Long-term experience with tepotinib in Japanese patients with MET exon 14 skipping NSCLC from the Phase II VISION study.

Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION.

Vasohibin-2-Targeting Therapies for the Treatment of Pancreatic Ductal Adenocarcinoma.

As pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and refractory, therapeutic options for this cancer are anticipated worldwide. We isolated vasohihibin-2 (VASH2) and observed its overexpression in various types of cancer. We then noticed that upregulated expression of VASH2 in patients with PDAC resulted in a conspicuous reduction in the postoperative survival period and further revealed that the abrogation of Vash2 expression in pancreatic cancer cells inhibited its growth and metastasis and augmented tumor infiltration of CD8+ cells in the mouse model. We developed VASH2-targeting therapies, 2',4'-BNA-based antisense oligonucleotide targeting VASH2 (VASH2-ASO) as a nucleotide-based therapy, and VASH2-peptide vaccine as an antibody-based therapy. We also showed that the VASH2-peptide vaccine inhibited PDAC metastasis in an orthotopic mouse model. Here, we expanded our analysis of the efficacy of VASH2-targeting therapies for PDAC. VASH2-ASO treatment inhibited the growth of primary tumors by reducing tumor angiogenesis, normalizing tumor vessels, preventing ascites accumulation and distant metastasis to the liver and lungs, and augmenting the infiltration of CD8+ cells in metastatic tumors. VASH2-peptide vaccine did not affect the infiltration of CD8+ cells into tumors. The present study revealed that VASH2-targeting therapies are promising options for the treatment of PDAC. VASH2-ASO therapy can be administered at any stage of PDAC. Because of the increase of CD8+ cell infiltration, the combination therapy with immune checkpoint inhibitors may be an attractive option. The VASH2-peptide vaccine therapy may be useful for preventing metastasis and/or recurrence after successful initial treatment.

Cyclin-dependent kinase (CDK) 4/6 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations.

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide, and EGFR mutation is the most common genetic alteration among Asian patients with lung adenocarcinoma. While osimertinib has been shown to be effective in lung cancer patients with EGFR mutation, the majority of patients eventually develop acquired resistance to treatment. We explored the significance of the cyclin D1 expression in patients with EGFR mutation and the potential efficacy of adding abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, simultaneously with osimertinib in vitro. MATERIALS AND METHODS: Immunohistochemical staining, using an anti-cyclin D1 antibody, of specimens from 83 patients with EGFR mutation (male, n = 27; pStage 0-I, n = 71) who were treated by surgical resection between 2017 and 2020, and the relationship between the cyclin D1 expression and clinicopathological factors was analyzed. Additionally, the combined effect of osimertinib and abemaciclib in lung cancer cell lines were analyzed using a growth inhibition test, and the signaling pathway underlying the combined effect was investigated. RESULTS: Cyclin D1 was negative in 18.1% of patients with EGFR mutation, and cyclin D1 negativity was associated with pStage ≥ II (p = 0.02), lymph node metastasis (p = 0.001), and lymphatic invasion (p = 0.01). The cyclin D1-negative group had significantly shorter recurrence-free survival (p = 0.02), although this difference disappeared when limited to pN0 patients. In EGFR mutated cell lines, the combination of osimertinib and abemaciclib demonstrated synergistic effects, which were thought to be mediated by the inhibition of AKT phosphorylation. CONCLUSION: Combination therapy with CDK4/6 inhibitors and EGFR-TKIs may be a promising approach.

NPM2 in malignant peritoneal mesothelioma: from basic tumor biology to clinical medicine.

