A single-arm, multicenter, phase 2 clinical study of recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate (MRG002) in HER2-positive unresectable locally advanced or metastatic urothelial carcinoma.

BACKGROUND: MRG002 is a novel HER2-targeted antibody-drug conjugate being investigated in the MRG002-006 trial to evaluate the efficacy and safety in HER2-positive urothelial carcinoma patients. METHODS: This is an open-label, single-arm, multicenter phase II study. Eligibility criteria included: histologically confirmed HER2 IHC 2 + or 3 + UC, prior received ≥ 1 standard treatment. Patients in this study received MRG002 every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was confirmed ORR per RECIST 1.1. RESULTS: As of February 24, 2023, a total of 43 patients were enrolled. The median age was 60. 9 patients were dosed at 2.6 mg/kg and 34 patients were dosed at 2.2 mg/kg. At baseline, most patients (29/43) received ≥ 2 lines of treatment and 35 (81.4%) patients had prior ICI therapy. FISH test was performed in 41 patients and 9 (22.0%) were positive. By the cut-off date, 41 patients were evaluable and the ORR was 53% (95%CI：38.9%-67.5%), with 6.9% CR, and the DCR was 83.7% (95%CI：70.0%-91.9%). The median PFS and OS for the 43 patients were 7.0 months (95%CI：5.4-NE) and 14.9 months (95%CI：11.9-NE), respectively. The ORR was 77.8% in 9 patients with positive HER2 FISH results. Most common treatment-related AEs were anemia (51.2%), alopecia (44.2%) and neutropenia (39.5%); most were grade 1 or 2. CONCLUSION: Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients. MRG002 at 2.2 mg/kg was well tolerated with a manageable toxicity.

Trilayered biomimetic hydrogel scaffolds with dual-differential microenvironment for articular osteochondral defect repair.

Commonly, articular osteochondral tissue exists significant differences in physiological architecture, mechanical function, and biological microenvironment. However, the development of biomimetic scaffolds incorporating upper cartilage, middle tidemark-like, and lower subchondral bone layers for precise articular osteochondral repair remains elusive. This study proposed here a novel strategy to construct the trilayered biomimetic hydrogel scaffolds with dual-differential microenvironment of both mechanical and biological factors. The cartilage-specific microenvironment was achieved through the grafting of kartogenin (KGN) into gelatin via p-hydroxyphenylpropionic acid (HPA)-based enzyme crosslinking reaction as the upper cartilage layer. The bone-specific microenvironment was achieved through the grafting of atorvastatin (AT) into gelatin via dual-crosslinked network of both HP-based enzyme crosslinking and glycidyl methacrylate (GMA)-based photo-crosslinking reactions as the lower subchondral bone layer. The introduction of tidemark-like middle layer is conducive to the formation of well-defined cartilage-bone integrated architecture. The in vitro experiments demonstrated the significant mechanical difference of three layers, successful grafting of drugs, good cytocompatibility and tissue-specific induced function. The results of in vivo experiments also confirmed the mechanical difference of the trilayered bionic scaffold and the ability of inducing osteogenesis and chondrogenesis. Furthermore, the articular osteochondral defects were successfully repaired using the trilayered biomimetic hydrogel scaffolds by the activation of endogenous recovery, which offers a promising alternative for future clinical treatment.

FOLFOXIRI plus cetuximab as conversion therapy for unresectable RAS/BRAF wild-type left-sided colorectal cancer with liver-limited metastases: a prospective dual-center pilot study.

