An open-label study of pemigatinib in cholangiocarcinoma: final results from FIGHT-202.

BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period. PATIENTS AND METHODS: The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently. CONCLUSIONS: Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202.

[Parameningeal or non-parameningeal head and neck rhabdomyosarcoma: a study based on propensity score matching and survival analysis].

Objective: To compare the prognoses between parameningeal and non-parameningeal head and neck rhabdomyosarcoma based on propensity score matching and to explore the prognostic factors of overall survival in patients with head and neck rhabdomyosarcoma. Methods: The medical records of 64 patients with pathologically diagnosed as head and neck rhabdomyosarcoma from January 2016 to May 2020 in Peking Union Medical College Hospital were retrospectively retrieved, including 31 males and 33 females, with an average age of (8.0±8.9) years. Kaplan-Meier method was used to draw and compare survival curves in subgroup analysis according to different histopathological characteristics. Patients were divided into non-parameningeal (27 cases) and parameningeal (37 cases) group based on the location of primary lesion. Patients were further selected using 1∶1 propensity score matching method. The basic clinical data and overall survival were compared before and after matching. Prognostic factors were anlysed using Cox's proportional hazards regression model. Results: In 64 patients with head and neck rhabdomyosarcoma, lower risk stratification, and lower TNM stage indicated higher overall survival (all P<0.05). Before matching, patients in parameningeal group presented with higher T stage and IRS (Intergroup Rhabdomyosarcoma Study) staging (all P<0.05). There were no significant differences in basic clinical data and 1-, 2-, and 3-year overall survival rates between two groups after matching(P>0.05). Tumor size smaller than 5 cm, embryonal histology, negative FOXO1 fusion gene, lower risk stratification, and lower TNM stage were associated with higher overall survival (all P<0.05). Among these, tumor size and histology were independent prognostic factors (HR=2.36, 95%CI:1.07-5.20, P=0.033; HR=5.54, 95%CI: 1.18-25.95, P=0.030). Conclusions: There is no significant difference in overall survival between patients with parameningeal and non-parameningeal rhabdomyosarcomas. Tumor size smaller than 5 cm and embryonal histology are two independent prognostic factors.

[Textual research on Xilei Powder].

Xilei Powder is a commonly used prescription for the treatment of oral ulcers, and is originally used to treat scarlet fever. Scarlet fever is a warm-toxin disease from the perspective of the theory of warm disease. It is a warm infectious disease caused by epidemic. Xilei Powder was recorded in the Chinese Pharmacopoeia from 1953 edition to 2010 edition. As China joined Convention on International Trade in Endangered Species of Wild Fauna and Flora(CITES), Xilei Powder was removed from the Chinese Pharmacopoeia of 2015 edition due to the limitation of the use of animal drugs, such as ivory and rhinoceros horn. Xilei Powder has been widely used to treat such diseases as otolaryngology, fever, gynecological diseases, digestive diseases, and tumors. Does Xilei Powder have a unique place in clinical application? Can stable and effective alternative drugs be derived from original prescription? Due to the lack of theoretical studies on Xilei Powder, by consulting ancient books, monographs and papers, we comprehensively summarized and studied historical evolution and prescription connotation of Xilei Powder, and analyzed its drug origin and clinical application, in the hope to promote the theoretical study and clinical application.

A modified longitudinal incision via transoral sublabial approach for removal of the nasal vestibular cyst: a clinical observation.

OBJECTIVE: The aim of this study was to investigate the clinical effect of the removal of nasal vestibular cysts through a modified longitudinal incision via a transoral sublabial approach. METHOD: In 28 cases, a nasal vestibular cyst was removed through a modified longitudinal incision via a transoral sublabial approach. A visual analogue scale score was used to evaluate the numbness of the nasal alar and upper lip. Post-operative complications were recorded. Medical photographs were used for assessment. RESULTS: For all patients, incisions reached clinical primary healing one week after surgery. All patients were free of post-operative haematoma, infection, oronasal fistula and malformation. In the first week and the first month after surgery, numbness of the nasal alar and upper lip was recorded in few cases. The patients were followed up for 2-57 months without recurrence. CONCLUSION: Removal of nasal vestibular cysts via a transoral sublabial approach with a modified longitudinal incision is a minimally invasive and simple surgical method with few complications and a quick recovery.

Role of rural general surgeons in managing vascular surgical emergencies.

