68Ga-FAPI-04 positron emission tomography/CT and laparoscopy for the diagnosis of occult peritoneal metastasis in newly diagnosed locally advanced gastric cancer: study protocol of a single-centre prospective cohort study.

INTRODUCTION: Accurate baseline clinical staging is critical to inform treatment decision-making for patients with gastric cancers. Peritoneal metastasis (PM) is the most common form of metastasis in gastric cancer and mainly diagnosed by diagnostic laparoscopy and peritoneal lavage evaluation. However, diagnostic laparoscopy is invasive and less cost-effective. It is urgent to develop a safe, fast and non-invasive functional imaging method to verify the peritoneal metastasis of gastric cancer. The aim of our study was to evaluate the proportion of patients in whom 68Ga-FAPI-04 positron emission tomography/CT (PET/CT) led to a change in treatment strategy and to assess the diagnostic accuracy of 68Ga-FAPI-04 PET/CT for the detection of occult peritoneal metastasis compared with laparoscopic exploration. METHODS AND ANALYSIS: In this single-centre, prospective diagnostic test accuracy study, a total of 48 patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma (cT4a-b, N0-3, M0, based on CT images) who are considering radical tumour surgery will be recruited. All participants will undergo 68Ga-FAPI-04 PET/CT before the initiation of laparoscopic exploration. The primary outcome is the proportion of patients with occult peritoneal metastatic lesions detected by 68Ga-FAPI-04 PET/CT, leading to a change in therapy strategy. The secondary outcomes include the diagnostic performance of 68Ga-FAPI-04 PET/CT for occult peritoneal metastasis, including sensitivity, specificity, accuracy, positive predictive value and negative predictive value. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of West China Hospital, Sichuan University (2022-1484). Study results will be presented at public and scientific conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2300067591.

Efficacy and safety of fruquintinib dose-escalation strategy for elderly patients with refractory metastatic colorectal cancer: A single-arm, multicenter, phase II study.

BACKGROUND: Fruquintinib has demonstrated significant improvement in overall survival (OS) among previously treated metastatic colorectal cancer (mCRC) patients. However, the utilization of fruquintinib has been constrained by various toxicities, such as hand-foot skin reaction (HFSR) and hypertension, particularly in elderly patients with reduced tolerance to the standard dosage. This study aims to investigate the efficacy and safety of fruquintinib dose-escalation strategy for elderly refractory mCRC patients. PATIENTS AND METHODS: This open-label, single-arm, phase II trial included patients aged 65 years or over with mCRC who had progressed after two or more lines of chemotherapy. Fruquintinib was administered for 21 consecutive days of a 28-day treatment cycle. The starting dose of fruquintinib was 3 mg/day and escalated to 4 mg/day in Week 2 and 5 mg/day in Week 3 if no significant drug-related toxicity was observed. The highest tolerated dose from Cycle 1 would be administered in Cycle 2 and all subsequent cycles. Before commencing treatment, all enrolled patients underwent a G8 questionnaire and comprehensive geriatric assessments. The primary endpoint of the study was progression-free survival (PFS). RESULTS: A total of 29 patients were enrolled and all started fruquintinib at 3 mg/day. Fifteen patients (51.7%) were subsequently escalated to 4 mg/day and 4 (13.8%) to 5 mg/day. Only four (13.8%) patients discontinued treatment due to adverse events (AEs). The median PFS was 3.8 months (95% CI, 2.7-4.9), and the median OS was 7.6 months (95% CI, 6.5-8.7). Treatment-related adverse events (TRAEs) were observed in all 29 patients (100%). The most frequently occurring (>10%) TRAEs greater than Grade 3 were HFSR (20.7%), hypertension (20.7%), and diarrhea (10.3%). CONCLUSION: Our study indicated that a dose of 4 mg/day was well tolerated by most elderly patients, suggesting that fruquintinib dose-escalation strategy during the first cycle could serve as a viable alternative to the standard 5 mg/day dosing.

