PD-1 blockade enhances the effect of targeted chemotherapy on locally advanced pMMR/MSS colorectal cancer.

BACKGROUND: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. METHODS: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. RESULTS: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively). CONCLUSIONS: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.

Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer.

Immune checkpoint inhibitor (ICI) therapy can induce complete responses in mismatch repair-deficient and microsatellite instability-high (d-MMR/MSI-H) colorectal cancers (CRCs). However, the underlying mechanism for pathological complete response (pCR) to immunotherapy has not been completely understood. We utilize single-cell RNA sequencing (scRNA-seq) to investigate the dynamics of immune and stromal cells in 19 patients with d-MMR/MSI-H CRC who received neoadjuvant PD-1 blockade. We found that in tumors with pCR, there is a concerted decrease in CD8+ Trm-mitotic, CD4+ Tregs, proinflammatory IL1B+ Mono and CCL2+ Fibroblast following treatment, while the proportions of CD8+ Tem, CD4+ Th, CD20+ B, and HLA-DRA+ Endothelial cells increase. Proinflammatory features in the tumor microenvironment mediate the persistence of residual tumors by modulating CD8+ T cells and other response-associated immune cell populations. Our study provides valuable resources and biological insights into the mechanism of successful ICI therapy and potential targets for improving treatment efficacy.

Case Report: Clinical benefit from multi-target tyrosine kinase inhibitor and PARP inhibitor in a patient with cancer of unknown primary with BRCA1 large genomic rearrangement.

Background: Cancer of unknown primary (CUP), which accounts for 3%-5% of new cancer cases every year, involves the presence of a type of histologically confirmed metastatic tumors whose primary site cannot be confirmed by conventional diagnostic methods. This difficulty in identifying the primary site means that CUP patients fail to receive precisely targeted therapy. Most patients are treated with empiric chemotherapy, with a median survival of 6 months and even poorer prognosis within an unfavorable subset of CUP. Case report: An 80-year-old woman presented with masses in the abdomen. Following comprehensive imagological and immunohistochemical examinations, she was diagnosed with CUP. She emphatically declined chemotherapy; thus, anlotinib has been administered with patient consent since 02/07/2019, and stable disease (SD) was observed for 2 years. During subsequent treatment, a large genomic rearrangement in BRCA1 was identified in the patient via NGS, and SD was observed for a further 6 months following olaparib treatment. The type of LGR identified in this patient was discovered to be BRCA1 exon 17-18 inversion (inv), which has never been previously reported. Conclusion: For CUP patients, a chemo-free regimen seems to be acceptable as a first-line treatment, and NGS-guided targeted treatment could improve patient outcomes.

Intratumoral CD8+ T cells as a potential positive predictor of chemoimmunotherapy response in PD-L1-negative advanced gastric cancer patients: a retrospective cohort study.

Background: Previous studies have shown that PD-L1-positive advanced gastric cancer (GC) patients could achieve clinical benefit after receiving immune checkpoint inhibitors (ICI) in initial or subsequent therapy. A number of prospective studies such as Keynote-158 have demonstrated that PD-L1-negative patients who tested as microsatellite instability-high (MSI-H) or tumor mutational burden-high (TMB-H) can benefit from ICIs. In the search for more biomarker for immunotherapy, some studies showed that patients with a specific characteristic to tumor microenvironment (TME) were associated with better prognosis. This study aimed to explore the association between the TME and immunotherapy in PD-L1 negative GC patients. Methods: This study was a retrospective cohort study. Twenty-six CPS PD-L1 negative stage IV advanced GC patients treated with chemoimmunotherapy in Shenzhen Hospital of Peking University were retrospectively enrolled according to the inclusion criteria. Their clinical characteristics were assessed and recorded by independent clinicians. Follow-up data was conducted through the Internet or visit. Respond to treatment was evaluated by RECIST 1.1. The primary outcome was progression-free survival (PFS). The level of tumor-infiltrating lymphocytes (TILs) was measured by multiplex immunofluorescence (mIF) among these patients. Cox proportional hazards analysis was performed to analyzed the correlation between PFS and clinical characteristics including TILs. Results: Among 26 patients, 5 patients (19.2%) were on complete response (CR) and 9 patients (34.6%) were in partial response (PR), while 7 patients (26.9%) experienced stable disease (SD). Intratumoral CD8+ T cells were obviously increased in CPS PD-L1 negative patients who responded to chemoimmunotherapy, compared with patients who did not respond (P=0.011). And higher level of CD8+ TILs was demonstrated to associate with better PFS in CPS PD-L1-negative patients treated with chemoimmunotherapy (HR =23.70, 95% CI: 1.15-488.30, P=0.04). Conclusions: Intratumoral CD8+ TILs may be a potential positive predictive factor of clinical response for chemoimmunotherapy in PD-L1-negative advanced GC. However, the results need to be further confirmed in a cohort with more subjects due to a limited sample sizes in present study.

