Spontaneous tumor regression mediated by human T cells in a humanized immune system mouse model.

Immunodeficient mice reconstituted with a human immune system (HIS mice) give rise to human T cells, which make them an attractive system to study human immune responses to tumors. However, such HIS mice typically exhibit sub-optimal responses to immune challenges as well as fail to develop antigen-specific B or T cell memory. Here we report HIS mice mediate spontaneous regression of human B cell lymphoma Raji. Tumor regression was dependent on CD4+ and CD8+ T cell responses and resulted in T cell memory. The T cell memory elicited was mainly Raji-specific, however some level of cross-protection was also elicited to a related B cell lymphoma cell line Ramos. Single-cell RNAseq analysis indicated activation of CD8+ T cells in regressing Raji tumors as well as clonal expansion of specific T cell receptors (TCRs). Cloning of TCRs from Raji-infiltrating T cells into a Jurkat reporter cell line showed reactivity specific for Raji tumor cells. Overall, we report a platform for studying in vivo human T cell tumor immunity by highlighting spontaneous Raji tumor regression, clonal TCR expansion, and T cell memory in HIS mice.

Is Substantial Lymphovascular Space Invasion Prognostic for Clinical Outcomes in Type II Endometrial Cancer?

AIMS: Substantial lymphovascular space invasion (LVSI) compared with none or focal LVSI is predictive of lymph node involvement and worse clinical outcomes in endometrioid-type endometrial carcinoma. We aimed to quantify the incidence of substantial LVSI in type II (clear cell and serous) endometrial cancer and correlate the extent of LVSI with clinical outcomes. MATERIALS AND METHODS: A retrospective review was conducted on type II endometrial cancer patients who underwent surgical management from July 2017 to December 2019 using the three-tier LVSI scoring system. Binary logistic regression and Cox regression were used to analyse predictors of lymph node involvement or survival outcomes, respectively. The Kaplan-Meier method and Log-rank test were used to analyse differences in locoregional disease-free survival (LR-DFS), distant metastasis disease-free survival (DM-DFS) and overall survival between patients with substantial versus none/focal LVSI. RESULTS: In 79 patients with type II endometrial carcinoma, no LVSI, focal LVSI and substantial LVSI was present in 48.1%, 15.2% and 36.7% of patients, respectively. Lymph nodes were involved in 0.0% with no LVSI, 20.0% with focal LVSI and 60.0% with substantial LVSI (P < 0.001). The median follow-up was 22.2 months. In patients with none/focal versus substantial LVSI, the 2-year LR-DFS and DM-DFS rates were 91.5% versus 71.4% (P = 0.01) and 90.2% versus 63.8% (P = 0.005), respectively. On univariate analysis, myometrial invasion ≥50%, tumour size ≥3.6 cm, substantial versus none/focal LVSI, lymph node involvement and omission of adjuvant radiotherapy were significant predictors for worse LR-DFS and DM-DFS (P < 0.05). DISCUSSION: Substantial LVSI has a high incidence in type II pathology at our institution and predicts for lymph node involvement and worse clinical outcomes.

A tetra-nuclear nickel(II) complex, [Ni4(L)4](ClO4)4·C2H3N·2H2O, with an asymmetric Ni4O4 open-cubane-like core.

A tetra-nuclear complex with an open-cubane-like core structure was synthesized from 2-meth-oxy-6-(pyridin-2-yl-hydrazonometh-yl)phenol (HL), namely, cyclo-tetra-kis-(µ-2-meth-oxy-6-{[2-(pyridin-2-yl)hydrazin-1-yl-idene]meth-yl}pheno-lato)tetra-nickel(II) tetra-kis-(perchlorate) aceto-nitrile monosolvate dihydrate, [Ni4(C13H12N3O2)4](ClO4)4·C2H3N·2H2O, and characterized using micro-analytical and spectroscopic techniques. The crystal-structure determination reveals the formation of a distorted Ni4O4 cubane-like core architecture encapsulated by four hydrazone Schiff base (HL) mol-ecules. A open-cube tetra-nuclear architecture is created in which nickel(II) ions of the NiN2O3 unit are connected by µ2-O anions of the phenolate moiety of HL. In this complex, each Ni centre has a slightly distorted square-pyramidal coordination environment. The supra-molecular architectures are stabilized via the presence of various inter-molecular hydrogen bonds and (ar-yl-aryl, ar-yl-chelate and chelate-chelate) stacking inter-actions.