Purpose: To explore the efficacy and safety of FOLFOXIRI plus cetuximab regimen as conversion therapy for patients with unresectable RAS/BRAF wild-type colorectal liver-limited metastases (CLM). Patients and methods: This was a dual-center, phase II trial with the rate of no evidence of disease (NED) achieved as the primary endpoint. All enrolled patients with initially unresectable left-sided RAS/BRAF wild-type colorectal liver-limited metastases received a modified FOLFOXIRI plus cetuximab regimen as conversion therapy. Results: Between October 2019 and October 2021, fifteen patients were enrolled. Nine patients (60%) achieved NED. The overall response rate (ORR) was 92.9%, and the disease control rate (DCR) was 100%. The median relapse-free survival (RFS) was 9 (95% CI: 0-20.7) months. The median progression-free survival (PFS) was 13.0 months (95% CI: 5.7-20.5), and the median overall survival (OS) was not reached. The most frequently occurring grade 3-4 adverse events were neutropenia (20%), peripheral neurotoxicity (13.3%), diarrhea (6.7%), and rash acneiform (6.7%). Conclusion: The FOLFOXIRI plus cetuximab regimen displayed tolerable toxicity and promising anti-tumor activity in terms of the rate of NED achieved and response rate in patients with initially unresectable left-sided RAS/BRAF wild-type CLM. This regimen merits further investigation.

Perioperative chemotherapy with docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) for the treatment of locally advanced gastric or gastro-esophageal junction adenocarcinoma (MATCH): an open-label, randomized, phase 2 clinical trial.

BACKGROUND: It remains unclear whether addition of docetaxel to the combination of a platinum and fluoropyrimidine could provide more clinical benefits than doublet chemotherapies in the perioperative treatment for locally advanced gastric/gastro-esophageal junction (LAG/GEJ) cancer in Asia. In this randomized, phase 2 study, we assessed the efficacy and safety of perioperative docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) in LAG/GEJ adenocarcinoma patients. METHODS: Patients with cT3-4 Nany M0 G/GEJ adenocarcinoma were randomized (1:1) to receive 4 cycles of preoperative DOS or SOX followed by D2 gastrectomy and another 4 cycles of postoperative chemotherapy. The primary endpoint was major pathological response (MPR). RESULTS: From Aug, 2015 to Dec, 2019,154 patients were enrolled and 147 patients included in final analysis, with a median age of 60 (26-73) years. DOS resulted in significantly higher MPR (25.4 vs. 11.8%, P = 0.04). R0 resection rate, the 3-year PFS and 3-year OS rates were 78.9 vs. 61.8% (P = 0.02), 52.3 vs. 35% (HR 0.667, 95% CI: 0.432-1.029, Log rank P = 0.07) and 57.5 vs. 49.2% (HR 0.685, 95% CI: 0.429-1.095, Log rank P = 0.11) in the DOS and SOX groups, respectively. Patients who acquired MPR experienced significantly better survival. DOS had similar tolerance to SOX. CONCLUSIONS: Perioperative DOS improved MPR significantly and tended to produce longer PFS compared to SOX in LAG/GEJ cancer in Asia, and might be considered as a preferred option for perioperative chemotherapy and worth further investigation.

Case report: Immunotherapy in rare high TMB pancreatic acinar carcinoma.

This case report details a patient with Pancreatic Acinar Cell Carcinoma (PACC), a rare malignancy with distinctive biological and imaging features. In the absence of standardized treatment protocols for PACC, we embarked on a diagnostic journey that led to the adoption of an innovative therapeutic regimen in our institution. A 45-year-old female patient presented with a pancreatic mass, which was histologically confirmed as PACC following a biopsy. Subsequent genomic profiling revealed a high tumor mutational burden (21.4/Mb), prompting the initiation of combined immunotherapy and targeted therapy. Notably, the patient experienced a unique adverse reaction to the immunotherapy-recurrent subcutaneous soft tissue nodules, particularly in the gluteal and lower limb regions, accompanied by pain, yet resolving spontaneously. Following six cycles of the dual therapy, radiological evaluations indicated a decrease in tumor size, leading to a successful surgical excision. Over a 20-month post-surgical follow-up, the patient showed no signs of disease recurrence. This narrative adds to the existing knowledge on PACC and highlights the potential efficacy of immunotherapy in managing this challenging condition, emphasizing the importance of close monitoring for any adverse reactions.

Nodal recurrence mapping and clinical target volumes after resection of intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma.

