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Introduction: Breast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43°C, and reirradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study. Methods and analyses: Patients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43°C) using water- filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated. [ABSTRACT FROM AUTHOR]

IntroductionBreast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43°C, and re-irradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study.Methods and analysesPatients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43°C) using water-filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated.RegistrationThe study is registered at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS00029221).

Desmoid tumor (DT) is a rare neoplasm characterized by the proliferation of myofibroblastic cells that infiltrates and invades adjacent tissues. Due to its locally aggressive and recurrent nature, DT often causes local symptoms and can be challenging to manage clinically. Therefore, identifying biomarkers that can predict the progression of DT and guide treatment decisions is critical. This review summarizes several biomarkers that have been implicated in active surveillance (AS) and the prediction of postoperative recurrence and attempts to elucidate their underlying mechanisms. Some of these novel markers could provide prognostic value for clinicians, and ultimately help facilitate optimal and accurate therapeutic decisions for DT. [ABSTRACT FROM AUTHOR]

IntroductionEndeavors in the molecular characterization of breast cancer opened the doors to endocrine therapies in ER+/HER2- breast cancer, increasing response rates substantially. Despite that, taxane-based neoadjuvant chemotherapy is still a cornerstone for achieving breast-conserving surgery and complete tumor resection in locally advanced cancers with high recurrence risk. Nonetheless, the rate of chemoresistance is high, and deselecting patients who will not benefit from chemotherapy is a significant task to prevent futile toxicities. Several multigene assays are being used to guide decisions on chemotherapy. However, their development as prognostic assays but not predictive assays limits predictive strength, leading to discordant results. Moreover, high costs impediment their use in developing countries. For global health equity, robust predictors that can be cost-effectively incorporated into routine clinical management are essential.MethodsIn this study, we comprehensively analyzed 5 GEO datasets, 2 validation sets, and The Cancer Genome Atlas breast cancer data to identify predictors of resistance to taxane-based neoadjuvant therapy in ER+/HER2- breast cancer using efficient bioinformatics algorithms.ResultsGene expression and gene set enrichment analysis of 5 GEO datasets revealed the upregulation of 63 genes and the enrichment of CTNNB1-related oncogenic signatures in non-responsive patients. We validated the upregulation and predictive strength of 18 genes associated with resistance in the validation cohort, all exhibiting higher predictive powers for residual disease and higher specificities for ER+/HER2- breast cancers compared to one of the benchmark multi-gene assays. Cox Proportional Hazards Regression in three different treatment arms (neoadjuvant chemotherapy, endocrine therapy, and no systemic treatment) in a second comprehensive validation cohort strengthened the significance of PTCH1 and CTNNB1 as key predictors, with hazard ratios over 1.5, and 1.6 respectively in the univariate and multivariate models.DiscussionOur results strongly suggest that PTCH1 and CTNNB1 can be used as robust and cost-effective predictors in developing countries to guide decisions on chemotherapy in ER +/HER2- breast cancer patients with a high risk of recurrence. The dual function of PTCH1 as a multidrug efflux pump and a hedgehog receptor, and the active involvement of CTNNB1 in breast cancer strongly indicate that PTCH1 and CTNNB1 can be potential drug targets to overcome chemoresistance in ER +/HER2- breast cancer patients.

This document is an erratum published in the journal Frontiers in Oncology. It corrects an error in the affiliation of several authors in a study titled "Protocol of the HISTOTHERM study: assessing the response to hyperthermia and hypofractionated radiotherapy in recurrent breast cancer." The corrected author list and affiliations are provided, and the publisher apologizes for the mistake. The original version of the article has been updated. [Extracted from the article]

