[Characteristics of the tumor microenvironment and therapeutic progress in malignant pleural effusion].

Malignant pleural effusion (MPE) can be secondary to various advanced malignant tumors. Although systemic anti tumor therapy may be effective in primary tumors, it cannot reduce the accumulation of MPE in proportion of the patients. The interaction of tumor cells, immune cells, and mesenchymal cells, as well as the abnormal proliferation of tumor-associated blood vessels, together create an immunosuppressive microenvironment for MPE, which promotes the abnormal proliferation of tumor cells and the accumulation of MPE. With the in-depth study of the tumor microenvironment, the application of local systemic anti-tumor therapy with local intrathoracic application of immune checkpoint inhibitors, immune cells, cytokines, and gene-mediated cytotoxic immunotherapy are able to alleviate the immunosuppressive tumor microenvironment and inhibit the accumulation of MPE. This article aimed to describe the tumor microenvironment in MPE and provide clues for identifying novel therapeutic targets.

Prevalence and burden of skin diseases among the elderly in Singapore: a 15-year clinical cohort study.

BACKGROUND: Populations around the world are rapidly ageing. The profile of skin diseases in the elderly is likely to present unique demands on the healthcare system. OBJECTIVES: To provide current data on the burden of skin diseases in Singaporean patients and identify differences in the pattern of skin diseases between elderly patients and the rest of the population. METHODS: This was a retrospective cohort study of 858 117 patients who attended the National Skin Centre between 2004 and 2018. Prevalence was calculated by grouping International Classification of Diseases codes into different categories of skin conditions based on Global Burden of Disease and American Academy of Dermatology classifications. Years lost to disability (YLDs) and disability-adjusted life years (DALYs) were calculated to report the morbidity and mortality of skin diseases. Differences of each skin condition between age groups were compared. RESULTS: The three most prevalent dermatoses across all age groups were dermatitis (33.3%), acne vulgaris (8.3%) and viral skin diseases (7.5%). The top three most common skin conditions among the elderly were dermatitis (37.7%), viral skin diseases (6.2%) and fungal skin diseases (4.3%). Decubitus ulcers, keratinocyte carcinomas and scabies represented a significant proportion of YLD per 100 000 in the elderly (P < 0.001). Malignant melanomas, keratinocyte carcinomas, cellulitis, pyoderma and decubitus ulcers contributed to high DALYs in patients aged 70-80 years. CONCLUSION: Aligning health systems with specific healthcare needs will reduce the disproportionately high burden of skin disease observed in the elderly.

A three-dimensional exoscope system for bilateral simultaneous cochlear implant surgery: how I do it.

BACKGROUND: This paper reports the first case of simultaneous bilateral cochlear implant surgery performed exclusively with a three-dimensional exoscope. It also discusses the optimum operative set-up and the feasibility of three-dimensional exoscopic ear surgery as an alternative to the microscope. METHOD: The Vitom three-dimensional exoscope system (Karl Storz) was used. RESULTS: The surgery was successfully completed, with no peri-operative complications. Both the operation time and the surgical outcome for the patient were comparable with the previous cochlear implant surgical procedures performed in our centre using the conventional operating microscope. CONCLUSION: This paper demonstrates that exclusive use of the three-dimensional exoscope is a viable alternative to the operating microscope for selected otological cases. It is clear that the three-dimensional exoscopic technique is potentially very promising for future surgical procedures, provided that cases are selected carefully to prevent compromising exposure, efficiency or patient safety.

Application of rigid bronchoscopy for emergent removal of tracheobronchial foreign body in paediatric cases: a learning curve study.