BACKGROUND: A rural general surgeon has historically been required to perform a wide variety of subspecialist procedures. Increasingly sub-specialized training programs have restricted younger surgeons' experience in the general surgery-associated subspecialties. Time critical vascular surgical emergencies are frequently encountered by rural general surgeons. This study aims to audit the prevalence of vascular surgical emergencies at a geographically remote regional centre and define the role of the general surgeon in managing these patients. METHODS: A single-centre, retrospective study was performed to analyse the outcomes of the patients who presented to Dubbo Base Hospital with an emergency vascular pathology or developed such a condition during admission, between October 2010 and June 2019. Patients were identified by relevant International classification of diseases (ICD) (10th revision) diagnostic codes for vascular emergencies. Acute complications following surgery for haemodialysis access were excluded. RESULTS: A total of 134 patients were identified during the study period and the majority were transferred to a tertiary centre for surgical intervention. Sixteen patients underwent emergency vascular surgery locally due to concerns about potential loss of life or limb if intervention was delayed by transfer; 69% of patients who underwent surgery locally survived with limb salvation. CONCLUSION: While most patients can safely be transferred to a tertiary centre, some require surgery locally in order to maximize chance of life or limb preservation. There is a strong argument for exposure of general surgical trainees with an interest in rural surgery to vascular surgery and other subspecialties.

[Application of image navigation assisted nasal endoscopic surgery in optic nerve decompression].

Objective:To explore the application and to evaluate the advantage of image navigation assisted nasal endoscopic surgery in optic nerve decompression. Method:Sixty patients accepted the image navigation assisted nasal endoscopic surgery therapy in optic nerve decompression were included in this retrospective study and followed up for about six months to four years. Result:The visual acuity was improved in 16 cases with visual acuity above light. One case is 10 cm index, two cases are 40 cm index, one case is 70 cm index, the visual acuity of rest 12 cases was between 0.04 and 0.30, two of them were missing from the field of view, the effective rate was 100%. The 44 cases without light sensation before operation, postoperative visual acuity was improved in 11 cases, four of which were light sensation and visible figure. Visual acuity of seven cases was between 0.03 and 0.08, one of them was missing from the field of view, the effective rate was 25%. No complications occurred. Conclusion:With the help of the image navigation, it is convenient and accurate to locate the anatomical marker sites such as orbital apex, optic canal and fracture site, internal carotid artery and so on, as a result, the accuracy and the success rate of the surgery were greatly improved.

Transoral and endoscope-assisted transoral approaches to resecting benign tumours of the parapharyngeal space located in the medial portion of the carotid sheaths and extending toward the skull base: our experience.

OBJECTIVE: Various surgical approaches have been described to remove tumours in the parapharyngeal space. This study investigated the feasibility of a transoral approach in the surgical management of parapharyngeal space benign tumours located in the medial portion of the carotid sheaths and extending toward the skull base. METHODS: Thirty-two patients were selected and underwent a transoral or an endoscope-assisted transoral approach in the surgical management of parapharyngeal space benign tumours located in the medial portion of the carotid sheaths. Medical photographs were used. RESULTS: All patients underwent complete resection of their lesions via a transoral or endoscope-assisted transoral approach. None of the patients demonstrated residual or recurrent neoplasms, either clinically or radiographically, during their follow up. CONCLUSION: Based on our studies, we assert that transoral and endoscope-assisted transoral approaches are suitable in managing parapharyngeal space benign tumours located in the medial portion of the carotid sheaths and extending toward the skull base.

[Wegner's granulomatosis of hypolarynx in a patient with laryngemphraxis: case report and review of literature].

Summary A patient suffered from progressive dyspnea and even laryngeal obstruction visited our department in May, 2017 and received emergency tracheotomy for assistance in breathing. There was no dysphagia, sore throat, fever, cough, hemoptysis and hematuresis. The pathological signs including facies dolorosa, three depressions sign, perforation of nasal septum. The laboratory examination showed that there were hematuresis and albuminuria. The urine bilirubin levels were elevated, antineutrophil cytoplasmic antibody (ANCA) was positive and antiproteinase 3 antibody was elevated. The electronic laryngoscope revealed the swelling of infraglottic region and laryngeal CT showed the subglottic area occupation and stenosis. The pulmonary CT showed the irregular mass shadow in lower lobe of right lung which was considered benign pathological changes. Finally, the diagnosis was subglottic Wegner's granulomatosis and result in laryngeal obstruction and need the first aid in clinic.

