Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma.

Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells.

Clonal relationship and alcohol consumption-associated mutational signature in synchronous hypopharyngeal tumours and oesophageal squamous cell carcinoma.

BACKGROUND: The patients with dual oesophageal squamous cell carcinoma (ESCC) and hypopharyngeal cancer (HPC) have poor prognosis; their underlying genetic pathogenesis is unclear. We hypothesise that development of synchronous ESCC/HPC depends on multicentricity or independent origin, rather than multifocality due to local or lateral spreading. METHOD: Multiple region whole-exome sequencing (M-WES) and clonality analysis were used to assess clonal relationship and spatial inter- or intra-tumour heterogeneity (ITH) in 62 tumour regions from eight dual ESCC/HPC and ten ESCC patients. RESULTS: All synchronous ESCC/HPC patients had COSMIC 16 mutation signatures, compared to only 40% ESCC in the current study (p = 0.013) and public data set (n = 165, p = 0.003). This alcohol consumption-related mutation signature 16, commonly involved in multiple alcohol-related cancers, was significantly associated with drinking and alcohol metabolism-related ADH1B rs1229984. The mutational landscape and copy number profiles were completely distinct between the two primary tumours; clonality analysis further suggested the two primary tumours shared no or only one clone accompanying independent subclone evolution. M-WES strategy demonstrated higher sensitivity and accuracy for detection of mutational prevalence and the late branch mutations among different regions in the ESCC tumours, compared to traditional sequencing analysis based on single biopsy strategy. Patients with high ITH assessed by cancer cell fraction analysis after M-WES were significantly associated with both relapse and survival. CONCLUSIONS: Our hypothesis-generating M-WES ITH assessment data have implications for prognostication. Collectively, our findings support multicentric independent clonal evolution, the field cancerisation theory, and suggest novel insights implicating an aetiologic role of alcohol metabolism in dual ESCC/HPC carcinogenesis.

Impact of Extracapsular Extension of Lymph Node in Adenocarcinoma of the Stomach.

BACKGROUND: Extracapsular extension (ECE) of lymph node may have important prognostic impact for patients with adenocarcinoma of the stomach, but it generally is ignored in staging systems and prognostic models. This study aimed to examine the impact that ECE of lymph node has on prognosis for patients with adenocarcinoma of the stomach. METHODS: The study analyzed 321 consecutive patients with gastric cancer who underwent radical gastrectomy between January 2008 and December 2015. None of these patients had distant metastases. Lymph node metastases were found in 187 patients. The ECE grade was evaluated according to the previously described system used in head and neck cancers. Deposits of cancer cells in sub-serosal fat without a recognizable lymph node were classified as ECE grade 4. Survival outcomes were compared using Kaplan-Meier and Cox regression analyses. A nomogram was constructed using identified significant prognostic factors. The predictive accuracy and model performance were measured by the concordance index (C-index). RESULTS: Patients with ECE(+) showed significantly worse 3-year overall survival (OS) and disease-free survival (DFS) than those without ECE. In the sensitivity analysis, ECE had independent prognostic value for both 3-year OS and 3-year DFS, whereas ECE grading showed little impact on mortality trend or disease progression trend. The ECE-based nomogram showed a significantly higher C-index than the pathological tumor and node staging (pTN) staging system. CONCLUSIONS: The adverse prognostic impact of ECE was validated. Sub-serosal tumor deposits without recognizable lymph node tissue are recommended for inclusion in the ECE definition. A nomogram involving ECE could provide better individual prediction of survival for patients with lymph node-positive gastric cancer.

Inflammatory myofibroblastic tumours of the urinary bladder: multi-centre 18-year experience.

