Cancers, Volume 14, Issue 12 (June-2 2022) – 218 articles

This study aimed to assess the usefulness of radiomics features of ¹⁸F-FDG PET/CT in patients with locally advanced esophageal cancers (ESCC) in predicting outcomes such as clinical tumor (cT) and nodal (cN) categories, PET response to induction chemotherapy (PET response), progression-free survival (PFS), and overall survival (OS). Pretreatment PET/CT images from patients who underwent concurrent chemoradiotherapy from July 2002 to February 2017 were segmented, and data were split into training and test sets. Model development was performed on the training datasets and a maximum of five features were selected. Final diagnostic accuracies were determined using the test dataset. A total of 86 PET/CTs (58 men and 28 women, mean age 65 years) were segmented. Due to small lesion size, 12 patients were excluded. The diagnostic accuracies as derived from the CT, PET, and combined PET/CT test datasets were as follows: cT category—70.4%, 70.4%, and 81.5%, respectively; cN category—69.0%, 86.2%, and 86.2%, respectively; PET response—60.0%, 66.7%, and 70.0%, respectively; PFS—60.7%, 75.0%, and 75.0%, respectively; and OS—51.7%, 55.2%, and 62.1%, respectively. A radiomics assessment of locally advanced ESCC has the potential to predict various clinical outcomes. External validation of these models would be further helpful. Full article

Considering the dismal survival rate, novel therapeutic strategies are warranted to improve the outcome of pancreatic ductal adenocarcinoma (PDAC). Combining nanotechnology for delivery of chemotherapeutics—preferably radiosensitizing agents—is a promising approach to enhance the therapeutic efficacy of chemoradiation. We assessed the effect of biodegradable ultrasmall-in-nano architectures (NAs) containing gold ultra-small nanoparticles (USNPs) enclosed in silica shells loaded with cisplatin prodrug (NAs-cisPt) combined with ionizing radiation (IR). The cytotoxic effects and DNA damage induction were evaluated in PDAC cell lines (MIA PaCa2, SUIT2-028) and primary culture (PDAC3) in vitro and in the chorioallantoic membrane (CAM) in ovo model. Unlike NAs, NAs-cisPt affected the cell viability in MIA PaCa2 and SUIT2-028 cells. Furthermore, NAs-cisPt showed increased γH2AX expression up to 24 h post-IR and reduced β-globin amplifications resulting in apoptosis induction at DNA and protein levels. Similarly, combined treatment of NAs-cisPt + IR in PDAC3 and SUIT2-028 CAM models showed enhanced DNA damage and apoptosis leading to tumor growth delay. Our results demonstrate an increased cytotoxic effect of NAs-cisPt, particularly through its release of the cisplatin prodrug. As cisplatin is a well-known radiosensitizer, administration of cisplatin prodrug in a controlled fashion through encapsulation is a promising new treatment approach which merits further investigation in combination with other radiosensitizing agents. Full article

Rising incidences of cutaneous melanoma have fueled the development of statistical models that predict individual melanoma risk. Our aim was to assess the validity of published prediction models for incident cutaneous melanoma using a standardized procedure based on PROBAST (Prediction model Risk Of Bias ASsessment Tool). We included studies that were identified by a recent systematic review and updated the literature search to ensure that our PROBAST rating included all relevant studies. Six reviewers assessed the risk of bias (ROB) for each study using the published “PROBAST Assessment Form” that consists of four domains and an overall ROB rating. We further examined a temporal effect regarding changes in overall and domain-specific ROB rating distributions. Altogether, 42 studies were assessed, of which the vast majority (n = 34; 81%) was rated as having high ROB. Only one study was judged as having low ROB. The main reasons for high ROB ratings were the use of hospital controls in case-control studies and the omission of any validation of prediction models. However, our temporal analysis results showed a significant reduction in the number of studies with high ROB for the domain “analysis”. Nevertheless, the evidence base of high-quality studies that can be used to draw conclusions on the prediction of incident cutaneous melanoma is currently much weaker than the high number of studies on this topic would suggest. Full article