Case report: Remarkable response to sintilimab, lenvatinib, and nab-paclitaxel in postoperative metastatic chemotherapy-resistant combined hepatocellular-cholangiocarcinoma.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a highly aggressive malignancy with a poor prognosis. However, there are no consensus treatment guidelines, and decisions are usually extrapolated from intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC). Given that cHCC-CCA owns the unequivocal presence of both hepatocytic and cholangiocytic differentiation, a combination regimen of anti-PD1 antibody, multikinase inhibitor, and chemotherapy targeting against both components might be an optimal choice. Case presentation: We present the case of a patient with postoperative metastatic chemotherapy-resistant cHCC-CCA who exhibited a durable response and reasonable tolerability to a combination therapy consisting of the anti-PD1 antibody sintilimab, multikinase inhibitor lenvatinib, and nab-paclitaxel, despite having a low tumor mutational burden (TMB-L), microsatellite stability (MSS), and negative programmed cell death 1 ligand 1 (PD-L1). Conclusion: The combination regimen of immune checkpoint inhibitor sintilimab, multikinase inhibitor lenvatinib, and chemotherapy with nab-paclitaxel, which targets both the HCC and ICC components, may represent a promising treatment option for patients with cHCC-CCA. Further research is warranted to validate these findings in larger patient cohorts.

Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial).

BACKGROUND: Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin-bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients. METHODS: The NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon's two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China. DISCUSSION: The NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.

Highly sensitive and extremely durable wearable e-textiles of graphene/carbon nanotube hybrid for cardiorespiratory monitoring.

Electroconductive textile yarns are of particular interest for their use as flexible and wearable sensors without compromising the properties and comfort of usual textiles. However, the detection of fine actions of the human body is quite challenging since it requires both the relatively higher sensitivity and stability of the sensor. Herein, highly sensitive, ultra-stable, and extremely durable piezoresistive wearable sensors were prepared by loading N-doped rGO and polydopamine-coated carbon nanotubes into silicon rubber tube. The wearable sensors thus produced show an excellent ability to sense subtle movement or stimuli with good sensitivity and repeatability. Furthermore, by bending the straight conductive silicon rubber tube (CSRT) into three different patterns, its sensitivity was then dramatically increased. Finally, the CSRT was found capable of sensing cardiorespiratory signals, indicating that the sensor would be an important step toward realizing bio-signal sensing for next-generation personalized health care applications.

The P2 purinoceptors in prostate cancer.

P2 purinoceptors are composed of ligand-gated ion channel type (P2X receptor) and G protein-coupled metabolite type (P2Y receptor). Both these receptors have played important roles in the prostate cancer microenvironment in recent years. P2X and P2Y receptors can contribute to prostate cancer's growth and invasiveness. However, the comprehensive mechanisms have yet to be identified. By summarizing the relevant studies, we believe that P2X and P2Y receptors play a dual role in cancer cell growth depending on the prostate cancer microenvironment and different downstream signalling pathways. We also summarized how different signalling pathways contribute to tumor invasiveness and metastasis through P2X and P2Y receptors, focusing on understanding the specific mechanisms led by P2X4, P2X7, and P2Y2. Statins may reduce and prevent tumor progression through P2X7 so that P2X purinergic receptors may have clinical implications in the management of prostate cancer. Furthermore, P2X7 receptors can aid in the early detection of prostate cancer. We hope that this review will provide new insights for future mechanistic and clinical investigations into the role of P2 purinergic receptors in prostate cancer.

PD-1 inhibitors plus nab-paclitaxel-containing chemotherapy for advanced gallbladder cancer in a second-line setting: A retrospective analysis of a case series.

Background: Gallbladder cancer (GBC) is a fatal cancer, and the efficacy of the current standard second-line chemotherapy for GBC is limited. Novel therapies need to be explored. This retrospective analysis was aimed to investigate the outcomes of patients treated at West China Hospital with PD-1 inhibitors combined with nab-paclitaxel-based chemotherapy (nab-paclitaxel monotherapy or nab-paclitaxel plus other cytotoxic agents) in a second-line setting. Methods: Between April 2020 and May 2022, the patients with advanced GBC receiving PD-1 inhibitors combined with nab-paclitaxel-based chemotherapy after resistance to first-line gemcitabine-based chemotherapy at West China Hospital were retrospectively screened. Results: Eleven patients were included, and all received gemcitabine-based chemotherapy as first-line therapy. Eight patients underwent next-generation sequencing (NGS), and all had microsatellite stability (MSS) and a low tumor mutation burden (TMB). Six patients were negative for PD-L1 expression and one patient was positive for PD-L1. Therapeutically relevant genetic alterations were not found. All patients received PD-1 inhibitors in combination with nab-paclitaxel-based chemotherapy as second-line therapy. Pembrolizumab was administered in 3 patients, and sintilimab was administered in eight patients. One patient had no measurable target lesion. Complete response (CR) was observed in one (10.0%) patient, partial response (PR) in four (40%) patients, and stable disease (SD) in four (40%) patients. The median progression-free survival (PFS) was 7.5 (95% CI: 2.5-12.5) months, and the median overall survival (OS) was 12.7 (95% CI: 5.5-19.9) months. The adverse events (AEs) were manageable. Conclusion: Our results suggest that PD-1 inhibitors combined with nab-paclitaxel-based chemotherapy as second-line therapy for advanced GBC might be a potential treatment and deserves further evaluation.