Background: Scarce evidence exists for clinical target volume (CTV) definitions of regional lymph nodes (LNs) in intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We investigated the mapping pattern of nodal recurrence after surgery for iCCA and cHCC-CCA and provided evidence for the nodal CTV definition. Methods: We retrospectively reviewed the medical records of patients with iCCA or cHCC-CCA who underwent surgery between 2010 and 2020. Eligibility criteria included patients pathologically diagnosed with iCCA or cHCC-CCA after surgery and a first recurrent event in regional LNs during follow-up. All recurrent LNs were registered onto reference computed tomography images based on the vascular structures to reconstruct the node mapping. Fifty-three patients were eligible. LN regions were classified into four risk groups. Results: Hepatic hilar and portal vein-vena cava were the most common recurrent regions, with recurrence rates of 62.3 % and 39.6 % (high-risk regions), respectively. Recurrence rates in the left gastric, diaphragmatic, common hepatic, superior mesenteric vessels, celiac trunk, and paracardial regions ranged from 15.1 % to 30.2 % (intermediate-risk regions). There were fewer recurrences in the para-aortic (16a1, a2, b1) and splenic artery and hilum regions, with rates <10 % (low-risk regions). No LN recurrence was observed in the para-oesophageal or para-aortic region (16b2) (very low-risk regions). Based on node mapping, the CTV should include high- and intermediate-risk regions for pathologically negative LN patients during postoperative radiotherapy. Low-risk regions should be included for pathologically positive LN patients. Conclusion: We provide evidence for CTV delineation in patients with iCCA and cHCC-CCA based on recurrent LN mapping.

Regorafenib monotherapy or combined with an immune-checkpoint inhibitor as later-line treatment for metastatic colorectal cancer: a multicenter, real-world retrospective study in China.

OBJECTIVE: To evaluate the efficacy and safety of regorafenib monotherapy or in combination with immune-checkpoint inhibitor while treating Chinese patients with metastatic colorectal cancer (mCRC): a real-world study. METHODS: The data of patients with metastatic colorectal cancer who received regorafenib-containing regimen as the third or later line treatment at ten Chinese hospitals from Aug 2017 to Jun 2020 were retrospectively analyzed, including dosing details, survival data as well as adverse events. Survival analysis was further performed for patients administrated with regorafenib monotherapy and combined with an immune-checkpoint inhibitor based on Kaplan-Meier and Cox regression methods. The primary endpoint was overall survival. RESULTS: A total of 537 patients were included with a median age of 61, among whom 376 received regorafenib monotherapy and 245 received regorafenib combined with immune-checkpoint inhibitors. The clinicopathological characteristics of the two groups at baseline were mainly balanced. No significant difference in progression-free survival (PFS) was observed in patients receiving regorafenib monotherapy or combination therapy (3.8 vs. 5.5 months, p = 0.170). In contrast, patients receiving combination therapy had a more prolonged overall survival (OS) than those receiving regorafenib monotherapy (13.5 vs. 10.0 months, p = 0.001). The treatment regimen and regorafenib dosage were significant prognostic factors in the multivariate analysis. Significant benefits in PFS and OS were achieved in KRAS mutant and anti-angiogenesis treatment-naïve subgroups receiving combination therapy compared to monotherapy. No apparent increase was recorded in treatment-related adverse events in patients receiving combination therapy. CONCLUSION: Regorafenib plus an immune-checkpoint inhibitor has already been a widely adopted strategy in the later-line treatment for mCRC in the real world. The combination therapy yielded a significantly prolonged overall survival than regorafenib alone, with a manageable safety profile in Chinese patients, and warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04835324. Registered 6th April 2021.

Identification of the six-hormone secretion-related gene signature as a prognostic biomarker for colon adenocarcinoma.