BACKGROUND: This review systematically summarizes gene biology features and protein structure of nucleoplasmin2 (NPM2) and the relationship between NPM2 and malignant peritoneal mesothelioma (MPM), in order to explore the molecular pathological mechanism of MPM and explore new therapeutic targets. METHODS: NCBI PubMed database was used for the literature search. NCBI Gene and Protein databases, Ensembl Genome Browser, UniProt, and RCSB PDB database were used for gene and protein review. Three online tools (Consurf, DoGSiteScorer, and ZdockServer), the GEPIA database, and the Cancer Genome Atlas were used to analyze bioinformatics characteristics for NPM2 protein. RESULTS: The main structural domains of NPM2 protein include the N-terminal core region, acidic region, and motif and disordered region. The N-terminal core region, involved in histone binding, is the most conserved domain in the nucleoplasmin (NPM) family. NPM2 with a large acidic tract in its C-terminal tail (NPM2-A2) is able to bind histones and form large complexes. Bioinformatics results indicated that NPM2 expression was correlated with the pathology of multiple tumors. Among mesothelioma patients, 5-year survival of patients with low-NPM2-expression was significantly higher than that of the high-NPM2-expression patients. NPM2 can facilitate the formation of histone deacetylation. NPM2 may promote histone deacetylation and inhibit the related-gene transcription, thus leading to abnormal proliferation, invasion, and metastasis of MPM. CONCLUSION: NPM2 may play a key role in the development and progression of MPM.

Long-term antitumor effect of lenvatinib on unresectable hepatocellular carcinoma with portal vein invasion.

Lenvatinib is a novel multikinase inhibitor that has recently shown antitumor activity against hepatocellular carcinoma (HCC) in a phase III trial. We report the case of a woman in whom lenvatinib showed long-term antitumor activity, and in whom computed tomography (CT) scans revealed a series of suggestive radiological changes on the intratumor vascularity. A 68-year-old woman with hepatitis C virus-related liver disease presented with multiple HCCs. Following previous therapy, including six sessions of transcatheter arterial chemoembolization, we introduced lenvatinib monotherapy. Lenvatinib could rapidly cause hypovascularity in the main hypervascular target lesion, and portal vein tumor thrombosis also became undetectable 11 months after the initiation of lenvatinib. These radiological changes suggested that lenvatinib could exert not only anti-angiogenic activity but also direct antitumoral effect. Of note, CT scans during lenvatinib treatment revealed the target lesion as a low-density area in the early arterial phase, whereas scans during drug interruption due to proteinuria showed that the lesion was enhanced in the arterial phase. Finally, near-complete response could be achieved as the best response. We successfully managed various adverse events including proteinuria and hypertension, and the patient was able to continue this lenvatinib therapy for more than 4 years with well-controlled general condition. We report the first case of a patient with HCC in whom lenvatinib monotherapy demonstrated long-term antitumor activity. Suggestive radiological changes reflecting intratumor vascularity as presented here should be considered in patients receiving lenvatinib for HCC.

Retrospective study comparing anti-EGFR monoclonal antibody plus cisplatin-based chemoradiotherapy versus chemoradiotherapy alone for stage II-IVb nasopharyngeal carcinoma and prognostic value of EGFR and VEGF expression.

OBJECTIVES: The benefits of adding anti-EGFR therapy to conventional chemoradiotherapy (CRT) for nasopharyngeal carcinoma (NPC) remain uncertain, possibly because only a subgroup of patients show better outcome. To address this issue, we compared the efficacy of CRT plus cetuximab (CTX) or nimotuzumab (NTZ) to CRT alone for stage II-IVb NPC and examined possible prognostic indicators, including tumour EGFR and VEGR expression levels. DESIGN, SETTING AND PARTICIPANTS: This retrospective study enrolled 1812 patients at initial NPC diagnosis at Nanfang Hospital Affiliated to Southern Medical University between January 2005 and December 2015. The cetuximab or nimotuzumab plus CRT group (CRT+NTZ/CTX) and the conventional chemoradiotherapy group (CRT) were matched by propensity scoring at 1:5, yielding 282 patients at clinical stage II-IVb with 47 in the CRT+NTZ/CTX group and 235 in the CRT group. MAIN OUTCOME MEASURES: The endpoints of the present study were locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS). Immunohistochemistry (IHC) was used to investigate EGFR and VEGF expression levels in 31 patients of the CRT+NTZ/CTX group. RESULTS: There were no significant differences in LRFS, DMFS and OS, haematologic toxicity reactions, and gastrointestinal reactions between CRT+NTZ/CTX and CRT groups. There was a positive correlation between EGFR and VEGF expression levels. Among CRT+NTZ/CTX patients, those with high EGFR and VEGF expression levels exhibited better DMFS. CONCLUSIONS: Addition of anti-EGFR to cisplatin-based CRT appears to benefit only a subset of stage II-IVb NPC patients, those with elevated EGFR and VEGF expression levels.