OBJECTIVES: To explore the factors associated with the operative duration for paediatric tracheobronchial foreign body removal by rigid bronchoscopy, and to analyse the learning curve for mastery of the rigid bronchoscopy skill. METHODS: A retrospective study was performed of paediatric cases of tracheobronchial foreign body removal by rigid bronchoscopy in our department from January 2007 to July 2019. Multivariate Cox regression analysis was used to analyse the factors associated with the operative duration. In addition, the learning curves for two doctors were evaluated by curve-fitting regression analysis. RESULTS: A total of 410 paediatric cases of tracheobronchial foreign body removal by rigid bronchoscopy were evaluated. The operative duration was significantly influenced by the skill of the doctor. The learning curves for both doctor A and doctor B demonstrated two typical phases: an initially rapidly changing learning phase followed by a steady consolidation phase. CONCLUSION: The operative duration for paediatric tracheobronchial foreign body removal by rigid bronchoscopy was associated with the skill of the doctor. In order to fully master the rigid bronchoscopy technique, doctors should perform a minimum number of procedures to pass the learning phase and reach the consolidation phase.

A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers.

Gastric cancer is among the most prevalent and deadliest of cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a Claudin18-IRES-CreERT2 allele to selectively drive conditional dysregulation of the Wnt, Receptor Tyrosine Kinase and Trp53 pathways within the gastric epithelium. This resulted in highly reproducible metastatic, chromosomal-instable-type gastric cancer. In parallel, we developed orthotopic cancer organoid transplantation models to evaluate tumour-resident Lgr5+ populations as functional cancer stem cells via in vivo ablation. We show that Cldn18 tumours accurately recapitulate advanced human gastric cancer in terms of disease morphology, aberrant gene expression, molecular markers and sites of distant metastases. Importantly, we establish that tumour-resident Lgr5+ stem-like cells are critical to the initiation and maintenance of tumour burden and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically relevant mechanistic insights into cancer progression and as preclinical models for evaluating therapeutic targets.

Giant pedunculated oesophageal liposarcomas: A review of literature and resection techniques.

INTRODUCTION AND PRESENTATION OF CASE: Liposarcomas are rare causes of oesophageal tumours, accounting for <1% of tumours. We present a case of a dedifferentiated oesophageal liposarcoma arising from a giant fibrovascular polyp for which resection was performed via a left cervical oesophagostomy with transgastric retrieval of tumour. We also review the existing literature focusing on discussion of resection techniques. DISCUSSION: To date, 62 cases of oesophageal liposarcoma have been reported in the literature. They usually occur in males (74.2%), with a median age of 66 years (range 38-84 years). Such tumours present most commonly with dysphagia (69.4%); usually arise from the cervical oesophagus (79%), and are well-differentiated. Treatment options include surgery and recently, endoscopic resection techniques such as submucosal dissection (ESD). CONCLUSION: Giant oesophageal liposarcomas are very rare tumours. Such tumours are usually polypoid, arising from a pedicle. As such, resection techniques have shifted away from oesophagectomy to less invasive means such as endoscopic resection or oesophagostomy. Decision on type of resection technique depends on tumour characteristics and location; with the guiding principle being resection with clear margins in order to prevent local recurrence.

Epidemiology and prognostic factors for mycosis fungoides and Sézary syndrome in a multi-ethnic Asian cohort: a 12-year review.

BACKGROUND: Limited information exists regarding survival of Asian patients with mycosis fungoides (MF) and Sézary syndrome (SS). OBJECTIVE: To evaluate the epidemiology, outcome and prognostic factors of these patients. METHODS: A retrospective review of MF/SS cases diagnosed from 2000 to 2011 at a tertiary referral dermatology centre in Singapore was performed. RESULTS: Of 246 patients, 63% were male and the median age at diagnosis was 49 years. 73.2% were Chinese, 12.6% Indian, 6.9% Malay and 7.3% Caucasian. A total of 239 patients (97.2%) had MF and seven had SS. Median follow-up duration was 6.3 years, and median duration of symptoms at diagnosis was 13 months. For patients with MF, the majority had early disease (92.8% stage IA-IIA). 3.8% were stage IIB, 1.7% stage III and 1.7% stage IV. Complete response to treatment occurred in 78.2%, partial response in 9.6%, persistent but non-progressive disease in 10.0% and disease progression in 4.1% of patients. Large cell transformation occurred in 4.1% of patients. Mean overall survival during this study was 12.7 years, with death occurring in 2.5% of patients (all ≥stage IIB at diagnosis). For patients with SS, 71.4% presented with stage IVA disease, 28.6% stage IVB. Complete response to treatment occurred in 14.2%, persistent but non-progressive disease in 28.6% and disease progression in 57.2% of patients. Mean overall survival was 3.3 years within this study, with death occurring in 42.9% of SS patients. Prognostic factors associated with favourable recurrence-free survival were male gender (P = 0.008), early disease stage (T1) at diagnosis (P < 0.001) and absence of maintenance treatment after remission (P = 0.01). CONCLUSION: Compared to Caucasian and East Asian cohorts, MF in South-East Asians was diagnosed at a younger age and associated with lower mortality, largely due to greater prevalence of hypopigmented MF.