OBJECTIVE: To review a series of inflammatory myofibroblastic tumours (IMTs) of the urinary bladder in 10 hospitals in Hong Kong. METHODS: A database search in the pathology archives of 10 hospitals in Hong Kong from 1995 to 2013 was performed using the key words 'inflammatory myofibroblastic tumour', 'inflammatory pseudotumour' and 'spindle cell lesion'. Patient characteristics, clinical features, histological features, immunohistochemical staining results and treatment outcomes were reviewed. RESULTS: Nine cases of IMT of the urinary bladder were retrieved. The mean age was 45.4 ± 22.8 years (range 11-78). Eight patients (88.9%) presented with haematuria and 5 patients (55.6%) had anaemia with a mean haemoglobin level of 6.8 ± 1.3 g/dl. Histologically, the majority of patients (77.8%) had a compact spindle cell pattern. Anaplastic lymphoma kinase staining was positive in 75% of cases. During a mean follow-up period of 43.4 months (range 8-94), none of them developed any local recurrence or distant metastasis. CONCLUSIONS: A high index of suspicion of IMT should be maintained for young patients presenting with bleeding bladder tumours and significant anaemia. IMTs of the urinary bladder run a benign disease course, and good prognosis can be achieved after surgical resection.

Shift in Tissue-Specific Immune Niches and CD137 Expression in Tuberculoma of Pembrolizumab-Treated Nasopharyngeal Carcinoma Patients.

The use of immune checkpoint inhibitors (ICIs) in cancer treatment has shown promise but can also have unintended consequences, such as reactivating latent tuberculosis (TB). To develop treatments that address ICIs-related adverse events, it is essential to understand cellular heterogeneity across healthy and pathological tissues. We performed cross-tissue multiplexed staining analysis on samples from two patients with TB reactivation during pembrolizumab treatment for metastatic nasopharyngeal carcinoma. CD8+ T cells, rather than CD4+ T cells, accumulated preferentially in the tuberculoma and were associated with increased production of IFNγ and expression of CD137. Additionally, CD137 enrichment played a role in the spatial organization of the tuberculoma, with specific interaction limited to spatial proximal cells between IFNγ+ CD137+ CD8+ T cells and IL12+ CD137+ type-1 macrophages. This unique feature was not observed in non-tumoral or tumoral tissues. Our analysis of public transcriptomic datasets supported the notion that this cellular interaction was more prominent in patients with durable ICI responses compared to those with non-ICI-related TB. We suggest that shifts towards CD137-rich immune niches are correlated with both off-target immune-related adverse events and anti-tumor efficacy. Targeting the tumor microenvironment through conditional activation of anti-CD137 signaling in combination with ICIs can modulate the reactivity of T cells and macrophages for localized tumor killing without the potential off-target immune-related risks associated with ICIs alone.

ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma.

Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63/IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.

Controversies on the treatment strategy for rectal submucosal cancer: case series and review of the literature.

Endoscopic submucosal dissection (SD) has emerged as one of the treatment strategies for submucosal rectal cancers. The present study reviewed the clinical outcomes of patients with rectal submucosal cancer treated by ESD. This was a retrospective review of four patients who had rectal tumor treated by ESD from 2010 to 2012 with histopathology showing T1 submucosal adenocarcinoma. The mean age (SD) was 69.5 (7.33) and the male to female ratio was 3:1. There were no post-ESD complications. The mean (SD) size of the tumors was 2.93 (0.87) cm. One patient with deep resection margin involvement received laparoscopic low anterior resection. Another with deep margin involvement of <1 mm refused surgery and was treated by chemoradiotherapy.There was no recurrence in all the cases with a mean follow-up duration of 461.3 (209.0) days. ESD was one of the important treatment strategies for T1sm-s rectal cancer especially when the risk of nodal metastasis was low. ESD spared the patient from colostomy when the T1 cancer was located in the lower third of the rectum. The role of adjuvant and neoadjuvant chemoradiotherapy remains controversial.

Percutaneous closure of gastrorenal shunt as adjunctive therapy for esophageal carcinoma.

The embolization of gastric varices is an established technique for acute bleeding in patients with portal hypertension. Here, we report an attempt to embolize a gastrorenal shunt to facilitate esophagectomy in a patient with an esophageal malignancy. To our knowledge, this is the first case in the literature to highlight the role of interventional medicine in the treatment of patients with esophageal malignancy.

Circulating Tumor DNA Dynamics as Prognostic Markers in Locally Advanced and Metastatic Esophageal Squamous Cell Carcinoma.