BACKGROUND: Colon adenocarcinoma (COAD) is a globally prevalent cancer, with hormone secretion playing a crucial role in its progression. Despite this, there is limited understanding of the impact of hormone secretion on COAD prognosis. This study aimed to establish a prognostic signature based on hormone secretion-related genes and to elucidate the potential functional mechanisms of these genes in COAD. METHODS: Using data from The Cancer Genome Atlas COAD cohort (TCGA-COAD), six hormone secretion-related genes were identified (CYP19A1, FOXD1, GRP, INHBB, SPP1, and UCN). These genes were used to develop a Hormone secretion score (HSS), which was then evaluated using the Kaplan-Meier curve and multivariable Cox analysis. The HSS model was further validated with external GEO cohorts (GSE41258, GSE39582, and GSE87211). Functional enrichment analyses were performed, and the CIBERSORT and TIDE algorithms were used to assess tumor infiltration. RESULTS: The study developed a prognostic signature, dividing patients into HSS-high and HSS-low groups. The HSS-high group showed a notably worse prognosis within the TCGA-COAD dataset and in three independent datasets: GSE41258, GSE39582, and GSE87211. Moreover, the HSS-high group predicted a shorter overall survival rate in patients maintaining microsatellite stability (MSS). The functional analysis associated HSS-high with the hypoxic, epithelial-mesenchymal transition (EMT), and TGF-ß signaling pathways and correlated with distant and lymph node metastases. The tumor immune microenvironment analysis revealed an elevated CIBERSORT score in the HSS-high group, suggesting an association with tumor metastasis. Further, the HSS-high group showed a higher TIDE score, indicating that patients with high HSS scores are less likely to benefit from Immune Checkpoint Inhibitor (ICI) therapy. CONCLUSIONS: This study demonstrated the prognostic significance of a HSS signature based on six hormone secretion-related genes in COAD. The findings suggest that this gene signature may serve as a reliable biomarker for predicting survival outcomes in COAD patients.

Comparison of clinicopathological characteristics and survival outcomes between gallbladder mucinous adenocarcinoma and gallbladder adenocarcinoma: A propensity score-matched study.

BACKGROUND: Gallbladder mucinous adenocarcinoma (GBMAC) is a rare subtype of gallbladder adenocarcinoma (GBAC), with limited knowledge of its survival outcomes from small case series and single-center retrospective analysis. AIM: To compare the clinicopathological characteristics of GBMAC with typical GBAC and its prognostic factors to gain insights into this field. METHODS: This study was conducted using data from the Surveillance, Epidemiology, and End Results database, including cases of GBMAC and typical GBAC diagnosed from 2010 to 2017. The Pearson chi-square test or Fisher exact test was used to examine the differences in clinicopathological features between these two cohorts. In addition, propensity score matching (PSM) analysis was performed to balance the selection biases. Univariate and multivariate Cox hazards regression analyses were performed to determine independent prognostic factors for cancer-specific survival (CSS) and overall survival (OS). The Kaplan-Meier curves and log-rank tests were used to assess the OS and CSS of GBMAC and typical GBAC patients. RESULTS: The clinicopathological and demographic characteristics of GBMAC were different from typical GBAC. They included a larger proportion of patients with unmarried status, advanced American Joint Committee on Cancer (AJCC) stage, higher T stage, higher N1 stage rate and lower N0 and N2 stage rates (P < 0.05). Multivariate analyses demonstrated that surgery [OS: Hazard ratio (HR) = 2.27, P = 0.0037; CSS: HR = 2.05, P = 0.0151], chemotherapy (OS: HR = 6.41, P < 0.001; CSS: HR = 5.24, P < 0.001) and advanced AJCC stage (OS: Stage IV: HR = 28.99, P = 0.0046; CSS: Stage III: HR = 12.31, P = 0.015; stage IV: HR = 32.69, P = 0.0015) were independent prognostic indicators for OS and CSS of GBMAC patients. Furthermore, after PSM analysis, there was no significant difference between GBMAC and matched typical GBAC patients regarding OS (P = 0.82) and CSS (P = 0.69). CONCLUSION: The biological behaviors of GBMAC are aggressive and significantly different from that of typical GBAC. However, they show similar survival prognoses. Surgery, chemotherapy, and lower AJCC stage were associated with better survival outcomes. Further research is needed in the future to verify these results.