Age is a potential predictive marker for the prognosis of cancer patients treated with immune checkpoint inhibitors (ICIs), but the appropriate age cutoff point is still controversial. We aimed to explore the influence of different age cutoff points on the prediction of prognosis for patients receiving ICIs and explore the mechanism underlying the appropriate age cutoff point from the aspects of gene mutation and expression, immune cell infiltration and so on. We applied cutoff points of 50, 55, 60, 65, 70, and 75 years old to divide 1660 patients from the Memorial Sloan-Kettering Cancer Center (MSKCC) immunotherapy cohort into older and younger groups and performed survival analysis of the six subgroups. The results showed that older patients had better survival than younger patients in accordance with the cutoff point of 50 years old [median overall survival (OS) (95% CI): 13.0 (10.5-15.5) months vs. 20.0 (16.7-23.3) months; p=0.002; unadjusted hazard ratio (HR) (95% CI): 0.77 (0.65-0.91)], whereas no significant difference was observed with other cutoff points. Further analysis of The Cancer Genome Atlas (TCGA) database and the MSKCC immunotherapy cohort data showed that the tumor mutation burden (TMB), neoantigen load (NAL), DNA damage response and repair (DDR) pathway mutation status, mutation frequencies of most genes (except IDH1, BRAF and ATRX), the expression of most immune-related genes and the degree of infiltration of most immune cells (such as CD8+ T cells and M1 macrophages) were higher in the elderly group (aged ≥50 years).

Mitotane has been used for the treatment of adrenocortical cancer (ACC) for over 50 years. Despite its widespread use both in monotherapy and in combination with chemotherapeutics, our knowledge of its mechanism of action and therapeutic efficacy is scarce. The number of patients with advanced ACC who have achieved complete remission documented by detailed clinical data is below ten. We report a case of a 64-year-old woman with a non-functional ACC. Histological examination showed vascular invasion, Ki67 of 10% and a mitotic count of 3/10 high-power field. Immunohistochemistry revealed p53 positivity. Pathological TNM grade was reported as T2N0M0, ENSAT stage 2. Nine months after the initial diagnosis, re-staging CT revealed multiple peritoneal nodules, lymph node and kidney metastases confirmed by histologic examination. Mitotane monotherapy was started with a maintenance dose between 2.0 and 2.5 grams/day. Partial remission was established at six months. Subsequently, for another 12 months, each of the three-monthly CT scans confirmed complete remission. Nineteen months after the initiation of mitotane, an unexpected sudden death occurred. A detailed autopsy work-up, performed in the full awareness of oncological history, confirmed complete remission. The authors review the molecular biomarkers and clinical features reported as predictors of response to mitotane monotherapy.

Cetuximab-based chemoimmunotherapy has been the standard of care for recurrent or metastatic squamous cell carcinoma of the head and neck (r/m SCCHN) for more than a decade. To date, no predictive or prognostic biomarkers have been established to further guide the systemic treatment with cetuximab-based chemoimmunotherapy in r/m SCCHN. Against this background, we retrospectively analyzed clinical and blood-based parameters from 218 r/m SCCHN patients treated with chemoimmunotherapy including cetuximab. Multivariate Cox-regression models were used to assess their prognostic or predictive value. Eastern Co-operative Oncology Group (ECOG) performance status (≥2), older age (≥61.8 years), anemia (hemoglobin

Age is a potential predictive marker for the prognosis of cancer patients treated with immune checkpoint inhibitors (ICIs), but the appropriate age cutoff point is still controversial. We aimed to explore the influence of different age cutoff points on the prediction of prognosis for patients receiving ICIs and explore the mechanism underlying the appropriate age cutoff point from the aspects of gene mutation and expression, immune cell infiltration and so on. We applied cutoff points of 50, 55, 60, 65, 70, and 75 years old to divide 1660 patients from the Memorial Sloan-Kettering Cancer Center (MSKCC) immunotherapy cohort into older and younger groups and performed survival analysis of the six subgroups. The results showed that older patients had better survival than younger patients in accordance with the cutoff point of 50 years old [median overall survival (OS) (95% CI): 13.0 (10.5-15.5) months vs. 20.0 (16.7-23.3) months; p=0.002; unadjusted hazard ratio (HR) (95% CI): 0.77 (0.65-0.91)], whereas no significant difference was observed with other cutoff points. Further analysis of The Cancer Genome Atlas (TCGA) database and the MSKCC immunotherapy cohort data showed that the tumor mutation burden (TMB), neoantigen load (NAL), DNA damage response and repair (DDR) pathway mutation status, mutation frequencies of most genes (except IDH1, BRAF and ATRX), the expression of most immune-related genes and the degree of infiltration of most immune cells (such as CD8+ T cells and M1 macrophages) were higher in the elderly group (aged ≥50 years). [ABSTRACT FROM AUTHOR]