Importance: Esophageal squamous cell carcinoma (ESCC) is a deadly disease with frequent recurrence. There are unmet needs for prognostic biomarkers for dynamically monitoring disease progression and detecting minimal residual disease. Objective: To examine whether circulating tumor DNA is clinically useful as a prognostic biomarker for ESCC recurrence and patient survival. Design, Setting, and Participants: This single-center, population-based cohort study consecutively enrolled 147 patients receiving curative (n = 74) or palliative (n = 73) treatment at the surgery and clinical oncology departments of Queen Mary Hospital in Hong Kong from August 1, 2016, to September 31, 2021. Patients were followed up for 2 years. Plasma samples were collected at different longitudinal time points for a prospective circulating tumor DNA (ctDNA) next-generation sequencing profiling study of 77 actionable genes. Intervention: Patients were treated with up-front surgery, neoadjuvant chemoradiotherapy plus surgery with or without adjuvant therapy, or palliative chemotherapy (CT). Main Outcomes and Measures: Detection of circulating tumor DNA (ctDNA), progression-free survival (PFS), and overall survival (OS). Results: A total of 478 serial plasma samples from 147 patients with locoregional or metastatic ESCC were prospectively analyzed. Among the 74 patients in the curative group (median [range] age, 66 [46-85] years; 56 [76.0%] male), 44 (59.5%) relapsed and 36 (48.6%) died. For patients receiving curative surgical treatment, a high ctDNA level (hazard ratio [HR], 7.84; 95% CI, 1.87-32.97; P = .005) and ctDNA alterations (HR, 5.71; 95% CI, 1.81-17.97; P = .003) at 6 months postoperation were independently associated with poor OS. Among patients receiving neoadjuvant chemoradiotherapy, postneoadjuvant ctDNA alterations were associated with poor PFS (HR, 3.16; 95% CI, 1.17-8.52; P = .02). In the 73 patients in the palliative group (median [range] age, 63 [45-82] years; 63 [86.0%] male), 71 (97.3%) had disease relapse and 68 (93.2%) died. Detectable pre-CT NFE2L2 alterations were independently associated with PFS (HR, 2.99; 95% CI, 1.35-6.61; P = .007) and OS (HR, 28.39; 95% CI, 7.26-111.03; P = 1.52 × 10-6), whereas high ctDNA levels (HR, 2.41; 95% CI, 1.18-4.95; P = .02) and alterations in pre-cycle III ctDNA (HR, 1.99; 95% CI, 1.03-3.85; P = .04) showed weaker associations with PFS. Alterations in pre-CT ctDNA were independently associated with OS (HR, 4.46; 95% CI, 1.86-10.69; P = 7.97 × 10-4). Conclusions and Relevance: The findings of this cohort study indicate that prognostic models incorporating ctDNA features are useful in ESCC. Both ctDNA level and NFE2L2 alterations pre-CT and before cycle III were found to be important prognostic factors in palliative groups, and ctDNA alterations after treatment and at 6 months after surgery may define high-risk groups for recurrence in the curative group. High-risk patients can benefit by a timely switch to the next therapeutic options.

Efficacy, safety, and correlative biomarkers of bintrafusp alfa in recurrent or metastatic nasopharyngeal cancer patients: a phase II clinical trial.

Background: The strategy of dual blockade of TGF-ß and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients. Methods: In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Findings: Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFß1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR. Interpretation: Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning. Funding: The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.

SMARCB1 (INI-1)-Deficient Sinonasal Carcinoma: A Systematic Review and Pooled Analysis of Treatment Outcomes.