[Advances in treatment of locally advanced hypopharyngeal cancer].

Hypopharyngeal cancer is a common malignant tumor of otorhinolaryngology,which is considered to be one of the head and neck tumor with poor prognosis.Hypopharyngeal cancer is insidious in its onset and progresses rapidly,leading to significant delay in diagnosis; Most patients are in late stage at diagnosis. Surgery combined with chemoradiotherapy is the main treatment of locally advanced hypopharyngeal cancer. Biological treatment has drawn more and more attentions. In this paper,we summarize the progress in the treatment of locally advanced hypopharyngeal cancer.

[Hypopharyngeal angiofibroma: a case report].

Swallowing obstruction, gradually increase, with a sore throat, no fever, no haemoptysis, no dyspnea, routine tests: blood routine, biochemical examination, blood coagulation routine, electrocardiogram, chest X-ray, did not show abnormalities.

Down-regulated long non-coding RNA H19 inhibits carcinogenesis of renal cell carcinoma.

Long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in cancer biology. LncRNA H19 has been recently shown to be upregulated and play important roles in several cancers such as breast cancer, bladder cancer, and gastric cancer. However, the role of H19 in clear cell renal carcinoma (ccRCC) remains largely unknown.The expression levels of lncRNA H19 in ccRCC tissues and renal cancer cell lines were evaluated by quantitative Real-time PCR (qRT-PCR). And its association with overall survival of patients was analyzed by statistical analysis. Small interfering RNA (siRNA) was used to suppress H19 expression in renal cancer cell lines. In vitro assays were performed to further explore its role in tumor progression.The relative level of H19 was significantly higher in ccRCC compared to the adjacent normal renal tissues. And higher expression of H19 was found in renal cancer cells compared to the nonmalignant renal cells HK-2. Furthermore, The ccRCC patients with higher H19 expression had more advanced clinical stage and poorer prognosis than those with lower expression, Kaplan-Meier analysis revealed that patients with higher H19 expression had a poorer overall survival and H19 expression could be an independent prognostic marker for ccRCC patient. The results of in vitro assays indicated that knockdown of H19 reduced cell proliferation, invasion, and migration. Our data suggested that lncRNA H19 might be considered as a potential prognostic indicator and a target for gene therapy of ccRCC.

Effect of codon optimization on expression levels of human cystatin C in Pichia pastoris.

Human cystatin C (CysC) is a cysteine proteinase inhibitor with many potential applications. To facilitate further studies of the functions and applications of CysC, we improved the heterologous expression of CysC using a basic codon optimization method. In this study, we cloned the high-GC content wild-type sequence of the CysC gene and also designed a slightly AT-biased sequence, with codons optimized for expression in the Pichia pastoris GS115 strain. Our results showed that the optimized coding sequence of human CysC increased the expression and secretion of the CysC protein by approximately 3- to 5-fold (90-96 mg CysC/L) in yeast, compared with the expression levels of the native CysC gene (17.9-18.4 mg CysC/L). We designed, constructed, and applied an optimized version of the CysC gene for the Pichia expression system. Our results demonstrate that the optimized coding sequence provides a higher yield of secreted CysC than that produced using the wild-type gene. Our data also serve as a practical example demonstrating a rational design strategy for the heterologous expression of secreted proteins.

Primary intraosseous ACC of mandible of possible salivary origin: A rare clinical entity.

INTRODUCTION: Adenoid cystic carcinoma (ACC) is a malignant tumor mainly of salivary origin which is well known for its deceptively benign histologic appearance characterized by indolent, locally invasive growth with high propensity for local recurrence and distant metastasis. PRESENTATION OF CASE: An unusual case of a 23-year-old woman was reported in our hospital. After investigations, it showed that it is a second primary intraosseous lesion of mandible that occurred subsequently after ACC of parotid gland. After diagnosis was established, resection of tumor and reconstruction with a free fibula flap was performed. Ten months follow-up showed no signs of recurrence or metastasis. DISCUSSION: Among the salivary neoplasms, adenoid cystic carcinoma is very rare and intraosseous lesions are even rarer. We found a total of 26 cases of primary ACC of the mandible reported in the literature. Pain and swelling were the most frequent symptoms. CONCLUSION: This case illustrates two key facts. First, not all cystic lesions are necessarily metastatic or recurrence. Second is, even though the exact origin of this tumor is unknown, central salivary gland tumors should be considered in the differential diagnosis of cystic lytic lesions in the mandible.

Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection.

Cancer research has been rightly and successfully focused on prevention, early detection, and identification of specific molecular targets that distinguish the malignant cells from the neighbouring benign cells. However, reducing lethal tissue injury caused by intensive chemoradiotherapy during treatment of late-stage metastatic cancers remains a key clinical challenge. Here we tested whether the induction of adult stem cells could repair chemoradiation-induced tissue injury and prolong overall survival in mice. We found that intestinal stem cells (ISCs) expressed Slit2 and its single-span transmembrane cell-surface receptor roundabout 1 (Robo1). Partial genetic deletion of Robo1 decreased ISC numbers and caused villus hypotrophy, whereas a Slit2 transgene increased ISC numbers and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin 1 (Rspo1; a Wnt agonist) plus Slit2 reduced ISC loss, mitigated gut impairment and protected animals from death, without concomitantly decreasing tumour sensitivity to chemotherapy. Therefore Rspo1 and Slit2 may act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.

Targeting role of glioma stem cells for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is known to be the most common and lethal malignant primary brain tumor. Despite vigorous basic and clinical studies over the past decades, the prognosis of patients with GBM has remained dismal. The fundamental problem with these malignancies occurs due to tumor cells' highly infiltrative nature, precluding a complete surgical resection, and a productive or acquired resistance to cytotoxic therapy. Recent studies demonstrated that GBMs exhibited remarkable cellular heterogeneity and hierarchy containing self-renewing glioma stem cells (GSCs). The malignant growth of GBM can be propagated and sustained by GSCs that are endowed with highly efficient clonogenic and tumor initiation capacities. GSCs can be identified with technical support and are responsible for the invasive potential and recurrence of GBMs. They share core signaling pathways with normal neural stem cells, but also display critical distinctions that provide important clues for useful therapeutic targets. Therefore, targeting GSCs becomes priorities for the development of novel therapeutic paradigms. Herein, we reviewed the existing and promising targeting therapies for GSCs which could effectively inhibit the tumor invasion, proliferation and recurrence of GBMs. Significant features of GSCs, such as invasive growth pattern, angiogenic potential, resistance to traditional therapy and differentiation, are important therapeutic targets. More promising strategies should target GSCs themselves by taking advantages of highthroughput technologies and dissecting the intrinsic molecular nature of GSCs. Novel chemical medicines targeting these GSCs may represent one of the most important directions. Hopefully, this could shed a light on the path we are going to.

Enhancement of humoral immunity in mice by coupling pUCpGs10 and aluminium to the HCV recombinant immunogen.

AIM: To investigate the enhancement of humoral immunity when CpG ODN (cytidine phosphate guanosine oligodeoxynucleotides) and aluminium adjuvants are complexed with the HCV (Hepatitis C virus) recombinant immunogen in mice. METHODS: After immunizing Balb/c mice with the recombination HCV antigen adjuvanted with pUCpGs10 and/or aluminium(antigen+CpG+alum, antigen+CpG, antigen+alum, antigen+PBS), enzyme-linked immunosorbent assay (ELISA) was used to measure the specific serum antibody titers of IgG, to determine the neutralization response to various peptide genotypes, and to determine the concentration of IL-6 and IL-10 in supernatants of in vitro cultured splenic lymphocytes. Enzyme-linked immunospot assay (ELISPOT) was used to quantify the non-specific and specific splenic antibody-secreting cells (ASCs), and flow cytometry (FCM) determined the ratio of different splenic lymphocytes. The serum of rabbits immunized with the recombinant pBVGST/HVR1 antigen immunoprecipitated the HCV isolated from 12 patients' serum. RESULTS: The sera antibody titers were 1:51200, 1:9051, 1:18102, 1:6400 respectively after the final immunization and demonstrated good neutralization responses to the six gene peptide containing 1a, 1b, 2a, 3a, 4a and 6a. The aluminum adjuvant increased the population of both specific ASCs (P < 0.01) and total ASCs(P < 0.05), with a proportional rise in concentrations of CD19+CD27+ (P < 0.05), as well as levels of IL-6, IL-10 (P < 0.05) in splenic lymphocytes. The results clearly indicated a significantly higher number of CD19+CD38+ splenic lymphocytes with the aluminum and pUCpGs10 adjuvant present compared to the control group(P < 0.05). Anti-HVR1 antibody in induced mice can cross-reactively capture HCV particles (10/12). CONCLUSIONS: 1. The aluminum adjuvant induces a potent Th2-biased immune response by increasing both the populations of specific and total ASCs and the ratio of CD19+CD27+ cells. 2. The pUCpGs10 complexed with the aluminum adjuvant boosts the population of plasma cells and increase the efficiency of the immune response. 3. The two adjuvants have synergistic effects on humoral immunity. 4. The recombinant HVR1 protein has the possibility of generating broadly reactive anti-HVR1 antibody.