9-Arylimino noscapinoids as potent tubulin binding anticancer agent: chemical synthesis and cellular evaluation against breast tumour cells.

A library of 9-arylimino derivatives of noscapine was developed by coupling of Schiff base containing imine groups. Virtual screening using molecular docking with tubulin revealed three molecules, 12-14 that bind with high affinity. An improved predicted free energy of binding (FEB) of -5.390, -6.506 and -6.679 kcal/mol for the molecules 12-14 was found compared to noscapine (-5.135 kcal/mol). Furthermore, molecular dynamics simulation in combination with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) revealed robust binding free energy of -166.03, -169.75 and -170.63 kcal/mol for the molecules 12, 13 and 14, respectively. These derivatives were strategically synthesized and experimentally validated for their anticancer activity. Tubulin binding assay revealed substantial binding of molecules 12-14 with purified tubulin. Further, their anticancer activity was demonstrated using two cancer cell lines (MCF-7 and MDAMB-231) and a panel of primary breast tumour cells. All these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 30.1 and 5.8 µM, which is 1.7 to 7.52 fold lower than that of noscapine. Further, these novel derivatives arrest cell cycle in the G2/M-phase followed by induction of apoptosis. Thus, 9-arylimino noscapinoids 12-14 have a great potential to be a novel therapeutic agent for breast cancers.

Early outcomes after definitive chemoradiation therapy with Vienna/Venezia hybrid high-dose rate brachytherapy applicators for cervical cancer: A single-institution experience.

PURPOSE: The Vienna and Venezia (Elekta) are hybrid intracavitary/interstitial brachytherapy (BT) applicators for cervical cancers unsuitable for intracavitary BT alone to improve target coverage or reduce critical organ dose. There is limited outcome data with the use of these applicators outside published experience of the EMBRACE group. We report feasibility and early outcomes with the use of these hybrid applicators at our institution. METHODS AND MATERIALS: Hybrid applicators were used to treat 61 patients with cervical cancer from November 2011 to December 2019. Indications for hybrid applicator use were involvement of the vagina in 10 patients (16%), residual central or parametrial disease in 46 patients (75%), and a narrow introitus in 5 patients (9%). Toxicities were graded using the CTCAE v4.0. Outcomes were assessed with the Kaplan-Meier method. RESULTS: Median follow-up was 16 months (IQR 9-32 mos). Median HRCTV volume was 31.6 cm3 (IQR 25-48 cm3). Median HRCTV D90 was 86.1 Gy (IQR 84.3-88.0 Gy). In 54 patients with follow-up PET/CT at 3 months, complete initial imaging response locally was seen in 46 patients.Estimated 12-month Kaplan-Meier overall survival, locoregional control, distant control, and recurrence-free survival estimates were 86.9%, 80.6%, 73.8%, and 65.9%, respectively. The 12-month incidence of Grade 3+ GI/GU chronic toxicities was 5.7%, consisting of vesicovaginal fistula, rectovaginal fistula, and ureterovesical fistula. CONCLUSIONS: Our single-institution data support the use of the hybrid applicators, as an alternative to traditional BT applicators when clinically warranted. Use of hybrid applicators is feasible with adequate coverage of disease in the vagina and parametrium.

Is the risk of substantial LVSI in stage I endometrial cancer similar to PORTEC in the North American population? - A single-institution study.