Postoperative recurarization after sugammadex administration in two patients who received neoadjuvant chemotherapy: case reports and literature review.

BACKGROUND: Preoperative neoadjuvant chemotherapy plays a critical role in multidisciplinary therapy for a variety of malignant tumours. Although oncologists consider myocardial injury to be the most concerning side effect of chemotherapy, unique chemotherapy-mediated skeletal muscular damage has received attention recently. CLINICAL FEATURES: We report two unusual cases of postoperative delayed respiratory failure following administration of the recommended sugammadex dosage for patients undergoing lengthy operations with deep neuromuscular blockade (NMB) after neoadjuvant chemotherapy. Based on clinical outcomes, especially the comparison of muscle imaging results in patients at different treatment time points, we concluded that NMB recurrence had a possible correlation with neoadjuvant chemotherapy-induced muscular damage. CONCLUSION: The early identification of neoadjuvant chemotherapeutic side effects on NMB could be instrumental for clinical safety, especially in cases of major surgery requiring deep NMB. Thus, the timing of NMB antagonism and the recommended dosage of sugammadex warrant special consideration in these patients. In addition to neuromuscular monitoring during the operation, a more extended and closer observation period in the postanesthesia care unit is warranted.

RéSUMé: CONTEXTE: La chimiothérapie néoadjuvante préopératoire joue un rôle crucial dans le traitement multidisciplinaire de diverses tumeurs malignes. Bien que les oncologues considèrent les lésions myocardiques comme l'effet secondaire le plus inquiétant de la chimiothérapie, des lésions musculosquelettiques spécifiques induites par la chimiothérapie ont récemment fait l'objet d'une attention plus précise. CARACTéRISTIQUES CLINIQUES: Nous signalons deux cas inhabituels d'insuffisance respiratoire postopératoire retardée suite à l'administration de la posologie recommandée de sugammadex chez des patient·es bénéficiant d'opérations prolongées avec blocage neuromusculaire (BNM) profond après une chimiothérapie néoadjuvante. Sur la base des résultats cliniques, en particulier de la comparaison des résultats d'imagerie musculaire chez les patient·es à différents moments du traitement, nous avons conclu que la récurrence du BNM avait une corrélation intéressante avec les lésions musculaires induites par la chimiothérapie néoadjuvante. CONCLUSION: L'identification précoce des effets secondaires de la chimiothérapie néoadjuvante sur le BNM pourrait jouer un rôle déterminant dans l'innocuité clinique, en particulier en cas de chirurgie majeure nécessitant un BNM profond. Ainsi, le moment de l'antagonisme du BNM et la posologie recommandée de sugammadex nécessitent une attention particulière chez ces patient·es. En plus du monitorage neuromusculaire pendant l'opération, une période d'observation plus longue et plus étroite en salle de réveil est justifiée.

Current neoadjuvant therapy for operable locally advanced esophageal cancer.

Locally advanced esophageal cancer has a poor prognosis, while an increasing number of patients are diagnosed with that. Neoadjuvant therapy has become a hot topic in treating locally advanced esophageal cancer to improve its survival benefit. The efficacy of neoadjuvant therapy followed by surgery has been confirmed by many studies, and neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy are included in the guidelines. In recent years, targeted therapy and immunotherapy have emerged, and more studies are evaluating the efficacy of combining them with neoadjuvant therapy for operable esophageal cancer patients. Even though the preliminary data is disappointing, many trials are still under investigation without improving survival benefits. New indexes used as surrogate endpoints (e.g., major pathologic response and pathological complete response) are emerging to accelerate the development and approval of neoadjuvant drugs. This review summarized the research progress in neoadjuvant therapy for locally advanced esophageal cancer and discussed which primary endpoint should be used in neoadjuvant therapy trials.

Neoadjuvant chemotherapy with modified FOLFOXIRI for locally advanced rectal cancer to transform effectively EMVI and MRF from positive to negative: results of a long-term single center phase 2 clinical trial.

