Efficacy and safety of anti-programmed death-1 antibody-based combination therapy in advanced or metastatic gastric or gastroesophageal junction cancer in Chinese patients: A real-world study.

PURPOSE: Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting. METHODS: In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety profile were measured and analyzed. RESULTS: In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia. CONCLUSIONS: Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.

Clinical-Molecular characteristics and Post-Translational modifications of colorectal cancer in north China: Implications for future targeted therapies.

This study delineated the elucidate molecular changes and their post-translational modifications (PTMs) in heterogenetic colorectal cancer (CRC) for a deeper understanding of the CRC pathophysiology and identifying potential therapeutic targets. In this retrospective study, the profiles of 13 hot spot gene mutations were analyzed and the microsatellite instability (MSI) status was determined.Employing the Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) assay, the clinical-pathological features of CRC were characterized in 249 Chinese patients. PTMs were quantified online.Among the patients with CRC, the mutation frequencies of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC genes were 47.8%, 3.6%, 4.8%, 13.7%, 55.8%, and 36.9%, respectively. The proportion of MSI-high (MSI-H) was 7.8%.Subsequent multiple logistic regression analysis showed significant associations including a link between lung metastasis and KRAS mutation, between liver metastasis and lymph node metastasis, between MSI-H and early-onset CRC (EOCRC) and KRAS mutation, between right-sided colon cancer and peritoneal metastasis, and between PIK3CA mutation and PTEN mutation. Patients with KRAS mutation presented with MSI-H, lung metastasis, and PIK3CA mutation. MSI-H, BRAF mutation, and PTEN mutation were more frequent in EOCRC. Phosphorylation and ubiquitylation were found in KRAS, BRAF, PTEN, and SMAD4; SUMOylation and ubiquitylation were observed in HRAS and NRAS; while phosphorylation was obvious in APC, P53, and MLH1. Notably, Phosphorylation and ubiquitylation were the two most common PTMs. The biological characteristics of CRC in Chinese patients have some unique clinical features, which can be explained by the genetic mutation profile, correlations among gene mutations and clinical characteristics. These distinctions set the Chinese patient population apart from their Western counterparts.

Aspergillus ball crawling out of pulmonary bullae.

Chest CT images of the patient in 2016, 2017, 2018, and 2019. The lesion was significantly larger compared with its size in 2016.

Case Report: Primary Pleural Angiosarcoma in a Patient With Klippel-Trenaunay Syndrome.

Klippel-Trenaunay syndrome (KTS) was demonstrated as a mosaic activating PIK3CA mutations related overgrowth syndrome. We present the first case of primary pleural angiosarcoma in a 17-year-old woman with a history of KTS. The combined targeted DNA and RNA sequencing revealed an activating mutation in PIK3CA in the tumor tissue. Our case suggested an association and perhaps a causal link between the two different PIK3CA-related genetic diseases.

Therapeutic Response of Soft Tissue Sarcoma With Novel SS18-POU5F1 Fusion: A Case Report.

A novel SS18-POU5F1 fusion gene was recently reported in soft tissue sarcoma occurring in three adolescent and young adult patients. Herein, we firstly reported the treatment response of SS18-POU5F1 sarcoma to immune checkpoint inhibitor, angiogenesis inhibitor, chemotherapy and radiotherapy. Our patient demonstrated no response to various systemic therapies including immune checkpoint inhibitor, angiogenesis inhibitor and chemotherapy. However, we noted that the SS18-POU5F1 sarcoma had a quick, robust but transient clinical response to radiotherapy. Further studies are needed to elucidate the mechanism underlying the different tumor response to radiotherapy and systemic therapy in this kind of tumor.

Melanotic Xp11 translocation renal cancer: a report of a distinctive case and a review of the literature.