[Clinical application of HRCT three-dimensional reconstruction in traumatic ossicular chain interruption].

Objective:To investigate the clinical value of HRCT three-dimensional reconstruction technique in traumatic auditory chain traumatic fracture. Method:The clinical data of 14 patients with traumatic ear ossicular chain interruption were analyzed retrospectively. To evaluate the injury site and degree of the auditory chain before surgery, all the 14 patients underwent,HRCT scanning and three-dimensional reconstruction. The reconstructed auditory chain was observed from multiple angles and compared with the surgical exploration results under microscope. Result:The coincidence rate between ossicular chain injury observed by temporal bone HRCT scan before operation and ossicular chain injury observed during surgery was only 28.57%, the coincidence rate between ossicular chain injury observed during surgery and ossicular chain injury observed by three-dimensional reconstruction is 85.71%.Therefore, three-dimensional reconstruction imaging technique could give the doctor more clearly and stereoscopic images for the destruction of ossicular chain. Conclusion:Preoperative three-dimensional reconstruction can display and diagnosis of auditory ossicular chain destruction more clearly. It can be used to accurately evaluate auditory ossicular chain pathological changes, to develop individualized surgical plans and assess the risk of surgery.

APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL.

Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells, resulting in clonal selection. Although most cancer-causing mutations have been detected in the protein-coding regions of the cancer genome; driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well.

Restoration of shoulder abduction in brachial plexus avulsion injuries with double neurotization from the spinal accessory nerve: a report of 13 cases.

In upper (C5-C7) and total (C5-T1) root avulsion brachial plexus injury, a method of double neurotization from a single donor spinal accessory nerve to two target nerves (suprascapular nerve and axillary nerve) may be done, leaving donor nerves available for reconstruction procedures to restore other aspects of upper limb function. A mean range of shoulder abduction of 91° (SD 25°) was achieved through this procedure in our study of 13 cases, of which seven cases were C5-C7 root avulsion and six cases were C5-T1 root avulsion brachial plexus injuries. Six of the former group and three of the latter group achieved >90° shoulder abduction. The technique of double neurotization from a single donor nerve provides favourable results in restoring shoulder abduction in avulsion brachial plexus injuries. LEVEL OF EVIDENCE: IV.

Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia.

The transcription factor TAL1/SCL is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1-regulated super-enhancer controlling the GIMAP locus, which resides within an insulated chromosomal locus in T-ALL cells. The GIMAP genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The GIMAP enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human GIMAP genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the GIMAP enhancer contributes to T-cell leukemogenesis.

Endoscopic transnasal approach to medial orbital lesions.

OBJECTIVE: This case report presents our experience of endoscopic transnasal management of medial intra- and extraconal lesions. CASE REPORT: An endoscopic transnasal approach to intra-orbital lesions was used for nine patients. Four patients had intraconal lesions and five had lesions in the extraconal space. Post-operatively, seven patients reported an improvement in visual acuity and two reported stable vision. There were no complications of cerebrospinal leakage or diplopia. CONCLUSION: This case series demonstrated the safety and effectiveness of an endoscopic transnasal approach to managing intraconal and extraconal lesions. This minimally invasive technique should be considered a valid alternative for accessing orbital tumours, particularly those located in the medial compartment.