(1) Background: SMARCB1 (INI-1)-deficient sinonasal carcinoma is a rare sinonasal malignancy; since its discovery and description in 2014, less than 200 cases have been identified. It is almost impossible to perform randomized-controlled trials on novel therapy to improve treatment outcomes in view of its rarity. We performed a systematic review of all the published case reports/series and included our patients for survival analysis. (2) Methods: In this systematic review, we searched from PubMed-MEDLINE, EMBASE, Scopus, Cochrane Library, CINAHL, and Google Scholar for individual patient data to identify and retrieve all reported SMARCB1-deficient sinonasal carcinoma. Clarification on treatment details and the most updated survival outcomes from all authors of the published case reports/series were attempted. Survival analysis for overall survival (OS) and identification of OS prognostic factors were performed. This systematic review was registered with PROSPERO (CRD42022306671). (3) Results: A total of 67 publications were identified from the systematic review and literature search. After excluding other ineligible and duplicated publications, 192 patients reported were considered appropriate for further review. After excluding duplicates and patients with incomplete pretreatment details and survival outcomes, 120 patients were identified to have a complete set of data including baseline demographics, treatment details, and survival outcomes. Together with 8 patients treated in our institution, 128 patients were included into survival analysis. After a median follow up of 17.5 months (range 0.3-149.0), 50 (46.3%) patients died. The 1-year, 2-year and 3-year OS rates were 84.3% (95% CI % 77.6-91.0), 62.9% (95% CI 53.1-72.7), and 51.8% (95% CI 40.8-62.8), respectively, and the median OS was 39.0 months (95% CI 28.5-49.5). Males (p = 0.029) and T4b disease (p = 0.013) were significant OS prognostic factors in univariable analysis, while only T4b disease (p = 0.017) remained significant in multivariable analysis. (4) Conclusions: SMARCB1-deficient sinonasal carcinoma is an extremely aggressive sinonasal malignancy with a dismal prognosis. Early diagnosis and a multimodality treatment strategy are essential for a better treatment and survival outcome.

Telomeres acquire distinct heterochromatin characteristics during siRNA-induced RNA interference in mouse cells.

Telomeres are protective structures present at the ends of linear chromosomes and consist of simple repeating-DNA sequences and specialized proteins [1, 2]. Integrity of the telomeres is important in maintaining genome stability[1-6]. RNA interference(RNAi) involves short double-stranded RNA (21-23 nucleotides long), termed short interference RNA(siRNA), resulting in the downregulation of genes with cognate sequences [7-9]. During transient siRNA-induced RNAi in mouse fibroblast cultures, we found significant reversible changes related to the telomeres. Telomeres acquired distinct heterochromatin features. There were increased bindings of Argonaute-1 (AGO1), telomeric repeat-binding factor 1(TERF1), and heterochromatin protein 1beta (HP1beta) on the telomeres. Histone H3 (lysine 9) was hypermethylated at the telomeres. The chromosome ends also were associated with an unidentified RNA. During RNAi, expression of a transgene inserted adjacent to the telomere was downregulated. In addition, the concentration of a group of heterogeneous high-molecular-weight RNA containing telomeric repeat sequences was increased, and this RNA formed a small number of transient, discrete nuclear foci. Our findings suggest that telomeres participate actively in the siRNA-induced RNAi process. These responses of telomeres to the RNAi process might partially account for the off-target effects of RNAi.

Deep Learning Predicts the Malignant-Transformation-Free Survival of Oral Potentially Malignant Disorders.

Machine-intelligence platforms for the prediction of the probability of malignant transformation of oral potentially malignant disorders are required as adjunctive decision-making platforms in contemporary clinical practice. This study utilized time-to-event learning models to predict malignant transformation in oral leukoplakia and oral lichenoid lesions. A total of 1098 patients with oral white lesions from two institutions were included in this study. In all, 26 features available from electronic health records were used to train four learning algorithms-Cox-Time, DeepHit, DeepSurv, random survival forest (RSF)-and one standard statistical method-Cox proportional hazards model. Discriminatory performance, calibration of survival estimates, and model stability were assessed using a concordance index (c-index), integrated Brier score (IBS), and standard deviation of the averaged c-index and IBS following training cross-validation. This study found that DeepSurv (c-index: 0.95, IBS: 0.04) and RSF (c-index: 0.91, IBS: 0.03) were the two outperforming models based on discrimination and calibration following internal validation. However, DeepSurv was more stable than RSF upon cross-validation. External validation confirmed the utility of DeepSurv for discrimination (c-index-0.82 vs. 0.73) and RSF for individual survival estimates (0.18 vs. 0.03). We deployed the DeepSurv model to encourage incipient application in clinical practice. Overall, time-to-event models are successful in predicting the malignant transformation of oral leukoplakia and oral lichenoid lesions.

