Methylation Pattern Mediated by m6A Regulator and Tumor Microenvironment Invasion in Lung Adenocarcinoma

Background. Recent research has established the existence of epigenetic modulation of the immune response. The possible involvement of RNA-n6-methyladenosine (m6A) alteration in tumor microenvironment (TME) cell invasion, on the other hand, is unknown. Methods. Based on 23 m6A regulators, we examined the alteration patterns of m6A in 629 LUAD tissues and comprehensively connected these modification patterns with TME cell invasion characteristics. The m6A score was calculated, and the m6A modification pattern of a single tumor was quantified using principal component analysis. Then, we further verified the expression of m6A related enzymes and the role hub gene (NOL10) closely related to survival in lung cancer cell lines. Results. Three separate m6A alteration modes have been discovered. TME cell invasion characteristics in the three modes were very similar to the three immunological phenotypes of tumors: immunological rejection, immunological inflammation, and immunological desert. We show that assessing the m6A modification pattern in a single tumor may help predict tumor inflammatory stage, subtype, TME interstitial activity, and prognosis. TME phenotypic inflammation is indicated by a high m6A score, which is characterized by elevated mutation load and immunological activation. The low m6A subtype showed matrix activation and ineffective immune infiltration, indicating that the TME phenotype of noninflammation and immunological rejection had a poor survival probability. Increased neoantigen burden was also linked to a high m6A score. Patients with a higher m6A score saw substantial therapeutic and clinical improvements. And reducing hub gene NOL10 expression substantially inhibited lung cancer cell growth and migration. Conclusions. This research shows that m6A alteration is critical in the creation of TME variety and complexity. The analysis of a single tumor’s m6A alteration pattern will aid in improving our knowledge of TME invasion features and guiding more effective immunotherapy tactics.

A case of solitary plasmacytoma of bone showing co-expression of both immunoglobulin light chains

Background Solitary plasmacytoma of bone (SPB) is a rare plasma cell neoplasm. It arises in bone as a single locus in the absence of any plasma cell myeloma lesions. Plasma cell neoplasms intrinsically express only one immunoglobulin light chain (IgL)—kappa or lambda—and using this fact, kappa/lambda deviation is the decisive factor for diagnosis. Co-expression of both IgLs in a single tumor cell is extremely rare. Case presentation We report a case of SPB that arose in the vertebra of a 52-year-old Japanese woman. Histologically, the resected mass showed diffuse plasma cell proliferation. Dual IgL expression was detected by flow cytometry, immunohistochemistry, and in situ hybridization (ISH) targeting IgL mRNA. Conclusion We have presented an extremely rare case of SPB showing dual expression of kappa and lambda IgLs. This unusual case of plasma cell neoplasia might represent a possible exceptional example of failure of “IgL isotypic exclusion.”

A Case of Solitary Plasmacytoma of Bone Showing Coexpression of Both Immunoglobulin Light Chains

Background: Solitary plasmacytoma of bone (SPB) is a rare plasma cell neoplasm. It arises in bone as a single locus in the absence of any plasma cell myeloma lesions. Plasma cell neoplasms intrinsically express only one immunoglobulin light chain (IgL) – kappa or lambda – and using this fact, kappa/lambda deviation is the decisive factor for diagnosis. Coexpression of both IgLs in a single tumor cell is extremely rare.Case presentation: We report a case of SPB that arose in the vertebra of a 52-year-old Japanese woman. Histologically, the resected mass showed diffuse plasma cell proliferation. Dual IgL expression was detected by flow cytometry, immunohistochemistry and in situ hybridization (ISH) targeting IgL mRNA.Conclusion: We have presented an extremely rare case of SPB showing dual expression of kappa and lambda IgLs. This unusual case of plasma cell neoplasia might represent a possible exceptional example of failure of “IgL isotypic exclusion”.

Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies

BackgroundIndividualized neoantigen-specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. It is assumed that clonal neoantigens are preferred targets for immunotherapy, but the distributions of clonal neoantigens are not well characterized across cancer types.MethodsWe combined multiregion sequencing (MR-seq) analysis of five untreated, synchronously sampled metastatic solid tumors with re-analysis of published MR-seq data from 103 patients in order to characterize their globally clonal neoantigen content and factors that would impact neoantigen targeting.ResultsBranching evolution in colorectal cancer and renal cell carcinoma led to fewer clonal neoantigens and to clade-specific neoantigens (those shared across a subset of tumor regions but not fully clonal), with the latter not being readily distinguishable in single tumor samples. In colorectal, renal, and bladder cancer, most tumors had few globally clonal neoantigens. Prioritizing mutations with higher purity-adjusted and ploidy-adjusted variant allele frequency enriched for globally clonal neoantigens (those found in all tumor regions), whereas estimated cancer cell fraction derived from clustering-based tools, surprisingly, did not. Neoantigen quality was associated with loss of neoantigen expression in the bladder cancer case, and HLA-allele loss was observed in the renal and non-small cell lung cancer cases.ConclusionsWe show that tumor type, multilesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection, and may also be important factors to consider in the development of biomarker strategies.