Mutant p53-R273H mediates cancer cell survival and anoikis resistance through AKT-dependent suppression of BCL2-modifying factor (BMF).

p53 is the most frequently mutated tumor-suppressor gene in human cancers. Unlike other tumor-suppressor genes, p53 mutations mainly occur as missense mutations within the DNA-binding domain, leading to the expression of full-length mutant p53 protein. Mutant p53 proteins not only lose their tumor-suppressor function, but may also gain new oncogenic functions and promote tumorigenesis. Here, we showed that silencing of endogenous p53-R273H contact mutant, but not p53-R175H conformational mutant, reduced AKT phosphorylation, induced BCL2-modifying factor (BMF) expression, sensitized BIM dissociation from BCL-XL and induced mitochondria-dependent apoptosis in cancer cells. Importantly, cancer cells harboring endogenous p53-R273H mutant were also found to be inherently resistant to anoikis and lack BMF induction following culture in suspension. Underlying these activities is the ability of p53-R273H mutant to suppress BMF expression that is dependent on constitutively active PI3K/AKT signaling. Collectively, these findings suggest that p53-R273H can specifically drive AKT signaling and suppress BMF expression, resulting in enhanced cell survivability and anoikis resistance. These findings open the possibility that blocking of PI3K/AKT will have therapeutic benefit in mutant p53-R273H expressing cancers.

Body fat composition impacts the hematologic toxicities and pharmacokinetics of doxorubicin in Asian breast cancer patients.

Body surface area (BSA)-based dosing leads to wide inter-individual variations in drug pharmacokinetics and pharmacodynamics, whereas body composition has been shown to be a more robust determinant of efficacy and toxicity of certain chemotherapeutic agents. We correlated various parameters of body composition with doxorubicin pharmacokinetics and hematologic toxicities in Asian patients with locally advanced or metastatic breast cancer. Our analysis included 84 patients from two studies who received pre- or post-operative single-agent doxorubicin; pharmacokinetic parameters were available for 44 patients. Body composition parameters were derived from CT cross-sectional images and population pharmacokinetic analysis was conducted using mixed-effects modeling. Higher intra-abdominal fat volume and fat ratio (intra-abdominal:total abdominal fat volume) correlated with greater incidence of grade 4 leukopenia on cycle 1 day 15 (mean intra-abdominal fat volume: 97.4 ± 46.5 cm(3) vs 63.4 ± 30.9 cm(3), p = 0.014; mean fat ratio: 0.43 ± 0.11 vs 0.33 ± 0.09, p = 0.012, grade 4 vs grade 0-3 leukopenia). On subset analysis, this relationship was maintained even in underweight patients. Concordantly, there were positive correlations between doxorubicin AUC and intra-abdominal fat volume as well as total abdominal fat volume (r (2) = 0.324 and 0.262, respectively, all p < 0.001). BSA and muscle volume did not predict for doxorubicin pharmacokinetics or toxicities. High-intra-abdominal fat volume but not BSA predicted for greater doxorubicin exposure and hematologic toxicities, suggesting that body composition is superior to BSA in determining doxorubicin pharmacokinetics and pharmacodynamics. Body composition has an emerging role in chemotherapy dose determination.

ERG rearrangement and protein expression in the progression to castration-resistant prostate cancer.

BACKGROUND: Approximately half of the prostate carcinomas are characterized by a chromosomal rearrangement fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG. Aim of this study was to comprehensively analyze the role and impact of the ERG rearrangement and protein expression on the progression to castration-resistant (CR) disease. METHODS: We used a tissue microarray (TMA) constructed from 114 hormone naive (HN) and 117 CR PCs. We analyzed the ERG rearrangement status by fluorescence in situ hybridization and the expression profiles of ERG, androgen receptor (AR) and the proliferation marker Ki67 by immunohistochemistry. RESULTS: Nearly half of the PC tissue specimens (HN: 38%, CR: 46%) harbored a TMPRSS2-ERG gene fusion. HN PCs with positive translocation status showed increased tumor cell proliferation (P<0.05). As expected, TMPRSS2-ERG gene fusion was strongly associated with increased ERG protein expression in HN and CR PCs (both P<0.0001). Remarkably, the study revealed a subgroup (26%) of CR PCs with ERG rearrangement but without any detectable ERG protein expression. This subgroup showed significantly lower levels of AR protein expression and androgen-regulated serum PSA (both P<0.05). CONCLUSIONS: In this study, we identified a subgroup of ERG-rearranged CR PCs without detectable ERG protein expression. Our results suggest that this subgroup could represent CR PCs with a dispensed AR pathway. These tumors might represent a thus far unrecognized subset of patients with AR-independent CR PC who may not benefit from conventional therapy directed against the AR pathway.