PURPOSE: Chemoradiotherapy (CRT) remains the standard treatment for locally advanced rectal cancer (LARC). This phase 2 clinical trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in LARC. PATIENTS AND METHODS: The patients with LARC (the lower edge more than 5 cm from the anal verge) received up to 5 cycles of mFOLFOXIRI. MRI was performed to assess the baseline and postchemotherapy TN stage. Radical resection was performed within 4-6 weeks from the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2 and a positive CRM. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: From February 2016 to March 2019, 50 patients were enrolled. Forty-eight (96%) were clinically node-positive, 28 (56.5%) with MRF invasion and 39 (78.4%) were EMVI positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range,1-5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients with cN + achieved a pathological node-negative status. The proportions of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively. Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or > toxicities included neutrocytopenia (50%), leukopenia (14%) and diarrhea (12%) during the neoadjuvant chemotherapy period. Clinically meaningful postoperative complications included pneumonia (n = 1), pelvic infection (n = 1) and anastomotic fistula (n = 1). With a median follow-up time of 51.2 months, local recurrences and distant metastases were confirmed in 3 (6.5%) and 9 (19.6%) of cases, respectively. The 3-year disease free survival (DFS) and overall survival (OS)rates were 75.8% and 86.8%. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect and seemed to be effective in eliminating EMVI and transforming the positive MRF to negative in LARC. The survival results are promising. The long-term follow-up showed promising DFS and OS rates accompanied by a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03443661, 23/02/2018.

Exploration of the immunogenetic landscape of hyperprogressive disease after combined immunotherapy in cancer patients.

The immune-genetic changes that occur in cancer patients experiencing hyperprogressive disease (HPD) during combined immunotherapy are unclear. In this study, HPD patients with pre- and post-HPD samples and non-HPD patients with solid tumors were molecularly characterized by genetic and tumor immune microenvironment (TiME) analyses of paired samples by whole-exome sequencing, RNA sequencing, and multiplex immunofluorescence. The genetic analysis of paired samples showed that almost all the tumor driver gene mutations were preserved between pre- and post-HPD tumors. HPD patients had higher frequencies of mutations in TP53 and CNN2, and a significantly higher mutant-allele tumor heterogeneity than non-HPD patients. Tumor IL-6 mRNA was upregulated in post-HPD samples vs. pre-HPD, accompanied by a potential immune suppressive TiME with an elevated M2/M1 ratio. Salvage treatment with irinotecan plus bevacizumab was effective in one HPD patient, who experienced prolonged survival. These genetic features and TiME characteristics might help identify the features of HPD after immunotherapy.

Recent advances in targeted therapy for pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%-90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC - erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.

Nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) as first-line treatment for advanced biliary tract adenocarcinoma: a phase 2 clinical trial.

Background: This study aimed to evaluate the efficacy and safety of a new combination of nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) for patients with advanced biliary tract carcinoma (BTC). Methods: Patients were treated with nab-paclitaxel at a dose of 125 mg/m2 on day 1 and 8, and S-1, 80 to 120 mg/day on days 1-14 of a 21-day cycle. Treatments were repeated until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR). The secondary endpoints were median progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: The number of patients enrolled were 54, and 51 patients were evaluated for efficacy. A total of 14 patients achieved partial response (PR) with an ORR of 27.5%. The ORR varied by sites, with 53.8% (7/13) for gallbladder carcinoma, 18.4% (7/38) for cholangiocarcinoma. The most common grade 3 or 4 toxicities were neutropenia and stomatitis. The median PFS and OS were 6.0 and 13.2 months, respectively. Conclusions: The combination of nab-paclitaxel with S-1 showed explicit antitumor activities and favorable safety profile in advanced BTC and could serve as a potential non-platinum and -gemcitabine-based regimen.

Less aggressive treatment for less aggressive disease? A retrospective single-center study of pulmonary-limited metastases associated with colorectal cancer.