Cohort study exploring the effect of lenvatinib on differentiated thyroid cancer.

Lenvatinib is a molecular-targeting agent that was recently approved in Japan for treatment of curatively unresectable, radioactive iodine-refractory, progressive differentiated thyroid cancer (DTC). Because only a few Japanese patients have received lenvatinib in clinical trials, there are limited domestic data on its safety and efficacy or prognostic factors. Therefore, a prospective observational study has been designed to collect safety and efficacy data in at least 300 patients with curatively unresectable DTC receiving lenvatinib therapy (24 mg/day), in order to find predictors of antitumor activity and survival. Patients with progressive curatively unresectable DTC refractory to radioiodine therapy will be enrolled and the primary endpoint will be overall survival. This study is designed to estimate the 95% confidence intervals of the 1-year and 2-year survival rates with a two-sided width of less than 10%. Secondary endpoints will be the time to treatment failure, time to strategy failure, progression-free survival time with clinical progressive disease, response rate, quality of life, safety, and patient reports. The ultimate goal is to obtain information for developing evidence-based guidelines for treatment of DTC, including recommendations on patient selection, dosages, and duration of treatment. This study has been registered with the UMIN Clinical Trials Registry (UMIN000022243).

Molecular pathogenesis and treatment strategy in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma, accounting for 30%-40% of all types of malignant lymphoma. Importantly, two distinct molecular subtypes, germinal center B-cell (GCB) type and activated B-cell (ABC) type, arising from B lymphocyte differentiation based on the gene expression profiling opened doors to uncover molecular pathogenesis in DLBCL. Since 2010, next-generation sequencing analyses have been revealing the landscape of genetic mutations in DLBCL. Reportedly, GCB DLBCL is characterized by the accumulation of genetic abnormalities of epigenetic modifiers. Conversely, the hallmark of ABC DLBCL is the constitutive activation of the NKκB signaling pathway due to mutations in related genes. From recent prospective trials, conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen, which is the current standard regimen for DLBCL, has been acknowledged as a well-established regimen for DLBCL. Currently, the development of a plethora of drugs targeting the activated signaling pathway and immune microenvironments is ongoing. To overcome this intractable disease with the present treatment, the breakthroughs based on molecular pathogenesis are required.

Gene aberrations for precision medicine against lung adenocarcinoma.

Lung adenocarcinoma (LADC), the most frequent histological type of lung cancer, is often triggered by an aberration in a driver oncogene in tumor cells. Examples of such aberrations are EGFR mutation and ALK fusion. Lung adenocarcinoma harboring such mutations can be treated with anticancer drugs that target the aberrant gene products. Additional oncogene aberrations, including RET, ROS1, and NRG1 fusions, skipping of exon 14 of MET, and mutations in BRAF, HER2, NF1, and MEK1, were recently added to the list of such "druggable" driver oncogene aberrations, and their responses to targeted therapies are currently being evaluated in clinical trials. However, approximately 30% and 50% of LADCs in patients in Japan and Europe/USA, respectively, lack the driver oncogene aberrations listed above. Therefore, novel therapeutic strategies, such as those that exploit the vulnerabilities of cancer cells with non-oncogene aberrations, are urgently required. This review summarizes the current status of research on precision medicine against LADC and enumerates the research priorities for the near future.