Durable response to the combination of pembrolizumab and nab-paclitaxel in a metastatic extrahepatic cholangiocarcinoma: A case report and literature review.

Background: Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor with poor overall survival. Although the first-line standard chemotherapy (gemcitabine plus cisplatin) combined with immunotherapy has yielded positive results with survival prolongation, the efficacy remains unsatisfactory, and new treatment modalities need to be explored. Case presentation: We report the case of a patient with metastatic extrahepatic CCA who achieved a durable response and good tolerance to the combination treatment of pembrolizumab and nab-paclitaxel following progression on gemcitabine plus capecitabine chemotherapy. The tumor samples of the patient revealed low TMB, MSS, negative PD-L1 expression, and negative CD8+ TIL expression. This patient was treated with 3 cycles of pembrolizumab plus nab-paclitaxel and cisplatin, followed by 5 cycles of pembrolizumab plus nab-paclitaxel. Finally, 10 cycles of pembrolizumab monotherapy were administered. The patient survived for over 27 months after the initiation of combined therapy and was still in continuous remission at the last follow-up. Conclusion: As far as we know, this is the first report that pembrolizumab plus nab-paclitaxel successfully treated a patient with advanced CCA. This combination therapy might be a potential treatment option for patients with cholangiocarcinoma, and further clinical trials are needed to explore the outcomes.

Rare DNA Mismatch Repair-Related Protein Loss in Patients with Intrahepatic Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma and Their Response to Immunotherapy.

PURPOSE: The patients with advanced mismatch repair deficiency (dMMR) cancers can benefit from programmed cell death 1 (PD-1) pathway blockade, regardless of the tumor type. Little is known about the prevalence of dMMR in intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (cHCC-CC). This study aimed to assess the mismatch repair (MMR)-related protein expression in patients with ICC and cHCC-CC. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded tumor specimens were obtained from patients undergoing surgery at the West china Hospital between 2009 and 2017. The immunoreactions for MLH1, MSH2, MSH6, and PMS2 were investigated to determine the MMR status. RESULTS: A total of 97 patients were evaluated, including 73 ICC patients and 24 cHCC-CC patients. The prevalence of dMMR was only found in two cases of 97 patients (2.06%). Both patients are ICC. In 24 cHCC-CC patients, no dMMR was observed. They did not receive an adjuvant chemotherapy after surgery. At the end of the follow-up, one patient was in a tumor-free state, and the other patient had local recurrence and metastasis. After receiving sintilimumab (an immune checkpoint inhibitor [ICI] for PD- 1), the patient had a partial response. CONCLUSION: DMMR was detected in few patients with ICC and cHCC-CC. Thus, it is not recommended to routinely evaluate the MMR status of patients with ICC or cHCC-CC after surgery, but that of patients with advanced ICC or cHCC-CC should be assessed.

MiR-199a-3p inhibition facilitates cardiomyocyte differentiation of embryonic stem cell through promotion of MEF2C.

MicroRNAs (miRNAs) is a small molecule (19-25 nucleotide) noncoding RNA that inhibits the expression of target messenger RNA (mRNA) at the posttranscriptional level as an endogenous regulator. There is an increasing evidence that miR-199a-3p has a significant effect on the development of multiple tumors. However, the specific roles of miR-199a-3p in myocardial differentiation of embryonic stem cell still need to be investigated. Method of the hanging drop was used to build the model of cardiomyocyte differentiation of stem cell and beating rate of embryoid bodies (EBs) was calculated. The levels of intracellular MEF2C, a-MHC, GATA4, Nkx2.5, and cTnT mRNA were measured by real-time quantitative polymerase chain reaction, while the expressions of miR-199a-3p were detected simultaneously. Protein levels of MEF2C, a-MHC, GATA4, Nkx2.5, and cTnT were quantified by western blot analysis. Immunoreactivities of MEF2C and cTnT were analyzed by immunofluorescence. The interaction between miR-199a-3p and its predicted target (3'-untranslated region of MEF2C mRNA) was verified by luciferase assay. MiR-199a-3p levels increased during cardiogenesis. MiR-199a-3p inhibitor increased the beating rate of EBs and promoted expressions of cardiac-specific markers (GATA4, Nkx2.5, cTnT, and a-MHC). Notably, miR-199a-3p inhibition brought upregulation of MEF2C, which is the target of miR-199a-3p that we predicted and verified experimentally. In addition, MEF2C siRNA decreased miR-199a-3p inhibitor promoted EBs beating and attenuated miR-199a-3p inhibitor-induced cTnT and MEF2C expressions. The results above showed that MEF2C was involved in the process of promoting the differentiation of stem cells into cardiac myocytes by miR-199a-3p inhibitors.