OBJECTIVES: A pooled analysis of PORTEC-1 & 2 identified substantial lymphovascular space invasion (LVSI) in 4.8% of patients, which predicted for pelvic recurrence, distant metastasis, and overall survival. Our institution implemented the PORTEC three-tier system of LVSI reporting (absent, focal, or substantial). We aimed to quantify the incidence of substantial LVSI in a North American population and to correlate extent of LVSI with lymph node (LN) involvement. METHODS: A retrospective review was conducted on patients with clinically uterine-confined, endometrioid type endometrial cancer who underwent surgical staging and were found to have pT1a-b disease. Binary logistic regression was used to assess predictors of LN involvement (defined as ITC, micrometastases, or macrometastases). RESULTS: In total, 438 patients with pT1a-b disease were identified. In the overall cohort and in the subset meeting PORTEC-1 inclusion criteria (n = 195), no LVSI was present in 67.4% and 50.8%; focal LVSI was present in 16.7% and 24.1%; and substantial LVSI was present in 16.0% and 25.1%, respectively. Among patients who underwent surgical LN assessment (79.2%, n = 347), LNs were involved in 3.3% without LVSI, 7.5% with focal LVSI (OR 2.4), and 15.2% with substantial LVSI (OR 5.3) (p = .005), with a similar trend in the PORTEC-1 cohort. Extent of LVSI correlated with disease burden in LN metastases. CONCLUSION: Our incidence of substantial LVSI was three to five times higher than reported by PORTEC and correlated with LN involvement. This questions the reproducibility of the three-tier LVSI reporting system and emphasizes the need for multi-institutional data outside PORTEC for confirmation of our findings.

Transcriptomic comparison of primary bovine horn core carcinoma culture and parental tissue at early stage.

AIM: Squamous cell carcinoma or SCC of horn in bovines (bovine horn core carcinoma) frequently observed in Bos indicus affecting almost 1% of cattle population. Freshly isolated primary epithelial cells may be closely related to the malignant epithelial cells of the tumor. Comparison of gene expression in between horn's SCC tissue and its early passage primary culture using next generation sequencing was the aim of this study. MATERIALS AND METHODS: Whole transcriptome sequencing of horn's SCC tissue and its early passage cells using Ion Torrent PGM were done. Comparative expression and analysis of different genes and pathways related to cancer and biological processes associated with malignancy, proliferating capacity, differentiation, apoptosis, senescence, adhesion, cohesion, migration, invasion, angiogenesis, and metabolic pathways were identified. RESULTS: Up-regulated genes in SCC of horn's early passage cells were involved in transporter activity, catalytic activity, nucleic acid binding transcription factor activity, biogenesis, cellular processes, biological regulation and localization and the down-regulated genes mainly were involved in focal adhesion, extracellular matrix receptor interaction and spliceosome activity. CONCLUSION: The experiment revealed similar transcriptomic nature of horn's SCC tissue and its early passage cells.

Comprehensive transcriptome profiling of squamous cell carcinoma of horn in Bos indicus.

Squamous cell carcinoma (SCC) of horn is frequently observed in Bos indicus affecting 1% of cattle population and accounting 83.34% of total tumours found. The transcriptome profile of horn cancer (HC) tissue and the matched normal (HN) tissue were analysed by RNA-seq using Roche 454 sequencing. A total of 1 504 900 reads comprising of 612 MB data were used to identify differentially expressed genes using CLC Genomic Workbench. These include up-regulation of KRT6A, KRT6B, KRT6C, KRT14, SFN, KRT84, PI3, COL17A1, ANLN, SERPINB5 and down-regulation of BOLA, SCGB1A1, CXCL17, KRT19, BPIFB1, NR4A1 and TFF3 in HC, which are involved in regulation of gene transcription, cell proliferation, apoptosis, cell survival and metabolic pathways. The qPCR analysis of several targets suggested concordance of gene expression profile with RNA-seq analysis. The present findings would provide basis for further screening of genes and identification of markers for early diagnosis and therapeutic intervention of HC.