Philadelphia chromosome-positive acute lymphoblastic leukemia and Down syndrome.

Children with Down syndrome (DS) are at high risk of developing acute lymphoblastic leukemia (ALL), but Philadelphia chromosome-positive (Ph+) ALL is rare in DS children. We report a case of Ph+ALL with DS complicated by chronic heart failure. Complete molecular remission was obtained after imatinib-combined chemotherapy, although infectious episodes during the neutropenic period worsened the heart condition. After two courses of intensification chemotherapy, the patient underwent reduced intensity stem cell transplantation from an HLA-identical sibling donor followed by post-transplant imatinib. The patient maintained molecular complete remission for >2 years. This case report is the first description of the safe and effective use of imatinib for DS-Ph+ALL. This case suggests the potential of molecular targeting therapy in DS-ALL, which is often complicated by congenital diseases, and the importance of treating DS-ALL while maintaining intensity and reducing treatment-related toxicity.

Chemotherapy and molecular targeting therapy for recurrent cervical cancer.

For patients with primary stage ⅣB, persistent, or recurrent cervical cancer, chemotherapy remains the standard treatment, although it is neither curative nor associated with long-term disease control. In this review, we summarized the history of treatment of recurrent cervical cancer, and the current recommendation for chemotherapy and molecular targeted therapy. Eligible articles were identified by a search of the MEDLINE bibliographical database for the period up to November 30, 2014. The search strategy included the following any or all of the keywords: "uterine cervical cancer", "chemotherapy", and "targeted therapies". Since cisplatin every 21 days was considered as the historical standard treatment for recurrent cervical cancer, subsequent trials have evaluated and demonstrated activity for other agents including paclitaxel, gemcitabine, topotecan and vinorelbine among others. Accordingly, promising agents were incorporated into phase Ⅲ trials. To examine the best agent to combine with cisplatin, several landmark phase Ⅲ clinical trials were conducted by Gynecologic Oncology Group (GOG) and Japan Clinical Oncology Group (JCOG). Through, GOG204 and JCOG0505, paclitaxel/cisplatin (TP) and paclitaxel/carboplatin (TC) are now considered to be the recommended therapies for recurrent cervical cancer patients. However, the prognosis of patients who are already resistant to chemotherapy, are very poor. Therefore new therapeutic strategies are urgently required. Molecular targeted therapy will be the most hopeful candidate of these strategies. From the results of GOG240, bevacizumab combined with TP reached its primary endpoint of improving overall survival (OS). Although, the prognosis for recurrent cervical cancer patients is still poor, the results of GOG240 shed light on the usefulness of molecular target agents to chemotherapy in cancer patients. Recurrent cervical cancer is generally considered incurable and current chemotherapy regiments offer only modest gains in OS, particularly for patients with multiple poor prognostic factors. Therefore, it is crucial to consider not only the survival benefit, but also the minimization of treatment toxicity, and maximization of quality of life (QOL).

Preferential HER2 expression in liver metastases and EGFR expression in peritoneal metastases in patients with advanced gastric cancer.