Comprehensive Analysis of Pyroptosis-Related Genes and Tumor Microenvironment Infiltration Characterization in Breast Cancer

BackgroundImmunotherapy has emerged as a significant strategy to treat numerous tumors. The positive response to immunotherapy depends on the dynamic interaction between tumor cells and infiltrating lymphocytes in the tumor microenvironment (TME). Pyroptosis, inflammation-induced cell death, is intricately associated with several tumors. However, the relationship between pyroptosis and clinical prognosis, immune cell infiltration, and immunotherapy effect is unclear in breast cancer (BRCA).MethodsWe comprehensively evaluated 33 pyroptosis-related genes and systematically assessed the relationship between pyroptosis and tumor progression, prognosis, and immune cell infiltration. The PyroptosisScore was used to quantify the pyroptosis pattern of a single tumor patient. We then assessed their values for predicting prognoses and therapeutic responses in BRCA.ResultsThree different modes of PyroptosisClusters were determined. The characteristics of TME cell infiltration in these three PyroptosisClusters were highly consistent with three immunophenotypes of tumors, including immune-excluded, immune-inflamed, and immune-desert phenotypes. Comprehensive bioinformatics analysis revealed that patients with a low PyroptosisScore had higher immune checkpoint expression, higher immune checkpoint inhibitor (ICI) scores, increased immune microenvironment infiltration, and were more sensitive to immunotherapy than those with a high PyroptosisScore.ConclusionsOur findings revealed the crucial role of pyroptosis in maintaining the diversity and complexity of TME. Pyroptosis is closely related to tumor progression, tumor prognosis, and immunotherapy response. Evaluating the PyroptosisScore of a single tumor can assist in understanding the characteristics of TME infiltration and lead to the development of more effective immunotherapy strategies.

Mechanisms and Clinical Significance of Tumor Lymphatic Invasion

Tumor-associated lymphatic vessels play an important role in tumor progression, mediating lymphatic dissemination of malignant cells to tumor-draining lymph nodes and regulating tumor immunity. An early, necessary step in the lymphatic metastasis cascade is the invasion of lymphatic vessels by tumor cell clusters or single tumor cells. In this review, we discuss our current understanding of the underlying cellular and molecular mechanisms, which include tumor-specific as well as normal, developmental and immunological processes “hijacked” by tumor cells to gain access to the lymphatic system. Furthermore, we summarize the prognostic value of lymphatic invasion, discuss its relationship with local recurrence, lymph node and distant metastasis, and highlight potential therapeutic options and challenges.

Cryoablation Using Liquid Nitrogen for Metastatic Lung Cancers

AimsTo identify factors that were associated with local control after cryoablation for metastatic lung tumors and to compare preserved pulmonary function according to tumor number.MethodsWe retrospectively evaluated 68 patients with 121 metastatic lung tumors that were treated with cryoablation using liquid nitrogen during 2013–2019. Primary outcome was whether local control was related with tumor size, histology, location, and distance to a vessel with a diameter of ≥3 mm. Secondary outcome was whether preserved pulmonary function varied according to number of treated tumors. ResultsMedian follow-up period was 32 months (range: 4–87 months).Histological types were carcinomas in 95 tumors and sarcoma in 26 tumors. Multivariate analysis revealed that local control was significantly associated with tumor size (p<0.001), histology (p<0.001), and distance from a vessel with a diameter of ≥3 mm (p=0.03). Among tumors with a diameter of ≥2.2 cm, poorer local control was observed for sarcomas (p<0.001) and tumors that were ≤3 mm from the vessel (p=0.009), although these relationships were not significant among tumors with a diameter of <2.2 cm (p=0.44 and p=0.16). Relative to cryoablation for a single tumor, cryoablation for multiple tumors was associated with significantly lower preservation of pulmonary function (p=0.002). ConclusionPoor local control after cryoablation was significantly associated with tumor size ≥2.2 cm, sarcoma histology, and tumors that were ≤3 mm from a vessel with a diameter of ≥3 mm. Preserved pulmonary function declined significantly with an increasing number of treated tumors.