Background: To compare the intraoperative and postoperative outcomes of indocyanine green (ICG) administration in robot-assisted partial nephrectomy (RAPN) and report the differences in the results between patients with benign and malignant renal tumors. Methods: From 2017 to 2020, 132 patients underwent RAPN at our institution, including 21 patients with ICG administration. Clinical data obtained from our institution’s RAPN database were retrospectively reviewed. Intraoperative, postoperative, pathological, and functional outcomes of RAPN were assessed. Results: The pathological results indicated that among the 127 patients, 38 and 89 had received diagnoses of benign and malignant tumors, respectively. A longer operative time (311 vs. 271 min; p = 0.006) but superior preservation of estimated glomerular filtration rate (eGFR) at 3-month follow-up (90% vs. 85%; p = 0.031) were observed in the ICG-RAPN group. Less estimated blood loss, shorter warm ischemia time, and superior preservation of eGFR at postoperative day 1 and 6-month follow-up were also noted, despite no significant differences. Among the patients with malignant tumors, less estimated blood loss (30 vs. 100 mL; p < 0.001) was reported in the ICG-RAPN subgroup. Conclusions: Patients with ICG-RAPN exhibited superior short-term renal function outcomes compared with the standard RAPN group. Of the patients with malignant tumors, ICG-RAPN was associated with less blood loss than standard RAPN without a more positive margin rate. Further studies with larger cohorts and prospective designs are necessary to verify the intraoperative and functional advantages of the green dye. Full article

(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy. Full article

There is growing evidence that tumour heterogeneity has an imperative role in cancer development, evolution and resistance to therapy. Continuing advancements in biomedical research enable tumour heterogeneity to be observed and studied more critically. As one of the most heterogeneous human cancers, melanoma displays a high level of biological complexity during disease progression. However, much is still unknown regarding melanoma tumour heterogeneity, as well as the role it plays in disease progression and treatment response. This review aims to provide a concise summary of the importance of tumour heterogeneity in melanoma. Full article

The aim of this study is to evaluate the real impact of COVID-19 during the entire 2020 period, compared with 2019. The data comes from a Cancer Registry in Northern Italy and we compared clinical and treatment characteristics of breast cancer by age, stage, treatment, and status screening. In 2020 there was no decrease in invasive tumours nor in in situ (513 vs. 493 and 76 vs. 73, respectively), while there was a significant decrease in surgery and increase in neoadjuvant chemotherapy (p = 0.016). In the screening range (aged 45–74), no change in stage and grading was observed. In the four periods examined there was an increase in new diagnoses during pre-lockdown, a decrease in tumours especially at age 75+ [IRR 0.45; 95%CI 0.25–0.79] during lockdown, a recovery of new diagnoses in women 45+ in the low incidence period while in the last period there was a significant increase only for ages 45–74 [IRR 1.48; 95% CI 1.11–1.98]. Screening activities were suspended from March to May, but over the summer and autumn the backlog was addressed. This suggests that a prompt resumption of programmed screening may have limited the impact of the pandemic on the delay of breast cancer diagnoses. Full article

Cancer-related mortality is primarily a consequence of metastatic dissemination and associated complications. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and tends to metastasize early, especially in the liver. Emerging evidence suggests that organs that develop metastases exhibit microscopic changes that favor metastatic growth, collectively known as “pre-metastatic niches”. By definition, a pre-metastatic niche is chronologically established before overt metastatic outgrowth, and its generation involves the release of tumor-derived secreted factors that modulate cells intrinsic to the recipient organ, as well as recruitment of additional cells from tertiary sites, such as bone marrow—all orchestrated by the primary tumor. The pre-metastatic niche is characterized by tumor-promoting inflammation with tumor-supportive and immune-suppressive features, remodeling of the extracellular matrix, angiogenic modulation and metabolic alterations that support growth of disseminated tumor cells. In this paper, we review the current state of knowledge of the hepatic pre-metastatic niche in PDAC and attempt to create a framework to guide future diagnostic and therapeutic studies. Full article