Treatment with sorafenib plus camrelizumab after splenectomy for primary splenic angiosarcoma with liver metastasis: A case report and literature review.

BACKGROUND: Primary splenic angiosarcoma (PSA) is an extremely rare and aggressive mesenchymal malignancy with high metastatic potential and a poor prognosis. There are no established treatment guidelines for PSA, even for adjuvant therapy. This rare case may provide a reliable therapeutic regime for a better prognosis. CASE SUMMARY: A 49-year-old female who complained of right-upper quadrant abdominal pain was diagnosed as having PSA with splenic rupture and liver metastasis. After splenectomy and liver tumor resection, she received sorafenib and camrelizumab therapy. After 15 mo of follow-up, she is in good condition, without recurrence or any identified metastasis. CONCLUSION: Immunotherapy combined with targeted therapy could be a potential option for the adjuvant therapy of PSA.

MYO1B enhances colorectal cancer metastasis by promoting the F-actin rearrangement and focal adhesion assembly via RhoA/ROCK/FAK signaling.

BACKGROUND: Colorectal cancer (CRC) has a high worldwide incidence and mortality. Tumor metastasis is one of the primary reasons for the poor prognosis of CRC patients. However, the mechanism underlying CRC metastasis is still unclear. Myosin 1B (MYO1B) is important for cell migration and motility and is part of the myosin superfamily that contains various myosins. Studies of prostate, cervical, and head and neck cancer have revealed preliminary findings concerning the effect of MYO1B on tumor metastasis. However, the role of MYO1B in CRC metastasis, as well as its underlying mechanism, remains unknown. METHODS: Quantitative real-time PCR and immunohistochemical staining methods were used to analyze the expression of MYO1B in human CRC and normal mucosa tissues. Lentivirus vector-based MYO1B oligonucleotides and short hairpin RNA (shRNA) were used to examine the functional relevance of MYO1B in CRC cells. Co-immunoprecipitation, western blotting, and immunofluorescence assays were used to investigate the underlying mechanism of MYO1B-mediated cell migration. RESULTS: The expression of MYO1B was increased in most CRC tissues and was positively associated with a greater risk of tumor metastasis and poor prognosis for patients. MYO1B was significantly associated with the migration and invasion properties of CRC cells in vitro and in vivo. MYO1B promoted F-actin rearrangement through the ROCK2/LIMK/Cofilin axis by enhancing the activation of RhoA. MYO1B also promoted the assembly of focal adhesions by targeting RhoA. CONCLUSIONS: MYO1B plays a vital role in CRC metastasis by promoting the activation of RhoA. MYO1B may not only be a valid biomarker for predicting the risk of metastasis and poor prognosis in CRC but may also be a potential therapeutic target for patients with a high risk of tumor metastasis.

The Predictive Value of MAP2K1/2 Mutations on Efficiency of Immunotherapy in Melanoma.