Incidence and species distribution of candidaemia in Asia: a laboratory-based surveillance study.

The epidemiology of candidaemia varies between hospitals and geographic regions. Although there are many studies from Asia, a large-scale cross-sectional study across Asia has not been performed. We conducted a 12-month, laboratory-based surveillance of candidaemia at 25 hospitals from China, Hong Kong, India, Singapore, Taiwan and Thailand. The incidence and species distribution of candidaemia were determined. There were 1601 episodes of candidaemia among 1.2 million discharges. The overall incidence was 1.22 episodes per 1000 discharges and varied among the hospitals (range 0.16-4.53 per 1000 discharges) and countries (range 0.25-2.93 per 1000 discharges). The number of Candida blood isolates and the total number of fungal isolates were highly correlated among the six countries (R² = 0.87) and 25 hospitals (R² = 0.77). There was a moderate correlation between incidence of candidaemia and the intensive care unit (ICU)/total bed ratio (R² = 0.47), although ICUs contributed to only 23% of candidaemia cases. Of 1910 blood isolates evaluated, Candida albicans was most frequently isolated (41.3%), followed by Candida tropicalis (25.4%), Candida glabrata (13.9%) and Candida parapsilosis (12.1%). The proportion of C. tropicalis among blood isolates was higher in haemato-oncology wards than others wards (33.7% versus 24.5%, p 0.0058) and was more likely to be isolated from tropical countries than other Asian countries (46.2% versus 18.9%, p 0.04). In conclusion, the ICU settings contribute, at least in part, to the incidence variation among hospitals. The species distribution is different from Western countries. Both geographic and healthcare factors contribute to the variation of species distribution.

Are Gujarati Asian Indians 'older' for their 'vascular age' as compared to their 'Chronological age'?

BACKGROUND: South Asians are known to carry higher burden of cardiovascular diseases when compared with their Caucasian counterparts. AIM: This study was designed to evaluate whether vascular age is advanced for Gujarati Asian Indians as matched to their chronological age in apparently healthy, asymptomatic population. We have also assessed the contributing risk factors for premature vascular ageing. DESIGN: It was cross-sectional study of 2483 individuals of Gujarat state in Western India having no past or present history of major illness including cardiovascular diseases. METHOD: The vascular age of the population was calculated using Framingham vascular age calculator. A relationship between risk factor prevalence and vascular ageing was evaluated using univariate analysis of variance. RESULTS: The mean chronological age of the study population was 46.8 (±10.35) years whereas mean vascular age was 53.34 (±16.05) years, and the difference (6.54±9.5) between both was statistically significant (P < 0.0001). Contributory risk factors for advanced vascular age apart from chronological age (75.4%) and male gender (66.2%) were the presence of dyslipidemia (60.4%) hypertension (57.34%) and increased waist circumference (WC) (male 39.7%, female 29%). Results of regression analysis showed that vascular age progression was highly associated with blood pressure (19.9, 95% CI: 14.34-27.63), followed by smoking (15.23, 95% CI: 8.4-27.59), and blood sugar (12.97, 95% CI: 3.48-48.25). CONCLUSION: The Gujarati Asian Indians are subjected to premature vascular ageing and henceforth routine screening for vascular age and risk factors prevalence is strongly advocated in this ethnic group.

Prophylactic treatment for cytosine arabinoside-induced keratoconjunctivitis.