Comprehensive single-cell sequencing reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of nasopharyngeal carcinoma.

The tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.

Liquid Biopsy Serial Monitoring of Treatment Responses and Relapse in Advanced Esophageal Squamous Cell Carcinoma.

(1) Background: Early predictive markers to track treatment responses are needed for advanced esophageal squamous cell carcinoma (ESCC) patients. We examined the prognostication and risk stratification role of liquid biopsy serial monitoring for this deadly cancer. (2) Methods: Circulating tumor cells (CTCs) and plasma cell-free DNA (cfDNA) were isolated from 60 ESCC patients treated by chemotherapy (CT) at five serial timepoints: baseline (CTC1/cfDNA1), CT pre-cycle III (CTC2/cfDNA2), CT post-cycle IV, end of CT and relapse. (3) Results: In 45/57 ESCC patients with evaluable CTC counts at CT pre-cycle III, positive CTC2 (≥3 CTCs) is independently associated with response at interim reassessment and progression-free survival (PFS) in multivariate analysis. In 42/57 ESCC patients with changes of CTC1/CTC2 and cfDNA1/cfDNA2, patients categorized into four risk groups based on the number of favorable and unfavorable changes of CTC1/CTC2 and cfDNA1/cfDNA2, were independently associated with overall survival (OS) by multivariate analysis. (4) Conclusions: CTC counts at pre-cycle III are independently associated with response at interim reassessment and PFS. Combined changes of CTC counts and cfDNA levels from baseline to pre-cycle III are independently associated with OS. Longitudinal liquid biopsy serial monitoring provides complementary information for prediction and prognosis for CT responses in advanced ESCC.

Outcome of radical excision of anorectal gastrointestinal stromal tumors in Hong Kong Chinese patients.

Anorectal gastrointestinal stromal tumor (GIST) is a rare disease entity with malignant potential. Medical records of six patients (median age 68 years) with anorectal GIST who underwent surgical treatment at our institution between 1992 and 1999 were retrospectively reviewed. Four patients presented with rectal bleeding. The tumors were located in the mid and lower rectum in 4 patients and in the anal canal in 2 patients. The median tumor diameter was 4.5 cm. One patient who had undergone local excisions in another hospital presented with recurrent GIST. He refused radical excision and underwent wide local excision again. He developed recurrence 2 years later and underwent salvage pelvic exenteration, but finally died of disseminated disease. Five patients underwent initial radical excision. Among them, 3 developed recurrences (one each local, distant and both) at a median duration of 50.3 months. Two patients died of the disease, while one patient who had both local and distant recurrences resected remained alive till the end of the study period (median duration of follow-up of the 5 patients was 84.6 months). At 5 years, of 5 patients who underwent initial radical excision, 3 and 4 patients, respectively, had disease-free and overall survival. Recurrence of anorectal GIST is common despite radical excision. Nevertheless, a reasonable survival rate can be achieved.

Topical Application of Mesenchymal Stromal Cells Ameliorated Liver Parenchyma Damage After Ischemia-Reperfusion Injury in an Animal Model.