All Inkjet-Printed Graphene-Silver Composite Ink on Textiles for Highly Conductive Wearable Electronics Applications.

Inkjet-printed wearable electronic textiles (e-textiles) are considered to be very promising due to excellent processing and environmental benefits offered by digital fabrication technique. Inkjet-printing of conductive metallic inks such as silver (Ag) nanoparticles (NPs) are well-established and that of graphene-based inks is of great interest due to multi-functional properties of graphene. However, poor ink stability at higher graphene concentration and the cost associated with the higher Ag loading in metal inks have limited their wider use. Moreover, graphene-based e-textiles reported so far are mainly based on graphene derivatives such as graphene oxide (GO) or reduced graphene oxide (rGO), which suffers from poor electrical conductivity. Here we report inkjet printing of highly conductive and cost-effective graphene-Ag composite ink for wearable e-textiles applications. The composite inks were formulated, characterised and inkjet-printed onto PEL paper first and then sintered at 150 °C for 1 hr. The sheet resistance of the printed patterns is found to be in the range of ~0.08-4.74 Ω/sq depending on the number of print layers and the graphene-Ag ratio in the formulation. The optimised composite ink was then successfully printed onto surface pre-treated (by inkjet printing) cotton fabrics in order to produce all-inkjet-printed highly conductive and cost-effective electronic textiles.

Engineering Graphene Flakes for Wearable Textile Sensors via Highly Scalable and Ultrafast Yarn Dyeing Technique.

Multifunctional wearable e-textiles have been a focus of much attention due to their great potential for healthcare, sportswear, fitness, space, and military applications. Among them, electroconductive textile yarn shows great promise for use as next-generation flexible sensors without compromising the properties and comfort of usual textiles. However, the current manufacturing process of metal-based electroconductive textile yarn is expensive, unscalable, and environmentally unfriendly. Here we report a highly scalable and ultrafast production of graphene-based flexible, washable, and bendable wearable textile sensors. We engineer graphene flakes and their dispersions in order to select the best formulation for wearable textile application. We then use a high-speed yarn dyeing technique to dye (coat) textile yarn with graphene-based inks. Such graphene-based yarns are then integrated into a knitted structure as a flexible sensor and could send data wirelessly to a device via a self-powered RFID or a low-powered Bluetooth. The graphene textile sensor thus produced shows excellent temperature sensitivity, very good washability, and extremely high flexibility. Such a process could potentially be scaled up in a high-speed industrial setup to produce tonnes (∼1000 kg/h) of electroconductive textile yarns for next-generation wearable electronics applications.

Scalable Production of Graphene-Based Wearable E-Textiles.

Graphene-based wearable e-textiles are considered to be promising due to their advantages over traditional metal-based technology. However, the manufacturing process is complex and currently not suitable for industrial scale application. Here we report a simple, scalable, and cost-effective method of producing graphene-based wearable e-textiles through the chemical reduction of graphene oxide (GO) to make stable reduced graphene oxide (rGO) dispersion which can then be applied to the textile fabric using a simple pad-dry technique. This application method allows the potential manufacture of conductive graphene e-textiles at commercial production rates of ∼150 m/min. The graphene e-textile materials produced are durable and washable with acceptable softness/hand feel. The rGO coating enhanced the tensile strength of cotton fabric and also the flexibility due to the increase in strain% at maximum load. We demonstrate the potential application of these graphene e-textiles for wearable electronics with activity monitoring sensor. This could potentially lead to a multifunctional single graphene e-textile garment that can act both as sensors and flexible heating elements powered by the energy stored in graphene textile supercapacitors.