High-dose cytosine arabinoside (Ara-C) is known to cause keratoconjunctivitis in a large proportion of patients. Topical steroids are a popular choice of prophylactic treatment. The objective of this survey was to evaluate the type, dose, frequency and duration of drops used in all centres (n = 117) participating in the acute myeloid leukaemia trial 15 (AML 15), and to assess adherence to the trial protocol prescribed guidelines. All centres used prophylactic treatment; however, the dose of Ara-C at which it was initiated varied from 100 to 6000 mg/m(2)/day. All centres used some form of steroid prophylaxis with prednisolone 0.5% being the most commonly used (98/117), but only 6 of the 117 centres initiated treatment at doses recommended in the trial protocol. Ten centres used lubricants in addition to steroids. No centre reported the use of non-steroidal anti-inflammatory drops. The duration of treatment ranged from 2 days prior to commencing Ara-C to 28 days post-treatment. Twenty-two centres reported complications of which preservative allergy was the commonest. There is a large variation in prophylactic treatment practice in the UK. Clear guidance on the use of prophylaxis and further studies are required to ascertain the most effective prophylactic treatment and regimen.

Compatibility of the thioamide functional group with beta-sheet secondary structure: incorporation of a thioamide linkage into a beta-hairpin peptide.

[structure: see text]. We report the incorporation of a thioamide linkage between the i + 2 and i + 3 residues of the type II' beta-turn of a peptide known to fold into a beta-hairpin conformation. Two-dimensional NMR spectroscopy and circular dichroism spectroscopy indicate that the thioxo peptide adopts a hairpin conformation similar to that of the oxo peptide and that the hairpin conformation persists at elevated temperatures. The results show that a thioamide linkage is compatible with beta-sheet secondary structure.

Autoamputation of the tongue.

Autoamputation is an uncommon phenomenon that has been reported for the fingers, toes, appendix, ovary, spleen, etc. Autoamputation of the tongue has never been reported. An elderly man with carcinoma of lateral pharyngeal wall and tonsil presented with an autoamputated tongue that was attached to the oral cavity with a thin band. The patient required detachment of the tongue and tracheostomy followed by radiotherapy for the primary tumour.

Intraoperative transesophageal echocardiography: correlation of echocardiographic findings and surgical pathology.

Before the introduction of transesophageal echocardiography (TEE) in the operating room, intraoperative echocardiography relied on epicardial imaging. The disadvantages of this approach included interference with the surgical procedure, limited windows, and potential distortion of cardiac structures. Consequently, multiplane TEE has now emerged as the intraoperative imaging method of choice. It provides high-resolution images of cardiac structures and excellent portraits of flow abnormalities. Intraoperative TEE does not interfere with the surgical field and procedure. TEE provides better imaging of the valves, atria, aorta, pulmonic vasculature, and pericardium, which are sometimes difficult to visualize by transthoracic echocardiography. TEE is especially beneficial in surgeries for valve replacement, valve repair, cardiac mass, aortic disease, congenital heart disease, and pericardial disease. Presurgical TEE provides information for surgical planning. TEE is helpful for the assessment of the immediate result of surgery and detection of complications that may need a prompt response. Thus, intraoperative TEE has a vital impact on management of cardiac surgery.

Radiation therapy in pseudotumour haemarthrosis.

Total or partial deficiency of factor VIII and IX in the coagulation cascade leads to haemophilia. Haemophilia affecting weight-bearing joints gives a 'pseudotumour' or haemarthrosis-like condition. Surgery and cryoprecipitate infusions have been the treatment for this condition. Radiocolloids and radiation therapy have been used with some benefit. One case of ankle pseudotumour which was treated by low-dose external beam radiation is presented here.

Fungal purulent constrictive pericarditis in a heart transplant patient.

Purulent pericarditis caused by Candida species is rare and is associated with very high mortality. Immunosuppressed transplant patients are particularly susceptible to fungal infections. We report a case of Candida purulent constrictive pericarditis in an immunocompromised heart transplant patient who was treated successfully with antifungal agents, surgical drainage, and pericardiectomy.

Evaluation of transperineal template implant technique in Indian cervical carcinoma patients.

The prognosis in advanced cervical cancer patients is poor specially in presence of distorted anatomy, gross residual growth etc. In these cases template implant offers good option for treatment. We have carried out the procedure in 19 patients with acceptable level of complication. Preliminary results have been described.