Postoperative Adjuvant Radiotherapy Can Delay the Recurrence of Desmoid Tumors After R0 Resection in Certain Subgroups

Background: When patients with desmoid tumors (DTs) present uncontrolled clinical symptoms, surgery is an effective treatment, but the high postoperative recurrence rate is a major problem. The significance of adjuvant radiotherapy has been debated for many years, and the significance of aggressive surgery has not been reported.Methods: Medical records for DT patients were collected. KM analysis and the Mann–Whitney U-test were performed to evaluate the role of radiotherapy and aggressive surgery in the entire cohort and different subgroups.Results: Of 385 DT patients, 267 patients with R0 resection were included in the final analysis. A total of 53 patients (19.85%) experienced recurrence. Although radiotherapy showed no significant effect on recurrence-free survival (RFS) or time to recurrence (TTR) in the entire cohort, radiotherapy delayed recurrence in the age ≤ 30 years old subgroup (TTR = 35 months with surgery plus radiotherapy, TTR = 11 months with surgery alone; p = 0.014) and the tumor diameter &gt;5 cm subgroup (TTR = 26 months with surgery plus radiotherapy, TTR = 11 months with surgery alone; p = 0.02) among patients with a single tumor. Aggressive surgery improved RFS in the tumor diameter &gt;5 cm subgroup (p = 0.049) but not the entire cohort.Conclusions: Although radiotherapy cannot improve RFS, it can delay recurrence in the age ≤ 30 years old subgroup and the tumor diameter &gt;5 cm subgroup among patients with a single tumor. For patients with large invasive tumors and multiple involved sites, aggressive surgery could be selected to achieve complete tumor resection to improve RFS.

Traditional Versus Microsphere Embolization for Hepatocellular Carcinoma: An Effectiveness Evaluation Using Data Mining

Background: For hepatocellular carcinoma (“HCC”), the current standard of treatment is hepatic artery embolization, generally through trans-catheter arterial chemoembolization (“TACE”). There are two types: traditional (“conventional” or “cTACE”) and microsphere (“DC bead TACE”). Unfortunately, the literature comparing the relative effectiveness of cTACE versus DC bead TACE is inconclusive, partially due to the complexity of HCC and its response to treatment. Data mining is an excellent method to extract meaning from complex data sets. Purpose: Through the application of data mining techniques, to compare the relative effectiveness of cTACE and DC bead TACE using a large patient database and to use said comparison to establish usable guidelines for developing treatment plans for HCC patients. Materials and Methods: The data of 372 HCC patients who underwent TACE in Taichung Veterans General Hospital were analyzed. The chi-square test was used to compare the difference in the effectiveness of the two therapies was compared. Logistic regression was used to calculate the odds ratios. Furthermore, using the C4.5 decision tree, the two therapies were classified into applicable fields. Chi-square test, the t-test, and logistic regression were used to verify the classification results. Results: In Barcelona Clinic Stages A and B cancers, cTACE was found to be 22.7% more effective than DC bead TACE. By using the decision tree C4.5 as a classifier, the effectiveness of either treatment for small tumors was 8.475 times than that for large tumors. DC bead TACE was 3.39 times more successful in treating patients with a single tumor than with multiple tumors. For patients with a single tumor, the chi-square test showed that 100–300 μm microspheres were significantly more effective than 300–500 μm. While these findings provide a reference for the selection of an appropriate TACE approach, we noted that overall accuracy was somewhat low, possibly due to the limited population. Conclusions: We found that data mining could be applied to develop clear guidelines for physician and researcher use in the case of complex pathologies such as HCC. However, some of our results contradicted those elsewhere in the literature, possibly due to a relatively small sample size. Significantly larger data sets with appropriate levels of granularity could produce more accurate results.

Heterogeneity Within Molecular Subtypes of Breast Cancer

Breast cancer is the quintessential example of how molecular characterization of tumor biology guides therapeutic decisions. From the discovery of the estrogen receptor to current clinical molecular profiles to evolving single cell analytics, the characterization and compartmentalization of breast cancer into divergent subtypes is clear. However, competing with this divergent model of breast cancer is the recognition of intratumoral heterogeneity, which acknowledges the possibility that multiple different subtypes exist within a single tumor. Intratumoral heterogeneity is driven by both intrinsic effects of the tumor cells themselves as well as extrinsic effects from the surrounding microenvironment. There is emerging evidence that these intratumoral molecular subtypes are not static; rather, plasticity between divergent subtypes is possible. Inter-conversion between seemingly different subtypes within a tumor drives tumor progression, metastases, and treatment resistance. Therapeutic strategies must therefore contend with changing phenotypes in an individual patient's tumor. Identifying targetable drivers of molecular heterogeneity may improve treatment durability and disease progression.