BACKGROUND: Despite recent clinical trials, the sensitivity and resistance of metastatic gastric cancer to anti-HER2 and anti-EGFR therapy are still unclear. MATERIALS AND METHODS: To clarify the HER2 and EGFR expression status in the metastatic sites, we immunohistochemically compared HER2 and EGFR expression between primary and metastatic tumors from 52 gastric cancer patients with liver metastases and 85 patients with peritoneal metastases. RESULTS: The HER2 positivity rate of primary and metastatic tumors in patients with liver metastases, especially with intestinal-type histology (70.6 and 80.0 %, respectively), was significantly higher than in primary and metastatic tumors (22.4 and 16.4 %, respectively) in patients with peritoneal metastases. HER2 positivity of the primary tumor and liver metastases showed good concordance (87.5 %) in patients with liver metastases. In contrast, the EGFR positivity rate of metastatic tumors (70.1 %) in patients with peritoneal metastases was significantly higher than that of metastatic tumors (37.5 %) in patients with liver metastases. HER2 and EGFR expression tended to be mutually exclusive, and HER2/EGFR double-positive cases were rare in patients with liver or peritoneal metastases. In four such patients with HER2/EGFR double-positive primary tumors, the HER2- and EGFR-positive areas were separate, and corresponding liver metastasis was only positive for HER2 and peritoneal metastasis only positive for EGFR. CONCLUSION: These results indicate that HER2 and EGFR are preferentially expressed in the liver and peritoneal metastases, respectively, which would be potential targets for anti-HER2 and anti-EGFR molecular therapy in metastatic gastric cancer patients.

Dual-molecular targeting nanomedicine upregulates synergistic therapeutic efficacy in preclinical hepatoma models.

Advanced hepatocellular carcinoma (HCC) is one of the most challenging cancers because of its heterogeneous and aggressive nature, precluding the use of curative treatments. Sorafenib (SOR) is the first approved molecular targeting agent against the mitogen-activated protein kinase (MAPK) pathway for the noncurative therapy of advanced HCC; yet, any clinically meaningful benefits from the treatment remain modest, and are accompanied by significant side effects. Here, we hypothesized that using a nanomedicine platform to co-deliver SOR with another molecular targeting drug, metformin (MET), could tackle these issues. A micelle self-assembled with amphiphilic polypeptide methoxy poly(ethylene glycol)-block-poly(L-phenylalanine-co-l-glutamic acid) (mPEG-b-P(LP-co-LG)) (PM) was therefore designed for combinational delivery of two molecular targeted drugs, SOR and MET, to hepatomas. Compared with free drugs, the proposed, dual drug-loaded micelle (PM/SOR+MET) enhanced the drugs' half-life in the bloodstream and drug accumulation at the tumor site, thereby inhibiting tumor growth effectively in the preclinical subcutaneous, orthotopic and patient-derived xenograft hepatoma models without causing significant systemic and organ toxicity. Collectively, these findings demonstrate an effective dual-targeting nanomedicine strategy for treating advanced HCC, which may have a translational potential for cancer therapeutics. STATEMENT OF SIGNIFICANCE: Treatment of advanced hepatocellular carcinoma (HCC) remains a formidable challenge due to its aggressive nature and the limitations inherent to current therapies. Despite advancements in molecular targeted therapies, such as Sorafenib (SOR), their modest clinical benefits coupled with significant adverse effects underscore the urgent need for more efficacious and less toxic treatment modalities. Our research presents a new nanomedicine platform that synergistically combines SOR with metformin within a specialized diblock polypeptide micelle, aiming to enhance therapeutic efficacy while reducing systemic toxicity. This innovative approach not only exhibits marked antitumor efficacy across multiple HCC models but also significantly reduces the toxicity associated with current treatments. Our dual-molecular targeting approach unveils a promising nanomedicine strategy for the molecular treatment of advanced HCC, potentially offering more effective and safer treatment alternatives with significant translational potential.

Stepwise Incremental Dose Schedule of Sirolimus Is Successfully Tolerated by a Patient With Lymphangioleiomyomatosis Who Was Initially Allergic to mTOR Inhibitors.