In recent years, MRI-guided radiotherapy (MRgRT) has taken an increasingly important position in image-guided radiotherapy (IGRT). Magnetic resonance imaging (MRI) offers superior soft tissue contrast in anatomical imaging compared to computed tomography (CT), but also provides functional and dynamic information with selected sequences. Due to these benefits, in current clinical practice, MRI is already used for target delineation and response assessment in patients with head and neck squamous cell carcinoma (HNSCC). Because of the close proximity of target areas and radiosensitive organs at risk (OARs) during HNSCC treatment, MRgRT could provide a more accurate treatment in which OARs receive less radiation dose. With the introduction of several new radiotherapy techniques (i.e., adaptive MRgRT, proton therapy, adaptive cone beam computed tomography (CBCT) RT, (daily) adaptive radiotherapy ensures radiation dose is accurately delivered to the target areas. With the integration of a daily adaptive workflow, interfraction changes have become visible, which allows regular and fast adaptation of target areas. In proton therapy, adaptation is even more important in order to obtain high quality dosimetry, due to its susceptibility for density differences in relation to the range uncertainty of the protons. The question is which adaptations during radiotherapy treatment are oncology safe and at the same time provide better sparing of OARs. For an optimal use of all these new tools there is an urgent need for an update of the target definitions in case of adaptive treatment for HNSCC. This review will provide current state of evidence regarding adaptive target definition using MR during radiotherapy for HNSCC. Additionally, future perspectives for adaptive MR-guided radiotherapy will be discussed. Full article

Locally advanced gastric cancer (LAGC) has a poor prognosis with surgical resection alone, and neoadjuvant treatment has been recommended to improve surgical and oncological outcomes. Although neoadjuvant chemotherapy has been established to be effective for LAGC, the role of neoadjuvant chemoradiotherapy (NCRT) remains under investigation. Clinical experience and research evidence on esophagogastric junction adenocarcinoma (e.g., cardia gastric cancers) indicate that the likelihood of achieving sustainable local control is higher through NCRT than through resection alone. Furthermore, NCRT also has an acceptable treatment-related toxicity and adverse event profile. In particular, it increases the likelihood of achieving an R0 resection and a pathological complete response (pCR). Moreover, NCRT results in higher overall and recurrence-free survival rates than surgery alone; however, evidence on the survival benefits of NCRT versus neoadjuvant chemotherapy (NCT) remains conflicting. For noncardia gastric cancer, the efficacy of NCRT has mostly been reported in retrospective studies, and several large clinical trials are ongoing. Consequently, NCRT might play a more essential role in unresectable LAGC, for which NCT alone may not be adequate to attain disease control. The continual improvements in systemic treatments, radiotherapy techniques, and emerging biomarkers can also lead to improved personalized therapy for NCRT. To elucidate the contributions of NCRT to gastric cancer treatment in the future, the efficacy, potential toxicity, predictive biomarkers, and clinical considerations for implementing NCRT in different types of LAGC were reviewed. Full article

Diffuse low-grade gliomas (LGG) commonly affect young adults and display a slow evolution, with a life expectancy that can surpass 15 years, thanks to multimodal therapeutic management. Therefore, preservation of quality of life (QoL), including sexual health, is mandatory. We systematically searched available medical databases of Pubmed, Cochrane, and Scopus for studies that reported data on sexual activity or dysfunction (SD) in LGG patients. We analyzed results to determine incidence of SD and its association with QoL in this population. Three studies focused on SD incidence in patients presenting specifically LGG, or brain tumors including LGG. They comprised 124 brain tumor patients, including 62 LGG, with SD incidence ranging from 44 to 63%. SD was reported by more than 50% of interrogated women in the three studies. Regarding QoL, two out of the three studies found significant associations between SD and alterations of QoL parameters, particularly in the field of social and functional wellbeing. Finally, we discussed those results regarding methods of evaluation, inherent biases, and therapeutic implications regarding antiseizure medications and also planning of surgery, chemo-, and radiotherapy. Our review showed that SD is highly prevalent but still poorly studied in LGG patients. As those patients are usually young and enjoy an active life, there is a need to assess more systematically the occurrence of SD in clinical routine, in order to adapt cancer treatments accordingly, to manage actively these troubles, and finally to improve patients’ QoL in the long run. Full article