Characterization of 236 novel alleles at the HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci from China Marrow Donor Program.

Two hundred and thirty-six novel human leukocyte antigen (HLA) alleles are described from volunteer donors of the China Marrow Donor Program: 71 HLA-A alleles, 79 HLA-B alleles, 43 HLA-C, 16 HLA-DRB1 alleles, 26 HLA-DQB1 and 1 HLA-DPB1. Two hundred and thirteen (90.3%) of the 236 novel alleles are single nucleotide substitution variants when compared with their most homologous allele. Seventy-eight of these single nucleotide variants are silent substitutions. The remaining novel alleles differ from their most similar allele by two to four nucleotide substitutions. Some of the novel alleles encode amino acid changes at positions not previously reported to be polymorphic, such as codons 57, 62, 67, 41 and 52 in HLA-A alleles; codons 133, 156, 201 and 215 in HLA-B alleles; codons 74, 208 and 225 in HLA-C; codons 25, 32 and 72 in HLA-DRB1; codons 20, 39 and 77 in HLA-DQB1.

Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis.

The Slit family of guidance cues binds to Roundabout (Robo) receptors and modulates cell migration. We report here that ectopic expression of Slit2 and Robo1 or recombinant Slit2 treatment of Robo1-expressing colorectal epithelial carcinoma cells recruited an ubiquitin ligase Hakai for E-cadherin (E-cad) ubiquitination and lysosomal degradation, epithelial-mesenchymal transition (EMT), and tumor growth and liver metastasis, which were rescued by knockdown of Hakai. In contrast, knockdown of endogenous Robo1 or specific blockade of Slit2 binding to Robo1 prevented E-cad degradation and reversed EMT, resulting in diminished tumor growth and liver metastasis. Ectopic expression of Robo1 also triggered a malignant transformation in Slit2-positive human embryonic kidney 293 cells. Importantly, the expression of Slit2 and Robo1 was significantly associated with an increased metastatic risk and poorer overall survival in colorectal carcinoma patients. We conclude that engagement of Robo1 by Slit2 induces malignant transformation through Hakai-mediated E-cad ubiquitination and lysosomal degradation during colorectal epithelial cell carcinogenesis.

Conversion of immortal liver progenitor cells into pancreatic endocrine progenitor cells by persistent expression of Pdx-1.

The conversion of expandable liver progenitor cells into pancreatic beta cells would provide a renewable cell source for diabetes cell therapy. Previously, we reported the establishment of liver epithelial progenitor cells (LEPCs). In this work, LEPCs were modified into EGFP/Pdx-1 LEPCs, cells with stable expression of both Pdx-1 and EGFP. Unlike previous work, with persistent expression of Pdx-1, EGFP/Pdx-1 LEPCs acquired the phenotype of pancreatic endocrine progenitor cells rather than giving rise to insulin-producing cells directly. EGFP/Pdx-1 LEPCs proliferated vigorously and expressed the crucial transcription factors involved in beta cell development, including Ngn3, NeuroD, Nkx2.2, Nkx6.1, Pax4, Pax6, Isl1, MafA and endogenous Pdx-1, but did not secrete insulin. When cultured in high glucose/low serum medium supplemented with cytokines, EGFP/Pdx-1 LEPCs stopped proliferating and gave rise to functional beta cells without any evidence of exocrine or other islet cell lineage differentiation. When transplanted into diabetic SCID mice, EGFP/Pdx-1 LEPCs ameliorated hyperglycemia by secreting insulin in a glucose regulated manner. Considering the limited availability of beta cells, we propose that our experiments will provide a framework for utilizing the immortal liver progenitor cells as a renewable cell source for the generation of functional pancreatic beta cells.