Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.

BACKGROUND: Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. METHODS: Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. RESULTS: Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. CONCLUSIONS: Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.

Targeting tumor-infiltrating CCR8+ regulatory T cells induces antitumor immunity through functional restoration of CD4+ Tconvs and CD8+ T cells in colorectal cancer.

BACKGROUND: Chemokine (C-C motif) receptor 8 (CCR8) is a chemokine receptor selectively expressed on tumor-infiltrating regulatory T cells (Tregs). Strong immunosuppression mediated by CCR8+ Tregs observed in breast and lung malignancies suggest for their functional significance in cancer therapy. To date, detailed characterization of tumor-infiltrating CCR8+ Tregs cells in colorectal cancer (CRC) is limited. METHODS: To study the presence and functional involvement of CCR8+ Tregs in CRC, we analyzed the proportions of CCR8-expressing T cells in different T cell subsets in tumor and adjacent normal tissues and peripheral blood mononuclear cells (PBMCs) from CRC patients by Flow cytometry. Also, we compared the distribution of CCR8+ T cells in malignant tissues and peripheral lymphoid organs from a subcutaneous CRC murine model. Bioinformatic analysis was performed to address the significance of CCR8 expression levels in CRC prognosis, immune regulatory gene expression profiles and potential molecular mechanisms associated with CCR8+ Tregs in CRC tumors. Further, we administrated an anti-CCR8 monoclonal antibody to CT26 tumor-bearing mice and examined the antitumor activity of CCR8-targeted therapy both in vivo and in an ex vivo confirmative model. RESULTS: Here, we showed that Tregs was predominantly presented in the tumors of CRC patients (13.4 ± 5.8, p < 0.0001) and the CRC subcutaneous murine model (35.0 ± 2.6, p < 0.0001). CCR8 was found to be preferentially expressed on these tumor-infiltrating Tregs (CRC patients: 63.6 ± 16.0, p < 0.0001; CRC murine model: 65.3 ± 9.5, p < 0.0001), which correlated with poor survival. We found that majority of the CCR8+ Tregs expressed activation markers and exhibited strong suppressive functions. Treatment with anti-CCR8 antibody hampered the growth of subcutaneous CRC tumor through effectively restoring the anti-tumor immunity of CD4+ conventional T cells (CD4+ Tconvs) and CD8+ T cells, which was confirmed in the ex vivo examinations. CONCLUSIONS: Collectively, these findings illustrate the importance of CCR8+ Tregs for an immunosuppressive microenvironment in CRC tumors by functional inhibition of CD4+ Tconvs and CD8+ T cells, and suggest for the applicable value of CCR8-targeted therapy for CRC.

Magnifying Endoscopy for Esophageal Ectopic Sebaceous Glands

Ectopic sebaceous glands are found very rarely in the esophagus; heretofore, several cases have been reported. The sebaceous gland is originally a source of an endodermal origin; however, there have been controversies regarding whether the origin of the esophageal ectopic sebaceous gland is ectodermal or endodermal. Ectopic sebaceous glands of the esophagus usually do not cause symptoms; thus, they are often found incidentally on endoscopy for routine health screening. Endoscopic findings are characterized by single or multiple yellow patches or nodular lesions of various sizes, sometimes with small central openings. We report two cases of esophageal ectopic sebaceous glands found incidentally during endoscopy with magnifying endoscopic findings. The lesions were in the mid-esophagus and lower esophagus, respectively, and both endoscopic findings were similar as multiple yellowish patches or plaques. Magnifying endoscopy revealed the openings of the excretory ducts surrounded by circular microvessels in both cases.