The aim of the current study was to evaluate the influence of severe radiation-induced lymphopenia (RIL) on the outcomes of esophageal cancer (EC). A systematic review and meta-analysis was performed through the PRISMA guideline. Seventeen studies were included in the current systematic review, with eight included in the meta-analyses. Meta-analyses found that severe RIL was associated with lower pathologic complete response (pCR) rate (odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.30–0.66, I² = 0%), inferior overall survival (OS) (hazard ratio (HR) = 1.50, 95% CI = 1.29–1.75, I² = 6%), and worse progression-free survival (PFS) (HR = 1.70, 95% CI = 1.39–2.07, I² = 0%) of EC patients. The lymphocyte nadir was found during 4–6 weeks after the start of radiotherapy. The leading dosimetric factors associated with severe RIL included larger PTV, higher dose to heart and body, and higher effective dose to the immune cells (EDIC). Clinical risk factors for RIL mainly comprised lower baseline ALC, higher tumor length and clinical stage, and distal EC. In conclusion, severe RIL might be associated with a lower pCR rate and worse OS and PFS of EC patients. Minimizing the dosimetric risk factors, especially in patients with clinical risk factors, might benefit their outcomes. Full article

This study aimed to retrospectively analyze the clinical outcomes of patients with pelvic and retroperitoneal bone and soft tissue sarcoma (BSTS). Overall, 187 patients with BSTS in the pelvis and retroperitoneal region treated at 19 specialized sarcoma centers in Japan were included. The prognostic factors related to overall survival (OS), local control (LC), and progression-free survival (PFS) were evaluated. The 3-year OS and LC rates in the 187 patients were 71.7% and 79.1%, respectively. The 3-year PFS in 166 patients without any distant metastases at the time of primary tumor diagnosis was 48.6%. Osteosarcoma showed significantly worse OS and PFS than other sarcomas of the pelvis and retroperitoneum. In the univariate analyses, larger primary tumor size, soft tissue tumor, distant metastasis at the time of primary tumor diagnosis, P2 location, chemotherapy, and osteosarcoma were poor prognostic factors correlated with OS. Larger primary tumor size, higher age, soft tissue tumor, chemotherapy, and osteosarcoma were poor prognostic factors correlated with PFS in patients without any metastasis at the initial presentation. Larger primary tumor size was the only poor prognostic factor correlation with LC. This study has clarified the epidemiology and prognosis of patients with pelvic and retroperitoneal BSTS in Japan. Full article

GI microbiota has been implicated in producing the inflammatory tumor microenvironment of several cancers. Women with ovarian cancer often report GI-related symptoms at diagnosis although minimal is known about the possible GI bacteria that may trigger pro-tumorigenic immune responses in early EOC. The purpose of this study was to investigate the influences of GI microbiota dysbiosis on serum inflammatory markers during EOC utilizing a rodent model. This experimental design consisted of C57BL/6 mice randomly assigned to either the microbiota dysbiosis group (n = 6) or control group (n = 5). The CD7BL/6 mice assigned to the microbiota dysbiosis group were administered a mixture of broad-spectrum antibiotics (bacitracin and neomycin) for 2 weeks. Both groups were injected intraperitoneally with mouse ovarian epithelial cells that induce ovarian tumorigenesis. Levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were assessed in the serum, and the composition of the GI microbiota in fecal samples was measured using 16S rRNA gene sequencing. Overall CRP serum levels were significantly lower and TNFα levels were significantly higher in the microbiota dysbiosis group compared to the control group. The abundances of microbiota that correlated with CRP serum levels in the combined groups were genus Parabacteroides, Roseburia, and Emergencia and species Ruminococcus faecis, Parabacteroides distasonis, Roseburia Faecis, and Emergencia timonensis. This study provides evidence to support for further investigation of the GI microbial profiles in patients at risk of EOC. Full article