Lymphangioleiomyomatosis (LAM) is a rare disease involving the proliferation of LAM cells in the lungs and the axial lymphatic system and mechanistic target of rapamycin (mTOR) inhibitors are the only effective medicines for treating it. Patients suffering from LAM, who are allergic to mTOR inhibitors can be treated by desensitizing them to the medicine. A 39-year-old woman presented with dyspnea caused by chylous pleural effusion, ascites, and retroperitoneal lymphangioleiomyomas. She was diagnosed with LAM based on the presence of LAM cell clusters (LCCs) in chylous pleural effusion and elevated serum vascular endothelial growth factor D (VEGF-D) concentration. She was allergic to cedars and yellowtails. Although she was started on sirolimus for treating LAM, the drug had to be discontinued on day 45 because of the appearance of a skin rash on her trunk. A year later, another oral mTOR inhibitor, everolimus, was initiated but had to be discontinued because of the appearance of cutaneous reactions. Since mTOR inhibitors are the only effective molecular-target medicines for LAM, desensitization to sirolimus was attempted by initiating exposure to sirolimus at a low dose followed by stepwise dose escalation. Eventually, the patient tolerated a dose of 0.5 mg/day of sirolimus, which resulted in a trough concentration of approximately 2 ng/ml in blood, without adverse cutaneous reactions; furthermore, clinically relevant effects were observed as her LAM condition reduced and stabilized. This case study illustrates that mTOR inhibitor therapy for LAM should not be abandoned because of allergic cutaneous reactions. Physicians must find a dose that balances adverse events and therapeutic effects to ensure continued treatment for patients with LAM. Furthermore, the possible mechanisms for mTOR inhibitor-induced cutaneous reactions have been discussed.

Efficacy and Safety of Anlotinib in Overall and Disease-Specific Advanced Gynecological Cancer: A Real-World Study.

Purpose: Anlotinib is a novel oral small-molecule multi-target tyrosine kinase inhibitor that has been approved for treating non-small cell lung cancer. However, its efficacy and safety among patients with advanced gynecological cancer have not been comprehensively evaluated. We conducted this study to address this issue in the real-world setting. Patients and Methods: Data from patients treated with Anlotinib for persistent, recurrent or metastatic gynecological cancer were collected from 17 centers from August 2018. The database lock-time was on March 2022. Anlotinib was administered orally on days 1-14 every 3 weeks until disease progression, severe toxicity occurred, or death. In this study, disease-specific advanced gynecological cancer was mainly referred to cervical, endometrial, and ovarian cancer. The outcomes included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: A total of 249 patients were analyzed, with a median follow-up of 14.5 months. The overall ORR and DCR were 28.1% [95% confidence interval (CI) 22.6% to 34.1%] and 80.7% (95% CI 75.3% to 85.4%), respectively. Specifically, the ORR varied from 19.7% to 34.4% and the DCR differed from 81.7% to 90.0% in disease-specific advanced gynecological cancer. The median PFS was 6.1 months and ranged from 5.6 to 10.0 months in the overall and disease-specific advanced gynecological cancer, respectively. Larger cumulative dosage of Anlotinib (>700 mg) was in general associated with longer PFS in the overall and disease-specific advanced gynecological cancer. The most common adverse event related to Anlotinib treatment was pain/arthralgia (18.3%). Conclusion: In conclusion, Anlotinib holds promise in treating patients with advanced gynecological cancer including its disease-specific types, with reasonable efficacy and tolerable safety.

A single-center retrospective analysis of the efficacy and safety of a modified regimen of irinotecan plus S-1 (IRIS) with molecular targeting agents as second-line chemotherapy in Japanese patients with recurrent or nonresectable colorectal cancer.