BACKGROUND: Ischemia-reperfusion injury (IRI) is commonly encountered after liver surgery. This study evaluated the hepatoprotective effects of topically applied adipose-derived mesenchymal stromal cells (ADMSCs) on hepatic IRI in a rat model. METHODS: ADMSCs from transgenic green fluorescent protein Sprague-Dawley rats were topically applied to the liver surface of Sprague-Dawley rats after hepatic IRI and fixed in position by fibrin glue (group A, n = 24). An equivalent amount of ADMSCs were administered through the portal (group B, n = 24) or tail vein (group C, n = 24). In the control group (group D, n = 20), no treatment was given to the IRI liver. RESULTS: All the rats in group A and group D survived. Within 2 days after hepatic IRI, only 50% of rats survived in group B, and ADMSCs were detected in thromboemboli within large vessels. 62.5% of the rats died in group C because most of the ADMSCs were trapped in the lungs. ADMSCs migrated across the liver capsule and homed to the injured liver parenchyma 3 days after topical application in group A. The homed ADMSCs expressed hepatocyte nuclear factor-4α and hepatocyte nuclear factor-1. Compared with group D, the rate of hepatic regeneration in group A was enhanced with less inflammation, smaller necrotic areas, and improved liver function. Proinflammatory cytokines IL-6, IL-21, and CD70 were significantly downregulated in group A by 6.3-, 2.7-, and 12.7-fold, respectively (P < 0.05). The neurogenic locus NOTCH homolog protein pathway was activated in the topical ADMSCs. CONCLUSIONS: Topically applied adipose-derived mesenchymal stromal cells demonstrated hepatoprotective effects on hepatic IRI in an animal model.

'Open-and-close' pituitary surgery in an acromegalic man presenting with excessive sweatiness.

Ectopic-acromegaly is rare. Diagnosing ectopic-acromegaly is challenging given that the clinical and biochemical manifestations can be almost indistinguishable from those of patients with growth hormone secreting pituitary adenomas. This case report highlights the importance of clinical vigilance in differentiating between the two conditions. A 41-year-old Caucasian man presented with typical features of acromegaly with an enlarged pituitary and a lung lesion. Although excision of the lung mass showed a carcinoid tumour, normalisation of growth hormone factors did not occur soon enough. This led to a presumed diagnosis of a pituitary adenoma. However, no pituitary tumour was identified during trans-sphenoidal surgery. Postoperatively, the patient improved clinically and biochemically. Retrospective histological examination of the excised lung lesion showed a small proportion of tumour cells containing growth hormone releasing hormone (GHRH), suggesting ectopic-GHRH production from the lung neuroendocrine tumour. An open-and-close trans-sphenoidal surgery could have been avoided in this patient with ectopic-GHRH acromegaly.

The aqueous extract of rhizome of Gastrodia elata Blume attenuates locomotor defect and inflammation after traumatic brain injury in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Traumatic brain injury (TBI) has an incident rate of 200-300 people per 100,000 annually in the developed countries. TBI has relatively high incidence at an early age and may cause long-term physical disability. Patients suffered from severe TBI would have motor and neuropsychological malfunctions, affecting their daily activities. Traditionally, Gastrodia elata Blume is a Chinese Medicines which was used for the head diseases, while their efficiency on reducing brain damage was still largely unknown. In the present study, we aimed to examine the effect of water extract of G. elata Blume (GE) against TBI and elucidate its underlying mechanism. MATERIALS AND METHODS: Sprague-Dawley rats were treated with GE for 7 days, immediately after controlled cortical impact-induced TBI. Impaired neurobehavioral functioning was measured on day 3 and 6 after TBI. Histology of TBI was examined to assess the extent of inflammation, and the expressions of pro-inflammatory cytokines were examined by immunofluorescence study on day 7. RESULTS: GE treatment significantly improved the impaired locomotor functions induced by TBI. GE treatment reduced inflammation and gliosis in the penumbral area. The increase in brain levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha observed in non-GE treated TBI rats were also reversed. CONCLUSIONS: GE treatment attenuated the locomotor deficit caused by TBI. The anti-inflammatory activity might be mediated by inhibition of pro-inflammatory cytokines responses in the TBI-brain.

The putative protein 6 of the severe acute respiratory syndrome-associated coronavirus: expression and functional characterization.

The SARS-CoV open reading frame 6 (ORF6) is transcribed into mRNA6 and encodes a putative 7.5 kDa accessory protein, SARS 6, with unknown function. In this study, we have confirmed the SARS 6 protein expression in lung and intestine tissues of the SARS patients and in SARS-CoV infected Vero E6 cells by immunohistochemistry. Further studies by immunoblot and confocal microscopy analyses revealed the expression and the endoplasmic reticulum (ER) localization of the recombinant SARS 6 protein in mammalian cells. Expression of SARS 6 protein in mammalian cells elicits biological activity of stimulating cellular DNA synthesis.