OBJECTIVE: To explore the appropriate treatment strategies, clinical outcomes, and prognostic factors of patients with pulmonary-limited metastases derived from colorectal cancer (CRC), usually manifested as a less aggressive course. METHODS: A retrospective review was conducted in 331 CRC patients diagnosed with pulmonary-limited metastases at a single institution between January 2011 and November 2017. The Kaplan-Meier method was used to calculate the overall survival (OS). Further analysis was conducted according to treatment modalities. Univariate and multivariate analyses were used to determine potential prognostic factors influencing OS. RESULTS: With a median follow-up time of 38.6 months, the median OS in all patients was 45.2 months. A total of 163 patients received intensive local treatment with a median OS of 76.4 months, whereas 168 patients received palliative systemic treatment with a median OS of 29.7 months. The median OS was 68.9 months for patients treated with radiotherapy/radiofrequency ablation, with similar efficacy compared to surgery group, whose OS had not reached yet. No survival benefits were observed from the additional targeted therapy in systemic treatment group. The prognostic analysis demonstrated unilateral/bilateral lesions, synchronous/metachronous metastases, intensive local treatment, and resection of primary lesion that were significantly associated with survival of patients. CONCLUSIONS: Intensive local treatment alone for pulmonary lesions was associated with excellent survival in certain patients with CRC presented with metastases confined to lungs. Doublet systemic chemotherapy as the first-line treatment also revealed satisfied efficacy and safety.

Phase Ib study of anlotinib combined with TQB2450 in pretreated advanced biliary tract cancer and biomarker analysis.

BACKGROUND AND AIMS: We evaluated the efficacy and safety of the antiangiogenic tyrosine kinase inhibitor anlotinib plus TQB2450, a programmed death-ligand 1 inhibitor in pretreated advanced biliary tract cancers (BTCs). APPROACH AND RESULTS: In this pooled analysis of two single-center, phase Ib clinical trials (TQB2450-Ib-05 and TQB2450-Ib-08 trials), 66 patients with advanced BTCs who had progressed or declined or were ineligible for first-line chemotherapy were included. With the treatment of anlotinib plus TQB2450, two patients achieved complete response, and 12 had a partial response assessed by Response Evaluation Criteria in Solid Tumors 1.1, yielding an objective response rate of 21.21%, a disease control rate (DCR) of 72.73%, and a clinical benefit rate (CBR) of 42.42%. With a median follow-up of 19.68 months, median progression-free survival (PFS) and overall survival (OS) were 6.24 (95% confidence interval [CI], 4.11-8.25) and 15.77 (95% CI, 10.74-19.71) months, respectively. Adverse events (AEs) were reported in 64 (96.97%) patients, and the most common grade 3 or worse treatment-related AEs included elevated levels of aspartate aminotransferase (7.58%), alanine aminotransferase (6.06%), and hypertension (6.06%). Patients with high tumor mutational burden (TMB; ≥5 mutations/Mbp) had a better CBR (70.8% vs. 22.2%), longer OS (14.32 vs. 9.64 months), and a trend toward longer PFS (7.03 vs. 4.06 months). Patients with kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations showed a lower CBR (12.5% vs. 58.8%) and shorter PFS (2.02 vs. 6.80 months) and OS (10.53 vs. 13.13 months). CONCLUSIONS: Anlotinib combined with TQB2450 showed promising efficacy and was well tolerated in advanced BTCs. KRAS mutation and high TMB might serve as predictors of treatment efficacy.

The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy for unresectable rectal cancer (SUNRISE): interim analysis of a randomized phase II trial.