Background: As the second-line chemotherapy for stage IV recurrent or nonresectable colorectal cancer, our hospital started a modified treatment regimen comprising of irinotecan plus S-1 (IRIS) [tegafur/gimeracil/oteracil (S-1)] plus molecular targeting agents (MTAs), i.e., an epidermal growth factor receptor (EGFR) inhibitor such as panitumumab (P-mab) or cetuximab (C-mab) or vascular endothelial growth factor (VEGF) inhibitor such as bevacizumab (B-mab) since October 2012. The purpose of this study is to evaluate the efficacy and safety of this modified regimen. Methods: This retrospective study included 41 patients with advanced recurrent colorectal cancer at our hospital whom at least 3 courses of chemotherapy were conducted from January 2015 to December 2021. Based on the location of the primary tumor, patients were classified into two group (right-sided group, proximal to the splenic curve, and left-sided, distal to the splenic curve). We assessed archived data on RAS and BRAF status and UGT1A1 polymorphisms and use of the VEGF inhibitor bevacizumab (B-mab) and the EGFR inhibitors panitumumab (P-mab) and cetuximab (C-mab). In addition, progression-free survival rate (36M-PFS) and the overall survival rate (36M-OS) were calculated. Furthermore, the respective median survival time (MST), the median number of treatment courses; the objective response rate (ORR) and clinical benefit rate (CBR) and the incidence of adverse events (AEs) were assessed as well. Results: There were 11 patients (26.8%) in the right-sided group, and 30 patients (73.2%) in the left-sided group. There were 19 patients with RAS wild type (46.3%) (1 in the right sided group and 18 in the left sided group). P-mab was used for 16 of these patients (84.2%), C-mab for 2 (10.5%), and B-mab for 1 (5.3%); the remaining 22 patients (53.7%). Ten patients in the right group and 12 patients in the left group were a mutated type and received B-mab. BRAF testing was performed in 17 patients (41.5%); as more than 50% of patients (58.5%) were included before the assay's introduction. Five patients in the right-sided group and 12 patients in the left-sided group had wild type. There was no mutated type. UGT1A1 polymorphism was tested in 16/41 patients: Eight were wild type (8/41 patients, 19.5%) and 8, mutated type. Regarding the *6/*28 double heterozygous type, there was only 1 patient in the right-sided group and the remaining 7 patients were in the left-sided group. The total number of chemotherapy courses was 299, and the median number, 6.0 (range, 3-20). PFS, OS, and MST were as follows: 36M-PFS (total/Rt/Lt), 6.2%/0.0%/8.5% (MST; 7.6/6.3/8.9 months); and 36M-OS (total/Rt/Lt), 32.1%/0.0%/44.0% (MST; 22.1/18.8/28.6 months). The ORR and CBR were 24.4% and 75.6%, respectively. The majority of AEs were grades 1 or 2 and were improved with conservative treatment. Grade 3 leukopenia was observed in 2 cases (4.9%), neutropenia in 4 cases (9.8%), and malaise/nausea/diarrhea/perforation in 1 case each (2.4%). Grade 3 leukopenia (2 patients) and neutropenia (3 patients) were more commonly observed in the left-sided group. Diarrhea and perforation were also common in the left-sided group. Conclusions: This second-line modified IRIS regimen with MTAs is safe and effective and results in good PFS and OS.

Osimertinib as first-line treatment for recurrent lung cancer patients with EGFR mutation.

Background: Although osimertinib was approved as adjuvant therapy for lung cancer patients with EGFR mutation in various countries, there is still some ongoing debate as osimertinib has been approved based on disease-free survival (DFS) rather than overall survival (OS). We curated a case series in which we documented patterns of recurrence and efficacy and safety of osimertinib after recurrence. Methods: Patients who received osimertinib as first-line treatment for postoperative recurrence between September 2018 and January 2023 were included. Clinicopathological factors, duration of osimertinib treatment (DoT), and adverse events were collected and analyzed. Results: Twenty patients received osimertinib [male, n=6; median age, 75 years (range, 55-85 years)]. The EGFR mutation type was L858R in 11 patients and exon 19 deletion in eight patients. The performance status (PS) was 0 or 1 in all but two patients, who had symptomatic brain metastasis and were therefore PS 3. The first site of postoperative recurrence was locoregional in five patients and distant in 15 patients, including seven with brain metastasis. As of February 2023, 10 patients were still on osimertinib, including three with brain metastasis. Patients with brain metastasis or poor PS had a considerably shorter DoT than their counterparts. Three patients with symptomatic brain metastasis or leptomeningeal metastasis initially responded to osimertinib, but all died of disease progression. Five patients discontinued osimertinib due to serious adverse effects (pneumonitis, drug eruption, and heart failure). Conclusions: Although osimertinib exerts great disease control, even in patients with brain metastasis or poor PS, their presence was associated with a poor prognosis, even with osimertinib treatment. Therefore, adjuvant osimertinib is recommended unless contraindicated.