Cetuximab-based chemoimmunotherapy has been the standard of care for recurrent or metastatic squamous cell carcinoma of the head and neck (r/m SCCHN) for more than a decade. To date, no predictive or prognostic biomarkers have been established to further guide the systemic treatment with cetuximab-based chemoimmunotherapy in r/m SCCHN. Against this background, we retrospectively analyzed clinical and blood-based parameters from 218 r/m SCCHN patients treated with chemoimmunotherapy including cetuximab. Multivariate Cox-regression models were used to assess their prognostic or predictive value. Eastern Co-operative Oncology Group (ECOG) performance status (≥2), older age (≥61.8 years), anemia (hemoglobin <11.80), and increased neutrophil-to-lymphocyte ratio (NLR ≥5.73) were independently and strongly associated with inferior overall survival (OS). To group patients according to risk profiles we established a prognostic clinical score (PCS) that can easily be used in clinical practice. The PCS stratified the cohort into low, intermediate, poor or very poor risk subgroups with median OS times of 23.4, 12.1, 7.5, and 4.0 months, respectively. Patients with low risk PCS had a prolonged progression-free survival (PFS) and increased overall response rate (ORR) under first-line cetuximab-based therapy. Interestingly, only patients with low and intermediate risk benefitted from the more intensive first-line cisplatin/cetuximab combination compared to carboplatin/cetuximab therapy, whereas the intensity of first-line treatment had no impact in the poor and very poor risk subgroups. Following external validation, particularly in the context of newly established first-line options, the PCS may guide clinical decision making and serve for stratification of patients with r/m SCCHN in future clinical trials. [ABSTRACT FROM AUTHOR]

Mitotane has been used for the treatment of adrenocortical cancer (ACC) for over 50 years. Despite its widespread use both in monotherapy and in combination with chemotherapeutics, our knowledge of its mechanism of action and therapeutic efficacy is scarce. The number of patients with advanced ACC who have achieved complete remission documented by detailed clinical data is below ten. We report a case of a 64-year-old woman with a non-functional ACC. Histological examination showed vascular invasion, Ki67 of 10% and a mitotic count of 3/10 high-power field. Immunohistochemistry revealed p53 positivity. Pathological TNM grade was reported as T2N0M0, ENSAT stage 2. Nine months after the initial diagnosis, re-staging CT revealed multiple peritoneal nodules, lymph node and kidney metastases confirmed by histologic examination. Mitotane monotherapy was started with a maintenance dose between 2.0 and 2.5 grams/day. Partial remission was established at six months. Subsequently, for another 12 months, each of the three-monthly CT scans confirmed complete remission. Nineteen months after the initiation of mitotane, an unexpected sudden death occurred. A detailed autopsy work-up, performed in the full awareness of oncological history, confirmed complete remission. The authors review the molecular biomarkers and clinical features reported as predictors of response to mitotane monotherapy. [ABSTRACT FROM AUTHOR]