Immediate breast construction with silicone prosthesis after nipple-areola complex sparing mastectomy / 中国组织工程研究

BACKGROUND:As Chinese women have the smaler breast capacity, the traditional breast conserving operation may lead to the poor breast shape, moreover, breast reconstruction with latissimus dorsi myocutaneous flap and transverse rectus abdominis myocutaneous flap is very difficult and has trauma and more complications. Therefore, the immediate breast construction with implants after nipple-areola complex sparing mastectomy is a good choice. OBJECTIVE: To investigate the feasibility of immediate breast construction using silicone prosthesis after nipple-areola complex sparing mastectomy. METHODS:The immediate breast reconstruction after nipple-areola complex sparing mastectomy was performed in 33 female patients with breast cancer (20 cases in the left side and 13 cases in the right side), aged 30-48 years. The effects of reconstructed breast were evaluated according to objective and subjective criteria during the folow-up. RESULTS AND CONCLUSION:Of the 33 cases, 2 cases had nipple-areola complex ischemic necrosis postoperatively and were cured quickly; 1 case had intra-operative blood loss > 800 mL and recovered wel after fluid and blood transfusion. The aesthetic outcome was wel in 31 cases and the satisfactory rate was 94% during 10-51 months of folow-up period. No recurrence and metastasis were found in al cases. The operation method of immediate breast reconstruction with implants after nipple-areola complex sparing mastectomy is maneuverable and has excelent aesthetic effects with no severe complications.

Role of insular cortex in amygdala-kindled seizures in rats / 中华神经医学杂志

Objective To investigate the role of insular cortex in amygdala-kindled seizures in rats.Methods Forty-eight healthy male SD rats were randomly divided into blank control group (n=8),sham-operated group (n=8) and amygdala-kindled group (n=32); no treatment was performed in the blank control group,and only implantation of electrodes was performed in the sham-operated group; implantation of electrodes and electrophotoluminescence were performed in the amygdala-kindled group to induce amygdala-kindled seizure models.Rats in the amygdala-kindled group was divided into 4sub-groups (n=8) at different times after the kindling (1,3,6 and 12 h).Fluorescence in situ hybridization and immunohistochemistry staining were employed to investigate the altered mRNA and protein expressions of activity-regulated cytoskeleton-associated protein (Arc) in the hippocampus and insula of the rat brain.Results As compared with that in the blank control group and sham-operated group,Arc mRNA expression in the amygdala-kindled sub-groups increased at 1 h after the kindling (P＜0.05),peaked at 3 h after the kindling (P＜0.05),and returned to basic level at 6 h after the kindling (P＞0.05).As compared with that in the blank control group and sham-operated group,Arc protein expression in the amygdala-kindled sub-groups increased at 3 h after the kindling,(P＜0.05),peaked at 6 h after the kindling (P＜0.05),and returned to basic level at 12 h after the kindling (P＞0.05).No significant difference on mRNA and protein expressions of Arc was noted between the sham-operated group and blank control group (P＞0.05).Conclusion Insular cortex,the amygdala and the hippocampus form a focus complex,which participates in the occurrence of temporal lobe epilepsy.

Epidemiology of Erectile Dysfunction in one Korean Rural Community / 신경정신의학

OBJECTIVES: The purpose of this study was to investigate the prevalence of erectile dysfunction (ED) in a rural area of Korea and to examine the relationship between the prevalence and correlates of subjects. METHOD: This study was done as a part of the chronic disease survey of rural area by the Asan Foundation. Among 30 years or older population from Jung Eup, a rural area of Korea, 711 male subjects were sampled using a cluster probability sampling method. Trained interviewers visited and interviewed subjects aged 30 years or older with a structured interview. ED was categorized as 'none', 'mild', 'moderate', or 'severe' according to the ability to 'attain and/or maintain an erection satisfactory for sexual intercourse'. Response rate was 54.3% (N=386). RESULTS: The age weighted prevalence of ED was 27.2% (minimal 14.1%, moderate 7.6%, severe 5.5%). Prevalence and severity increased with age. Liver disease and underweight were significantly (p<0.05) associated with ED. Smoking seemed to be correlated with ED, but did not reach statistically significant level. CONCLUSION: ED was highly prevalent in the rural community of Korea. Medical, sociodemographic, and lifestyle variables associated with ED may alert physicians to patients at risk for ED and offer insight to its etiology.