BACKGROUND: Melanotic Xp11 translocation renal cancer (TRC) is a newly described exceedingly rare tumor, and its characterization remains controversial. This study aimed to describe a case of distinctive melanotic Xp11 TRC and to elucidate its clinicopathological and molecular genetic features. CASE PRESENTATION: A 44-year-old Chinese female presented with a left renal mass. Abdominal ultrasonography and computed tomography (CT) scans revealed a 4.5 cm × 4.0 cm mass in the left kidney. Grossly, the well-demarcated mass was black with moderately firm consistency. Microscopic examination indicated that the tumor was characterized by the presence of nests and cords of polygonal cells with clear and granular eosinophilic cytoplasm, central round to oval nuclei and occasional nucleoli. Intracytoplasmic melanin was observed in approximately 45% of tumor cells. Uniquely, the tumor presented with intranuclear eosinophilic pseudoinclusions and thick-walled stromal blood vessels. IHC showed that tumor cells were diffusely positive for TFE3 and exhibited patchy and weak HMB45 staining. FISH confirmed the presence of TFE3 rearrangement. CONCLUSION: This case is the twentieth published case of melanotic Xp11 TRC. Moreover, the present patient had a favorable prognosis given that she was disease free at her 113-month postoperative follow-up. Our case adds to the small body of literature on these exceptionally rare tumors and widens their clinicopathological spectrum.

CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to erlotinib via transcriptional regulation of EGFR.

BACKGROUND: CUL4A has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear. METHODS: Expression level of CUL4A was examined by RT-PCR and Western blot. Forced expression of CUL4A was mediated by retroviruses, and CUL4A silencing by shRNAs expressing lentiviruses. Growth capacity of lung cancer cells was measured by MTT in vitro and tumorigenesis in vivo, respectively. RESULTS: We found that CUL4A was highly expressed in human lung cancer tissues and lung cancer cell lines, and this elevated expression positively correlated with disease progression and prognosis. Overexpression of CUL4A in human lung cancer cell lines increased cell proliferation, inhibited apoptosis, and subsequently conferred resistance to chemotherapy. On other hand, silencing CUL4A expression in NSCLC cells reduced proliferation, promoted apoptosis and resulted in tumor growth inhibition in cancer xenograft model. Mechanistically, we revealed CUL4A regulated EGFR transcriptional expression and activation, and subsequently activated AKT. Targeted inhibition of EGFR activity blocked these CUL4A induced oncogenic activities. CONCLUSIONS: Our results highlight the significance of CUL4A in NSCLC and suggest that CUL4A could be a promising therapy target and a potential biomarker for prognosis and EGFR target therapy in NSCLC patients.

Increasing breadth of the frontal lobe but decreasing height of the human brain between two Chinese samples from a Neolithic site and from living humans.

Morphological observation and measurements of endocasts have played a vital role in research on the evolution of the human brain. However, endocasts have never been used to investigate how the human brain has evolved since the Neolithic period. We investigated the evolution of the human brain during the Holocene by comparing virtual endocasts from Beiqian site (a Neolithic Chinese site) and a sample of Chinese modern-day humans. Standardized measurements and indices were taken to provide quantification of the overall endocast shape, including the length, breadth, height, frontal breadth, and the ratio of frontal breadth to breadth, as well as the cranial capacity. We found that the height of the endocasts and cranial capacity have decreased between our two samples, whereas the frontal breadth and sexual dimorphism have increased. We argue that these changes can be caused by random genetic mutation and epigenetic change in response to changes in the environment.

The protective effects of resveratrol on Schwann cells with toxicity induced by ethanol in vitro.