PURPOSE: The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy (SCPRT) for unresectable rectal cancer is assessed with a planned interim analysis. METHODS AND MATERIALS: Patients diagnosed with clinical stage T3-4 or regional lymph node-positive disease with positive mesorectal fascia or T4b disease evaluated by pelvic MRI were randomly assigned to the SCPRT-boost group (25 Gy in 5 fractions plus 4 Gy delivered to the gross tumor volume, followed by four cycles of chemotherapy) or preoperative chemoradiotherapy group (50 Gy in 25 fractions with concurrent chemotherapy). Then, patients received total mesorectal excision surgery after preoperative treatment. The primary endpoint was the R0 resection rate. The interim analysis was performed when 42 patients completed their assigned treatments. RESULTS: From October 2018 to November 2019, a total of 43 patients were enrolled, and 42 patients were included in the interim analysis. During preoperative therapy, grade 3 or above toxicities were observed in 10/21 (47.6%) patients in the experimental group, and 4/21 (19.0%) patients in the control group. A total of 17 (81.0%) and 13 (61.9%) patients in the experimental group and control group underwent surgery, respectively. Overall, 65.1% of the patients achieved R0 resection in the intention-to-treat analysis. Surgery-related adverse complications were observed in 2 patients (11.8%) in the experimental group and 1 patient (7.7%) in the control group. CONCLUSION: Our results show that the toxicity of an MRI simulation-guided boost after SCPRT for unresectable rectal cancer is acceptable. Thus, this clinical trial will be continued as planned.

Intracellular and extracellular factors of colorectal cancer liver metastasis: a pivotal perplex to be fully elucidated.

Metastasis is the leading cause of death in colorectal cancer (CRC) patients, and the liver is the most common site of metastasis. Tumor cell metastasis can be thought of as an invasion-metastasis cascade and metastatic organotropism is thought to be a process that relies on the intrinsic properties of tumor cells and their interactions with molecules and cells in the microenvironment. Many studies have provided new insights into the molecular mechanism and contributing factors involved in CRC liver metastasis for a better understanding of the organ-specific metastasis process. The purpose of this review is to summarize the theories that explain CRC liver metastasis at multiple molecular dimensions (including genetic and non-genetic factors), as well as the main factors that cause CRC liver metastasis. Many findings suggest that metastasis may occur earlier than expected and with specific organ-anchoring property. The emergence of potential metastatic clones, the timing of dissemination, and the distinct routes of metastasis have been explained by genomic studies. The main force of CRC liver metastasis is also thought to be epigenetic alterations and dynamic phenotypic traits. Furthermore, we review key extrinsic factors that influence CRC cell metastasis and liver tropisms, such as pre-niches, tumor stromal cells, adhesion molecules, and immune/inflammatory responses in the tumor microenvironment. In addition, biomarkers associated with early diagnosis, prognosis, and recurrence of liver metastasis from CRC are summarized to enlighten potential clinical practice, including some markers that can be used as therapeutic targets to provide new perspectives for the treatment strategies of CRC liver metastasis.

A predictive model for early death in elderly patients with gastric cancer: A population-based study.

Background: The mean age of gastric cancer (GC) patients has increased due to the aging society. Elderly GC patients with poor physical status tend to develop complications during the treatment courses, which cause early death. This study aimed to identify risk factors and establish nomograms for predicting total early death and cancer-specific early death in elderly GC patients. Methods: Data for elderly GC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. These patients were randomly assigned to a training cohort and a validation cohort. The univariate logistic regression model and backward stepwise logistic regression model were used to identify independent risk factors for early death. Nomograms were constructed to predict the overall risk of early death and their performance was validated by receiver operating characteristic (ROC) curve, calibration curve, decision curve analyses (DCA), integrated discrimination improvement (IDI), and net reclassification improvement (NRI) in both training and validation cohorts. Results: Among the 3102 enrolled patients, 1114 patients died within three months from the first diagnosis and 956 of them died due to cancer-specific causes. Non-Asian or Pacific Islander (API) race, non-cardia/fundus or lesser/greater curvature, higher AJCC stage, no surgery and no chemotherapy were all related to a high risk of both all-cause early death and cancer-specific early death. Higher T stage and N0 stage were only positively related to total early mortality, while liver metastasis was only positively related to cancer-specific early mortality. Based on these identified factors, two nomograms were developed for predicting the risk of all-cause and cancer-specific early death, which showed good performance with the AUC of the nomograms were 0.775 and 0.766, respectively. The calibration curves, DCAs, NRI, and IDI also confirmed the value of these nomograms. Conclusions: These nomogram models were considered a practical tool to identify the early death of elderly GC patients and help provide a more individualized treatment strategy.