. Compared to before these efforts, the SSS decreased, resulting in a reduced incidence of Grade 3 complications.

Novel function of ascorbic acid as an angiostatic factor.

Endothelial permeability is increased by vascular endothelial cell growth factor and decreased by antioxidants. Whether or not l-ascorbic acid (Asc), which decreases endothelial permeability by stimulating the endothelial barrier function, is anti-angiogenic (angiostatic) remains unknown. We examined the role of Asc on angiogenesis using two assay systems. At first, the potential role of Asc on four steps of angiogenesis was investigated in cultured bovine microvascular endothelial cells. Asc inhibited the formation of vessel-like tubular structures of endothelial cells cultured on Matrigel; however, it did not decrease the activity of plasminogen activator (PA), which creates the space into which vascular vessels extend. Furthermore, even at high concentrations, Asc did not inhibit either the proliferation or migration of endothelial cell cultures. Secondly, whether Asc inhibited in vivo angiogenesis or not was studied on chick chorioallantoic membrane (CAM) during the 4-6 days of embryogenesis when neovascularization is rapid. It also revealed that angiogenesis was dose-dependently inhibited by Asc from 0.5 micro mol/CAM with half-maximal inhibition at 2.5 micro mol/CAM. Because it was previously reported that the endothelial barrier function decreases permeability via the stimulation of collagen synthesis induced by Asc, we treated CAM with the inhibitor of collagen synthesis, l-azetidine 2-carboxylic acid (AzC). This compound partially attenuated the angiostatic function of Asc on CAM. To understand the involvement of an antioxidant activity in the angiostatic function of Asc, we further examined the effect of glutathione (GSH), which is an endogenous antioxidant, on angiogenesis in CAM and endothelial cells. GSH inhibited CAM angiogenesis, as well as the formation of vessel-like tubular structures of endothelial cell cultures on Matrigel. Both Asc and GSH inhibited hydrogen peroxide (H(2)O(2)) induced tubular morphogenesis. These findings suggest that Asc affects angiogenesis through both its antioxidant properties and the stimulation of collagen synthesis. As the angiostatic activity of Asc may be one of the many effects involved in host resistance to the growth or invasiveness of solid cancer, it may be useful as a supplementary therapy in various angiogenic diseases.