BPA, a chemical used in the preparation of polycarbonate plastics, is an endocrine disruptor. Exposure to BPA has been suggested to be a risk factor for breast cancer because of its potential to induce estrogen receptor signaling in breast cancer cells. More recently, it has been recognized that BPA also binds to the G protein-coupled estrogen receptor and other nuclear receptors, in addition to estrogen receptors, and acts on immune cells, adipocytes, and fibroblasts, potentially modulating the TME. The TME significantly impacts the behavior of cancer cells. Therefore, understanding how BPA affects stromal components in breast cancer is imperative to adequately assess the association between exposure to BPA and the risk of breast cancer. This review examines the effects of BPA on stromal components of tumors to highlight their potential role in the carcinogenic effect of BPA. As a result, I propose considerations for the risk assessment of BPA exposure and studies needed to improve understanding of the TME-mediated, breast cancer-promoting effect of BPA. Full article

In retroperitoneal sarcoma (RPS), the change in the tumor grade from the primary tumor to the first local recurrence, and the effect of this change on prognosis, are unknown. The aim of this study is to analyze whether these changes affect the prognosis of RPS. Patients who underwent surgery for a first locally recurrent RPS at Samsung Medical Center from January 2001 to February 2020 were included. The pathologic features of primary and recurrent tumors were compared, and the outcomes were measured. A total of 49 patients were investigated. There were 25 patients with different grades of primary and recurrent tumors. The improving, stable, and worsening groups contained 16 (32.7%), 24 (49%), and 9 (18.3%) patients, respectively. There was no significant difference in the prognosis between the three groups. In the analyses of the factors that affect the OS, a high grade of the primary tumor (p = 0.023) and the size of the recurrent tumor (p = 0.032) were statistically significant in both univariate and multivariate analyses. In a factor analysis of the second LR, a high-grade recurrent tumor (p = 0.032) was the only significant factor. There were tumor-grade changes between the primary tumor and recurrent tumor in RPS. However, the most important factor in prognosis is a high grade of the primary tumor. Full article

Extranodal marginal zone lymphoma (EMZL) encompasses a subgroup of non-Hodgkin lymphomas that often present with localized involvement and may manifest in a diversity of organs and tissues. EMZL pathogenesis is in some cases linked to chronic inflammation/infection, which may impose additional diagnostic and clinical challenges. The most studied and established connection is the presence of Helicobacter pylori in gastric EMZL. Due to its heterogeneity of presentation and intricate pathological features, treatment can be complex, and staging systems are decisive for the choice of therapy. Nevertheless, there is no consensus regarding the most suitable staging system, and recommendations vary among different countries. As a rule of thumb, in limited stages, a local therapy with surgery or radiation is the preferred option, and it is potentially curative. Of note, eradicating the causal agent may be an important step of treatment, especially in gastric EMZL, in which Helicobacter pylori eradication remains the first-line therapy for the majority of patients. In patients with more advanced stages, watch-and-wait is a valuable option, especially amongst those without clear indications for systemic therapy, and it may be carried on for several years. If watch-and-wait is not an option, systemic therapy may be needed. Even though several agents have been tested as monotherapy or in combination in recent years, there is no consensus regarding the first-line therapy, and decisions can vary depending on individual factors, such as age, clinical performance and stage. This review aims to discuss the several aspects of EMZL, including genetic milieu, pathogenesis and staging systems, that may influence the choice of therapy. In addition, we present a summary of evidence of several systemic therapies, compare different recommendations worldwide and discuss future perspectives and novelties in its therapy. Full article

