Therapeutic effiacy of T cells expressing chimeric antigen receptor derived from a mesothelin-specific scFv in orthotopic human pancreatic cancer animal models

Novel CAR T cells targeting mesothelin (MSLN) expressed on pancreatic cancer cells were developed to overcome the limit of the clinical efficacy of CAR T cell therapy for pancreatic cancer patients. Optimal single-chain variable fragments (scFv) binding to MSLN were selected based on the binding activity and the functional effectiveness of various scFv containing CAR-expressing T cells. Engineered MSLN CAR T cells showed successful anti-tumor activity specific to MSLN expression level. Furthermore, MSLN CAR T cells were evaluated for the anti-cancer efficacy in orthotopic mouse models bearing pancreatic cancer cells, MIA Paca-2, MSLN-overexpressed MIA Paca-2 or endogenously MSLN-expressing AsPC-1. Mice were randomized into control, mock treated, MS501 BBz treated, MS501 28z treated or MS501 28BBz treated group. Mice were monitored by weekly IVIS imaging and tumors were harvested and analyzed by immunohistochemical analyses. MSLN CAR T cells produced the therapeutic effect in orthotopic animal models with complete remission in significant number of mice. Histopathological analysis indicated that CD4+ and CD8+ MSLN CAR T cells infiltrated pancreatic tumor tissue and led to cancer cell eradication. Our results demonstrated the anti-tumor efficacy of MSLN CAR T cell therapy against pancreatic cancer, suggesting its therapeutic potential.     

Primary intraventricular gliosarcoma on MRI: A challenging diagnosis

Gliosarcoma (GS) is an uncommon central nervous system tumor with several characteristics of a malignant neoplasm and poor prognosis. The majority of GS reports describe a predilection for the cerebral hemispheres, and cases of intraventricular GS are extremely rare, with only a few reported. In addition, intraventricular GS has not been associated with any unique radiographic or clinical features, which can result in misdiagnosis as other intraventricular tumor types. In this report, we present the case of a 32-year-old woman with GS in the trigone of the lateral ventricle and provide a retrospective review of similar, previously reported cases.     

A Case of Mucosal Fixed Drug Eruption Caused by Tamsulosin Administration

Fixed drug eruption (FDE) is a rare type of drug reaction that involves the skin and, less commonly, the mucosal membranes. It is characterized by clinically well-defined erythematous patches or plaques with or without blisters, which relapse at the same location if the causative agent is readministered. Tamsulosin is an alpha-1 adrenergic receptor blocker used to treat benign prostatic hyperplasia, and its common side effects are dizziness and headache. Only one case of cutaneous FDE due to tamsulosin administration has been reported but no other case of mucosal involvement has been reported to date. Therefore, we present a case of mucosal FDE caused by tamsulosin administration along with a literature review.     

A phase I study to evaluate the safety,tolerability, pharmacodynamic and pharmacokinetic profiles of ocular GLH8NDE in healthy male adults

GLH8NDE, a derivative of eupatilin, is currently under development to treat dry eye disease. We conducted a randomized, double‐masked, placebo‐controlled, single‐ and multiple‐day study to evaluate safety, tolerability, pharmacodynamics, and pharmacokinetics of ocular GLH8NDE in healthy male adults. Subjects randomly received topical ocular dosing of GLH8NDE or its matching placebo for a day, then for 7 consecutive days with a 62‐h washout at one of the following daily doses: 9, 18, 36 (Koreans), and 36 mg (Whites). The study drug was administered in divided doses over 10 h with 2‐ or 5‐h intervals. Thirty‐nine (97.5%) out of 40 subjects completed the study. A total of 17 subjects experienced 31 treatment‐emergent adverse events, all of which were mild in severity and recovered without sequelae. Neither pathological changes in eye compartments nor clinically significant systemic effects were observed. GLH8NDE was rapidly absorbed reaching the peak concentration within 0.25–0.75 h postdose. The systemic exposure as measured by area under the concentration‐time curve from time of administration up to the time of the last quantifiable concentration (AUC_last) after single‐day administration of the same dose was 109% higher in Koreans than in Whites. In conclusion, GLH8NDE was safe and well‐tolerated in healthy Korean and White male adults at 9–36 mg/day after single‐ and multiple‐day administrations.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

GLH8NDE (7‐carboxymethyloxy‐3′,4′,5′‐trimethoxy flavone) is a derivative of eupatilin, which is currently under clinical development to treat dry eye disease (DED). GLH8NDE has been effective in various experimentally induced DED animal models. Ocular GLH8NDE has never been studied in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I study evaluated the safety, tolerability, pharmacodynamic, and pharmacokinetic profiles of ocular GLH8NDE in humans. In addition, the ethnic difference in the systemic exposure to GLH8NDE was assessed between Korean and White healthy male adults.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Ocular doses of GLH8NDE from 9 to 36 mg per day after single‐ and multiple‐day administrations were safe and well‐tolerated in Korean and White healthy male adults. GLH8NDE was rapidly absorbed in a dose‐proportional manner. The systemic exposure to GLH8NDE was higher in Koreans than in Whites. GLH8NDE at 9 and 36 mg per day increased tear break‐up time (TBUT) from baseline whereas TBUT was decreased in the placebo group.

• HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?

This study shows that GLH8NDE is safe and well‐tolerated in healthy Korean and White male adults over the dose range of 9–36 mg per day. GLH8NDE has a potential to be developed as a useful treatment option for DED. Further research should take account the ethnic differences in the systemic exposure to GLH8NDE.     

A case of cutaneous extranodal natural killer/T-cell lymphoma clinically and histopathologically mimicking interface dermatitis

Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare but aggressive cancer characterised by angiocentric and angiodestructive infiltration by NK-cells, or cytotoxic T-cell types. Histopathologically, ENKTL shows a multinodular or diffuse infiltration localised to vascular structures, resulting in angiodestruction and necrosis. We present a patient with an initially suspected diagnosis of benign interface dermatitis with a differential diagnosis of mycosis fungoides that was later found to be an aggressive extranodal natural killer/T-cell lymphoma of a nasal type and with a dismal prognosis.     

Surgical management of lipomas: Proposal of the Z‐incision design and surgical algorithm based on tumor size

Surgical excision is the treatment of choice for lipomas. However, linear incision methods or minimal extraction techniques often do not provide a sufficient surgical view. Therefore, removing large lipomas is often difficult. To present the Z‐incision and half Z‐incision designs for lipoma extraction, this retrospective study analyzed lipomas surgically excised at our institution between September 2015 and December 2018. The area of surgical field exposed by the Z‐incision versus that exposed by the linear incision was calculated using a schematic model. Cure rate, complications, and surgical field area were investigated. A total of 84 lipomas were included. A Z‐ or half Z‐incision was used to treat 30 lipomas, while a linear incision was used to treat 54 lipomas. The mean diameter of the mass in the Z‐ or half Z‐incision group was 47.7 mm (range, 15–160 mm), larger than that in the linear incision group (25.5 mm; range, 7–59 mm) (p < .001). The Z‐incision involved making rectangular windows by lifting 2 triangular flaps. According to our mathematical model, the Z‐incision provided a larger surgical field area than that provided by the linear incision based on stretched angles (1.81 times larger at 30° and 3.14 times larger at 15°). The Z‐ and half Z‐incisions were successfully performed in all but 1 lipoma (29 lipomas, 96.7%). There was 1 lipoma that resulted in postoperative complications (seroma, 3.3%). The Z‐incision design can be a useful alternative technique for the extirpation of lipomas, especially large lipomas. Here, we proposed a surgical algorithm for lipoma surgery based on tumor size.