Arthroscopic debridement of intercarpal ligament and triangular fibrocartilage complex tears.

INTRODUCTION: Wrist arthroscopy has evolved since its inception to become an essential diagnostic and therapeutic tool for the management of various wrist disorders. Our study aimed to examine the outcomes of arthroscopic debridement in the treatment of scapholunate (SL), lunotriquetral (LT) and triangular fibrocartilage complex (TFCC) tears. METHODS: We conducted a retrospective review of 68 consecutive wrist arthroscopies performed at our institution between January 2000 and July 2005. All the patients complained of wrist pain, which often interfered with their daily activities, work or sports. A standard arthroscopic technique was employed in all. Any intercarpal ligament or TFCC tears found were debrided. RESULTS: There were 42 patients with TFCC tears, 58 with SL tears and 49 with LT tears. At a mean follow-up time of 16.6 months, 85.3% of the patients reported an improvement in symptoms and 27.9% had improved range of motion. Grip strength improved by 11.8%. All except two patients returned to their original activities. Outcome following arthroscopic debridement was determined using the Mayo Modified Wrist Score. Based on the postoperative wrist scores of 47 patients, 24 were rated excellent, 17 good, four fair and two poor. By comparing the pre- and postoperative wrist scores of 31 patients, we were able to demonstrate significant improvement in patients who underwent wrist arthroscopies. CONCLUSION: Our study demonstrated that there is a definite role for arthroscopic debridement in the management of SL, LT and TFCC tears.

ERG protein expression and genomic rearrangement status in primary and metastatic prostate cancer--a comparative study of two monoclonal antibodies.

BACKGROUND: Overexpression of the ERG protein is highly prevalent in prostate cancer (PCa) and commonly results from gene fusions involving the ERG gene. Recently, N-terminal epitope-targeted mouse and a C-terminal epitope-targeted rabbit monoclonal anti-ERG antibody (ERG-MAbs) have been introduced for the detection of the ERG protein. Independent studies reported that immunohistochemistry (IHC) with both ERG-MAbs highly correlates with the underlying ERG gene rearrangement status. However, comparative studies of both antibodies are lacking. Here, we are among the first to compare the mouse ERG-MAb with the rabbit ERG-MAb for their concordance on the same PCa cohort. Furthermore, we assessed whether the ERG protein expression is conserved in lymph node and distant PCa metastases. METHODS: We evaluated tissue microarrays of 278 specimens containing 265 localized PCa, 29 lymph node, 30 distant metastases and 13 normal prostatic tissues. We correlated ERG protein expression with ERG rearrangement status using an ERG break-apart fluorescence in-situ hybridization assay and IHC of both ERG-MAbs. RESULTS: ERG expression and ERG rearrangement status were highly concordant regardless of whether the mouse or rabbit ERG-MAb was used (97.8% versus 98.6%, respectively). Of interest, both ERG antibodies reliably detected the ERG expression in lymph node and distant PCa metastases, of which a subset underwent decalcification. Lymphocytes only revealed immunoreactivity using the rabbit ERG-MAb. If ERG protein expression was present in localized PCa, we observed the same pattern in the corresponding lymph node metastases. CONCLUSIONS: By demonstrating a broad applicability of IHC to study ERG protein expression using either antibody, this study adds an important step toward a facilitated routine clinical application. Further, we demonstrate that the clonal nature of the ERG rearrangement is not restricted to the genomic level, but proceeds in the proteome. Together, our results simplify future efforts to further eliucidate the biological role of ERG in PCa.

Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers.

BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking. METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome. RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome. CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.