Schwann cells (SCs) are the myelin forming cells in the peripheral nervous system, they play a key role in the pathology of various polyneuropathies and provide trophic support to axons via expression of various neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Ethanol (EtOH) adversely affected both SCs proliferation and myelin formation in culture. Resveratrol (Res) has been shown to regulate many cellular processes and to display multiple protective and therapeutic effects. Whether Res has protective effects on SCs with EtOH-induced toxicity is still unclear. The protective efficacy of Res on EtOH-treated SCs in vitro was investigated in the present study. Res improved cell viability of the EtOH-treated SCs. Hoechst 33342 staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate nick-end labeling analysis showed that the EtOH-induced apoptosis was inhibited by Res. The effects of Res were blocked by the 5'-adenosine monophosphate-activated protein kinase inhibitor Compound C and the silencing information regulator T1 inhibitor nicotinamide. Res could increase the mRNA and protein levels of BDNF and GDNF in the EtOH-treated SCs. However, the EtOH-induced increase of NGF in the SCs is inhibited by Res. The data from the present study indicate that Res protects SCs from EtOH-induced cell death and regulates the expression of neurotrophicfactors. Res and its derivative may be effective for the treatment of neuropathic diseases induced by EtOH.

Neuroprotective effects of resveratrol on embryonic dorsal root ganglion neurons with neurotoxicity induced by ethanol.

Studies have established that ethanol (EtOH) consumption results in damage to the peripheral nervous systems. Although the pathobiological mechanism is still unclear, oxidative stress is known to play an important role in EtOH-induced neurotoxicity. Because resveratrol (Res) is attracting increased attention due to its antioxidative properties, we investigated the neuroprotective efficacy of Res in ethanol-treated embryonic dorsal root ganglion (DRG) neurons in vitro. Organotypic DRG explants and a dispersed cell culture model were used to evaluate the effects of Res on EtOH-induced neurotoxicity. Res increased the number of extended nerve fibers and neurons that migrated from the DRG explants. Hoechst 33342 staining and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end-labeling analysis showed that the EtOH-induced apoptosis was inhibited by Res. The effects of Res were blocked by the 5'-adenosine monophosphate-activated protein kinase inhibitor Compound C and the sirtuin 1 inhibitor nicotinamide. The elevation of oxidative/nitrosative stress, as measured by the amount of reactive oxygen species, malondialdehyde, nitrite, glutathione and superoxide dismutase activity, was also attenuated by Res. The data from the present study indicate that Res protects DRG neurons from EtOH-induced neurotoxicity. Res and its derivative may be effective for the treatment of diseases characterized by axonopathy and neuron loss induced by EtOH.

Expression of mRNAs for PPT, CGRP, NF-200, and MAP-2 in cocultures of dissociated DRG neurons and skeletal muscle cells in administration of NGF or NT-3.

Both neurotrophins (NTs) and target skeletal muscle (SKM) cells are essential for the maintenance of the function of neurons and nerve-muscle communication. However, much less is known about the association of target SKM cells with distinct NTs on the expression of mRNAs for preprotachykinin (PPT), calcitonin-gene related peptide (CGRP), neurofilament 200 (NF-200), and microtubule associated protein 2 (MAP-2) in dorsal root ganglion (DRG) sensory neurons. In the present study, a neuromuscular coculture model of dissociated dorsal root ganglion (DRG) neurons and SKM cells was established. The morphology of DRG neurons and SKM cells in coculture was observed with an inverted phase contrast microscope. The effects of nerve growth factor (NGF) or neurotrophin-3 (NT-3) on the expression of mRNAs for PPT, CGRP, NF-200, and MAP-2 was analyzed by real time-PCR assay. The morphology of DRG neuronal cell bodies and SKM cells in neuromuscular coculture at different conditions was similar. The neurons presented evidence of dense neurite outgrowth in the presence of distinct NTs in neuromuscular cocultures. NGF and NT-3 increased mRNA levels of PPT, CGRP, and NF-200, but not MAP-2, in neuromuscular cocultures. These results offer new clues towards a better understanding of the association of target SKM cells with distinct NTs on the expression of mRNAs for PPT, CGRP, NF-200 and MAP-2, and implicate the association of target SKM cells and NTs with DRG sensory neuronal phenotypes.