Background: MAP2K1/2 genes are mutated in approximately 8% of melanoma patients; however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. This study focused on the correlation between MAP2K1/2 gene mutations and the treatment response. Methods: Six metastatic melanoma clinical cohorts treated with immune checkpoint inhibitors [anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) or anti-programmed cell death-1 (PD-1)] were recruited in this study. RNA expression profiling results from each of these six cohorts and the Cancer Genome Atlas (TCGA) melanoma cohort were analysed to explore the mechanism related to immune activation. Results: Compared to patients with wild-type MAP2K1/2, those with MAP2K1/2 mutations in an independent anti-CTLA-4-treated cohort had higher objective response rates, longer progression-free survival, and longer overall survival (OS). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the OS. However, there was no correlation between MAP2K1/2 mutations and OS in the anti-PD-1-treated cohort. Subgroup Cox regression analysis suggested that patients with MAP2K1/2 mutations received fewer benefits from anti-PD-1 monotherapy than from anti-CTLA-4 treatment. Furthermore, transcriptome profiling analysis revealed that melanoma tumours with MAP2K mutation was enriched in CD8+ T cells, B cells, and neutrophil cells, also expressed high levels of CD33 and IL10, implying a potential mechanism underlying the benefit of melanoma patients with MAP2K1/2 mutations from anti-CTLA-4 treatment. Conclusions: MAP2K1/2 mutations were identified as an independent predictive factor for anti-CTLA-4 therapy in melanoma patients. Anti-CTLA-4 treatment might be more effective than anti-PD-1 therapy for patients with MAP2K1/2-mutated melanoma.

Comprehensive analysis of DNA damage repair deficiency in 10,284 pan-cancer study.

BACKGROUND: Disruption of the DNA damage repair (DDR) gene is related to cancer progression, treatment selection, and is subjected to radiation and targeted therapies with limited success. This paper conducted a comprehensive analysis to explore the distribution of DDR mutations in Chinese pan-cancer patients. METHODS: A total of 10,284 consecutive cases were analyzed in 24 cancer types [non-small cell lung cancer (NSCLC) 29.0%, liver 12.0%, colorectum 10.7%, etc.]. Tumor tissue samples were subjected to next generation sequencing (NGS) using a 381 gene panel incorporating 100 microsatellite loci. The association of deleterious somatic DDR mutation (del-sDDRmut) with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1) expression of pan-cancers was evaluated. Genomic and clinical data from public cohorts of immunotherapy were analyzed to demonstrate the association between del-sDDRmut and clinical survival. RESULTS: Del-sDDRmut were found in 802 (7.6%) of all cases, and were most common in cancers of the endometrium, prostate, bladder, etc. cancer with a higher TMB also had a higher prevalence of mutations in DDR pathways. The results of the ridge regression analysis showed that 20 DDR genes were significantly associated with TMB [false discovery rate (FDR) <0.01]. A total of 8,899 patients had both TMB and MSI-data in pan-cancers. Seventy-four percent of patients with MSI-high (MSI-H) were accompanied by del-sDDRmut/TMB-high (TMB-H). The largest proportion of patients with microsatellite stability (MSS) with DDR mutations were classified as TMB-H. The top 6 tumors (NSCLC, melanoma, esophagus, head and neck, thyroid, and mediastinal) had the highest prevalence of PD-L1 ≥1%, and DDR mutations were significantly associated with a higher percent of PD-L1 positive (P<0.05). Furthermore, in the immune cohort analysis of NSCLC, patients with del-sDDRmut significantly improved median progression-free survival (mPFS) and median overall survival (mOS) compared to wild-type DDR patients (P=0.002 and P=0.043), with higher TMB observed (P<0.001). CONCLUSIONS: This study explored the association of DDR mutations with TMB, MSI-H, and PD-L1 expression, and revealed that patients with DDR mutations have a significantly improve prognosis than wild-type patients on immunotherapy.

Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) amplification is a molecular driver for a subset of colorectal cancers (CRCs) and one of the major causes of anti-epidermal growth factor receptor (EGFR) treatment failure. Compared to dual anti-HER2 treatments, which have been shown to be effective in HER2-positive metastatic CRC patients, single-agent anti-HER2 therapy is rarely used to treat CRC. CASE SUMMARY: Herein, we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA (ctDNA) testing by next-generation sequencing following the failure of two lines of therapy. Subsequently, the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo. Moreover, serial ctDNA detection was used to monitor the efficacy of lapatinib. The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response. However, a high level of HER2 amplification was detected again at the time of disease progression. Finally, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression, which may explain the acquired resistance to lapatinib. CONCLUSION: This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy. It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.

Isosteviol prevents the development of isoprenaline­induced myocardial hypertrophy.

Isosteviol sodium (STVNa), which is a derivate of the natural sweet­tasting glycoside stevioside, has recently been developed and it has been determined that this compound exhibits neuro­ and cardio­protective properties. In the current study, whether STVNa interferes with the development of cardiac hypertrophy, which is induced by isoprenaline (Iso), was investigated in an experimental rat model. Rats were treated with a vehicle (0.9% NaCl; control), isoprenaline (Iso; 5 mg/kg) or Iso (5 mg/kg) with STVNa (4 mg/kg; Iso + STVNa). Cardiomyocytes were isolated using enzymatic dissociation and were treated with 5 µM Iso for 24 h and co­treated with 5 µM STVNa. Brain natriuretic peptide (BNP) mRNA expression was determined using PCR analysis. Cell surface area, intracellular reactive oxygen species (ROS), mitochondrial transmembrane potential (ΔΨm), cytoplasmic Ca2+ and Ca2+ and contractile function were examined using a laser scanning confocal microscope. The current study demonstrated that STVNa inhibited Iso­induced cardiac hypertrophy by inhibiting cardiomyocyte size. STVNa significantly reduced cell surface area and decreased BNP mRNA expression in ventricular cardiomyocyte Iso­induced hypertrophy. STVNa was also revealed to restore ΔΨm and reduce ROS generation and intracellular Ca2+ concentration when compared with the Iso­treated group. Additionally, STVNa preserved Ca2+ transients in hypertrophic cardiomyocytes. In conclusion, the present study demonstrated that STVNa protects against Iso­induced myocardial hypertrophy by reducing oxidative stress, restoring ΔΨm and maintaining Ca2+ homeostasis.

Electrochemically triggered degradation of silicon membranes for smart on-demand transient electronic devices.

Transient electronics is an emerging technology that enables unique functional transformation or the physical disappearance of electronic devices, and is attracting increasing attention for potential applications in data secured hardware as an ultimate solution against data breaches. Developing smart triggered degradation modalities of silicon (Si) remain the key challenge to achieve advanced non-recoverable on-demand transient electronics. Here, we present a novel electrochemically triggered transience mechanism of Si by lithiation, allowing complete and controllable destruction of Si devices. The depth and microstructure of the lithiation-affected zone over time is investigated in detail and the results suggest a few hours of lithiation is sufficient to create microcracks and significantly promote lithium penetration. Finite element models are proposed to confirm the mechanism. Electrochemically triggered degradation of thin film Si ribbons and Si integrated circuit chips with metal-oxide-semiconductor field-effect transistors from a commercial 0.35 micrometer complementary metal-oxide-semiconductor technology node is performed to demonstrate the potential applications for commercial electronics. This work opens new opportunities for versatile triggered transience of Si-based devices for critical secured information systems and green consumer electronics.

Attenuation of ischemia/reperfusion-induced inhibition of the rapid component of delayed rectifier potassium current by Isosteviol through scavenging reactive oxygen species.