The Inhibitory Effects of Anti-ERC/Mesothelin Antibody 22A31 on Colorectal Adenocarcinoma Cells, within a Mouse Xenograft Model.

The expression of Renal Carcinoma (ERC)/mesothelin is enhanced in a variety of cancers. ERC/mesothelin contributes to cancer progression by modulating cell signals that regulate proliferation and apoptosis. Based on such biological insights, ERC/mesothelin has become a molecular target for the treatment of mesothelioma, pancreatic cancer, and ovarian cancer. Recent studies revealed about 50-60% of colorectal adenocarcinomas also express ERC/mesothelin. Therefore, colorectal cancer can also be a potential target of the treatment using an anti-ERC/mesothelin antibody. We previously demonstrated an anti-tumor effect of anti-ERC antibody 22A31 against mesothelioma. In this study, we investigated the effect of 22A31 on a colorectal adenocarcinoma cell line, HCT116. The cells were xenografted into BALB/c nu/nu mice. All mice were randomly allocated to either an antibody treatment group with 22A31 or isotype-matched control IgG1κ. We compared the volume of subsequent tumors, and tumors were pathologically assessed by immunohistochemistry. Tumors treated with 22A31 were significantly smaller than those treated with IgG1κ and contained significantly fewer mitotic cells with Ki67 staining. We demonstrated that 22A31 exhibited a growth inhibitory property on HCT116. Our results implied that ERC/mesothelin-targeted therapy might be a promising treatment for colorectal cancer.

Elevated METTL9 is associated with peritoneal dissemination in human scirrhous gastric cancers.

Methylation, the most common chemical modification of cellular components such as DNA, RNA, and proteins, impacts biological processes including transcription, RNA processing, and protein dynamics. Although abnormal expression of methyltransferase can lead to various diseases including cancers, little is known about the relationship between methyltransferase and cancers. Here we aimed to understand the role of methyltransferase in cancer metastasis. We found that elevated methyltransferase-like 9 (METTL9) is closely associated with the acquisition of metastatic activity in human scirrhous gastric cancers. The stable knockdown of METTL9 via an shRNA vector technique in our original metastatic cells from scirrhous gastric cancer patients significantly inhibited migration and invasion. In metastatic cells, METTL9 protein is predominantly localized in mitochondria, and the METTL9 knockdown significantly reduced mitochondrial Complex I activity. METTL9 can be a candidate of molecular targets to inhibit peritoneal dissemination of scirrhous gastric cancers. This report is the first to describe the relationship between METTL9 and cancer metastasis.

Emerging Roles of Cancer Stem Cells in Bladder Cancer Progression, Tumorigenesis, and Resistance to Chemotherapy: A Potential Therapeutic Target for Bladder Cancer.

Bladder cancer (BC) is a complex and highly heterogeneous stem cell disease associated with high morbidity and mortality rates if it is not treated properly. Early diagnosis with personalized therapy and regular follow-up are the keys to a successful outcome. Cancer stem cells (CSCs) are the leading power behind tumor growth, with the ability of self-renewal, metastasis, and resistance to conventional chemotherapy. The fast-developing CSC field with robust genome-wide screening methods has found a platform for establishing more reliable therapies to target tumor-initiating cell populations. However, the high heterogeneity of the CSCs in BC disease remains a large issue. Therefore, in the present review, we discuss the various types of bladder CSC heterogeneity, important regulatory pathways, roles in tumor progression and tumorigenesis, and the experimental culture models. Finally, we describe the current stem cell-based therapies for BC disease.