The survival rate for patients with high-risk neuroblastomas remains poor despite new improvements in available therapeutic modalities. A detailed understanding of the mechanisms underlying clinical responses to multimodal treatment is one of the important aspects that may provide precision in the prediction of a patient's clinical outcome. Our study was designed as a detailed comparative analysis of five selected proteins (DDX39A, HMGA1, HOXC9, NF1, and PBX1) in one cohort of patients using the same methodical approaches. These proteins were already reported separately as related to the resistance or sensitivity to retinoids and as useful prognostic markers of survival probability. In the cohort of 19 patients suffering from high-risk neuroblastomas, we analyzed initial immunohistochemistry samples obtained by diagnostic biopsy and post-induction samples taken after the end of induction therapy. The expression of DDX39A, HMGA1, HOXC9, and NF1 showed varied patterns with almost no differences between responders and non-responders. Nevertheless, we found very interesting results for PBX1: non-responders had significantly higher expression levels of this protein in the initial tumor samples when compared with responders; this expression pattern changed inversely in the post-induction samples, and this change was also statistically significant. Moreover, our results from survival analyses reveal the prognostic value of PBX1, NF1, and HOXC9 expression in neuroblastoma tissue. In addition to the prognostic importance of PBX1, NF1, and HOXC9 proteins, our results demonstrated that PBX1 could be used for the prediction of the clinical response to induction chemotherapy in patients suffering from high-risk neuroblastoma.

The survival rate for patients with high-risk neuroblastomas remains poor despite new improvements in available therapeutic modalities. A detailed understanding of the mechanisms underlying clinical responses to multimodal treatment is one of the important aspects that may provide precision in the prediction of a patient's clinical outcome. Our study was designed as a detailed comparative analysis of five selected proteins (DDX39A, HMGA1, HOXC9, NF1, and PBX1) in one cohort of patients using the same methodical approaches. These proteins were already reported separately as related to the resistance or sensitivity to retinoids and as useful prognostic markers of survival probability. In the cohort of 19 patients suffering from high-risk neuroblastomas, we analyzed initial immunohistochemistry samples obtained by diagnostic biopsy and post-induction samples taken after the end of induction therapy. The expression of DDX39A, HMGA1, HOXC9, and NF1 showed varied patterns with almost no differences between responders and non-responders. Nevertheless, we found very interesting results for PBX1: non-responders had significantly higher expression levels of this protein in the initial tumor samples when compared with responders; this expression pattern changed inversely in the post-induction samples, and this change was also statistically significant. Moreover, our results from survival analyses reveal the prognostic value of PBX1, NF1, and HOXC9 expression in neuroblastoma tissue. In addition to the prognostic importance of PBX1, NF1, and HOXC9 proteins, our results demonstrated that PBX1 could be used for the prediction of the clinical response to induction chemotherapy in patients suffering from high-risk neuroblastoma. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43°C, and re-irradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study., Methods and Analyses: Patients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43°C) using water-filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated., Registration: The study is registered at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS00029221)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Thomsen, Sahlmann, Bronsert, Schilling, Poensgen, May, Timme-Bronsert, Grosu, Vaupel, Gebbers, Multhoff and Lüchtenborg.)