Isosteviol has been demonstrated to play a protective role during ischemia reperfusion (I/R) myocardial infarction. However, the underlying electrophysiological mechanisms of isosteviol are still unknown. Our previous study showed that the rapid component of the delayed rectifier potassium channel (IKr) plays an important role in the prolongation of I/R-induced QT interval-related arrhythmia. This study aimed to investigate whether isosteviol could attenuate I/R-induced prolongation of the action potential duration (APD) along with inhibition of IKr, and we aimed to clarify the electrophysiological mechanism of isosteviol to determine its cardioprotective effects in guinea pigs. We observed that the APD90 were 298.5±41.6ms in control, 528.6±56.7ms during I/R, and reduced to 327.8±40.5ms after 10µmol/L of isosteviol treatment. The IKr currents were 1.44±0.06 pA·pF-1in the control group, 0.50±0.07pA·pF-1during I/R, and recovered to 1.20±0.12pA·pF-1after 10µmol/L of isoteviol treatment. Moreover, isosteviol reduced the over-production of reactive oxygen species (ROS) during I/R. Importantly, isosteviol does not affect the IKr and human ether-a-go-go-related gene currents of normal cardiomyocytes. It attenuated the I/R-induced inhibition of IKr due to reduced over-production of ROS. Furthermore, isosteviol is safe and has no cardiotoxicity, and it might be beneficial for coronary reperfusion therapy.

Inhibition of rapid delayed rectifier potassium current (IKr) by ischemia/reperfusion and its recovery by vitamin E in ventricular myocytes.

Ischemia/reperfusion (I/R) induces prolongation of QT interval and action potential duration (APD), which is a major cardiac electrical disorder in patients with arrhythmias. However, the mechanism of QT interval prolongation induced by I/R remains unclear. In the present study, we hypothesized that the rapid component of delayed rectifier potassium (IKr) channel plays an important role in I/R-induced QT interval prolongation. We observed a marked attenuation of IKr and a significant prolongation of action potential duration (APD) in a simulated I/R system with sodium dithionite (Na2S2O4) in ventricular myocytes of guinea pigs. The IKr current density was inhibited by 64% and APD increased by 87% respectively. Moreover, the inhibition of IKr is primarily ascribed to overproduction of reactive oxygen species (ROS) by I/R, which can be partly reversed by antioxidant vitamin E (100µmol/L). The value of IKr tail current density increased from 0.516±0.040 pA/pF in I/R to 0.939±0.091 pA/pF when treated with vitamin E. Moreover, we also demonstrated that QTc interval was increased by I/R and reversed by Vitamin E in isolated guinea pig hearts. In conclusion, the inhibition of IKr is one of the underlying mechanisms of prolongation of QT interval and APD in I/R. Vitamin E might have a benefit in coronary reperfusion therapy.

Isosteviol Sensitizes sarcKATP Channels towards Pinacidil and Potentiates Mitochondrial Uncoupling of Diazoxide in Guinea Pig Ventricular Myocytes.

KATP channel is an important mediator or factor in physiological and pathological metabolic pathway. Activation of KATP channel has been identified to be a critical step in the cardioprotective mechanism against IR injury. On the other hand, desensitization of the channel to its opener or the metabolic ligand ATP in pathological conditions, like cardiac hypertrophy, would decrease the adaption of myocardium to metabolic stress and is a disadvantage for drug therapy. Isosteviol, obtained by acid hydrolysis of stevioside, has been demonstrated to play a cardioprotective role against diseases of cardiovascular system, like anti-IR injury, antihypertension, antihyperglycemia, and so forth. The present study investigated the effect of isosteviol (STV) on sarcKATP channel current induced by pinacidil and mitochondrial flavoprotein oxidation induced by diazoxide. Our results showed that preincubating cells with STV not only increased the current amplitude and activating rate of sarcKATP channels induced by pinacidil but also potentiated diazoxide-elicited oxidation of flavoprotein in mitochondria.