Introduction: Endeavors in the molecular characterization of breast cancer opened the doors to endocrine therapies in ER+/HER2- breast cancer, increasing response rates substantially. Despite that, taxane-based neoadjuvant chemotherapy is still a cornerstone for achieving breast-conserving surgery and complete tumor resection in locally advanced cancers with high recurrence risk. Nonetheless, the rate of chemoresistance is high, and deselecting patients who will not benefit from chemotherapy is a significant task to prevent futile toxicities. Several multigene assays are being used to guide decisions on chemotherapy. However, their development as prognostic assays but not predictive assays limits predictive strength, leading to discordant results. Moreover, high costs impediment their use in developing countries. For global health equity, robust predictors that can be cost-effectively incorporated into routine clinical management are essential., Methods: In this study, we comprehensively analyzed 5 GEO datasets, 2 validation sets, and The Cancer Genome Atlas breast cancer data to identify predictors of resistance to taxane-based neoadjuvant therapy in ER+/HER2- breast cancer using efficient bioinformatics algorithms., Results: Gene expression and gene set enrichment analysis of 5 GEO datasets revealed the upregulation of 63 genes and the enrichment of CTNNB1-related oncogenic signatures in non-responsive patients. We validated the upregulation and predictive strength of 18 genes associated with resistance in the validation cohort, all exhibiting higher predictive powers for residual disease and higher specificities for ER+/HER2- breast cancers compared to one of the benchmark multi-gene assays. Cox Proportional Hazards Regression in three different treatment arms (neoadjuvant chemotherapy, endocrine therapy, and no systemic treatment) in a second comprehensive validation cohort strengthened the significance of PTCH1 and CTNNB1 as key predictors, with hazard ratios over 1.5, and 1.6 respectively in the univariate and multivariate models., Discussion: Our results strongly suggest that PTCH1 and CTNNB1 can be used as robust and cost-effective predictors in developing countries to guide decisions on chemotherapy in ER +/HER2- breast cancer patients with a high risk of recurrence. The dual function of PTCH1 as a multidrug efflux pump and a hedgehog receptor, and the active involvement of CTNNB1 in breast cancer strongly indicate that PTCH1 and CTNNB1 can be potential drug targets to overcome chemoresistance in ER +/HER2- breast cancer patients., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ozcan.)

Desmoid tumor (DT) is a rare neoplasm characterized by the proliferation of myofibroblastic cells that infiltrates and invades adjacent tissues. Due to its locally aggressive and recurrent nature, DT often causes local symptoms and can be challenging to manage clinically. Therefore, identifying biomarkers that can predict the progression of DT and guide treatment decisions is critical. This review summarizes several biomarkers that have been implicated in active surveillance (AS) and the prediction of postoperative recurrence and attempts to elucidate their underlying mechanisms. Some of these novel markers could provide prognostic value for clinicians, and ultimately help facilitate optimal and accurate therapeutic decisions for DT., Competing Interests: The authors declare that this review was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Sun, Zhou, Shen, Zhu, Chen and Huang.)

BCL2-family proteins have a central role in the mitochondrial apoptosis machinery and their expression is known to be deregulated in many cancer types. Effort in the development of small molecules that selectively target anti-apoptotic members of this family i.e., Bcl-2, Bcl-xL, Mcl-1 recently opened novel therapeutic opportunities. Among these apoptosis-inducing agents, BH3-mimetics (i.e., venetoclax) led to promising preclinical and clinical activity in B cell malignancies. However, several mechanisms of intrinsic or acquired resistance have been described ex vivo therefore predictive markers of response as well as mechanism-based combinations have to be designed. In the present study, we analyzed the expression of the BCL2-family genes across 10 mature B cell malignancies through computational normalization of 21 publicly available Affimetrix datasets gathering 1,219 patient samples. To better understand the deregulation of anti- and pro-apoptotic members of the BCL2-family in hematological disorders, we first compared gene expression profiles of malignant B cells to their relative normal control (naïve B cell to plasma cells, n = 37). We further assessed BCL2-family expression according to tissue localization i.e., peripheral blood, bone marrow, and lymph node, molecular subgroups or disease status i.e., indolent to aggressive. Across all cancer types, we showed that anti-apoptotic genes are upregulated while pro-apoptotic genes are downregulated when compared to normal counterpart cells. Of interest, our analysis highlighted that, independently of the nature of malignant B cells, the pro-apoptotic BH3-only BCL2L11 and PMAIP1 are deeply repressed in tumor niches, suggesting a central role of the microenvironment in their regulation. In addition, we showed selective modulations across molecular subgroups and showed that the BCL2-family expression profile was related to tumor aggressiveness. Finally, by integrating recent data on venetoclax-monotherapy clinical activity with the expression of BCL2-family members involved in the venetoclax response, we determined that the ratio (BCL2 + BCL2L11 + BAX)/BCL2L1 was the strongest predictor of venetoclax response for mature B cell malignancies in vivo .