Purpose: Cryoablation (CrA) is a minimally invasive treatment that can be used in primary and metastatic liver cancer. The purpose of this study was to assess the effectiveness of CrA in patients with hepatocellular carcinoma (HCC) and liver metastases. Methods: We retrospectively evaluated the patients who had CrA for HCC or liver metastases between 2015 and 2020. Technical success, complete ablation, CrA-related complications, local tumor progression, local recurrences, and distant metastases were evaluated in the study population. In patients with HCC, the median survival was also estimated. Results: Sixty-four liver tumors in 49 patients were treated with CrA (50 metastases and 14 HCC). The mean tumor diameter was 2.15 cm. The mean follow-up was 19.8 months. Technical success was achieved in the whole study population. Complete tumor ablation was observed after one month in 92% of lesions treated with CrA (79% and 96% in the HCC Group and metastases Group, respectively, p < 0.001). Local tumor progression occurred in 12.5 of lesions, with no difference between the study groups (p = 0.105). Sixteen patients (33%) developed local recurrence (45% and 29% in the HCC Group and metastases Group, respectively, p = 0.477). Seven patients (14%) developed distant metastases in the follow-up period. Ten patients (20.8%) underwent redo CrA for local recurrence or incomplete tumor ablation. Minor complications were observed in 14% of patients. In patients with HCC, the median survival was 22 months. Conclusions: CrA can be safely used for treatment of HCC and liver metastases not amenable of surgical resection. Further studies are necessary to better define the role of CrA in the multidisciplinary treatment of liver malignancies. Full article

Metastases to the thyroid gland arise from other malignant tumors such as renal cell carcinoma, colorectal cancer, lung cancer, and breast cancer. In clinical practice, the incidence is low, and the symptoms are not specific, so it is often missed and misdiagnosed. It is finally diagnosed via the comprehensive application of many diagnostic methods, such as ultrasound, fine-needle aspiration biopsy, and immunohistochemistry analysis. Surgery-based comprehensive treatment is often adopted, but because it is usually in the late stage of the primary tumor, the prognosis is poor. In order to better understand the related characteristics of thyroid metastatic cancer and then improve the clinical diagnosis and treatment and the prognosis of patients, in this paper, we systematically summarize the research status of thyroid metastatic cancer. Full article

Tumor-specific antigens can activate T cell-based antitumor immune responses and are ideal targets for cancer immunotherapy. However, their identification is still challenging. Although mass spectrometry can directly identify human leukocyte antigen (HLA) binding peptides in tumor cells, it focuses on tumor-specific antigens derived from annotated protein-coding regions constituting only 1.5% of the genome. We developed a novel proteogenomic integration strategy to expand the breadth of tumor-specific epitopes derived from all genomic regions. Using the colorectal cancer cell line HCT116 as a model, we accurately identified 10,737 HLA-presented peptides, 1293 of which were non-canonical peptides that traditional database searches could not identify. Moreover, we found eight tumor neo-epitopes derived from somatic mutations, four of which were not previously reported. Our findings suggest that this new proteogenomic approach holds great promise for increasing the number of tumor-specific antigen candidates, potentially enlarging the tumor target pool and improving cancer immunotherapy. Full article

Subsets of Neurofibromatosis Type 1 (NF1)-associated solid tumors have been shown to display high frequencies of ATRX mutations and the presence of alternative lengthening of telomeres (ALT). We studied the phenotype of combined NF1 and ATRX deficiency in malignant solid tumors. Cell lines derived from NF1-deficient sporadic glioblastomas (U251, SF188), an NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1), an NF1-derived sarcoma cell line (JHH-CRC65), and two NF1-deficient MPNST cell lines (ST88-14, NF90.8) were utilized. Cancer cells were treated with ATR inhibitors, with or without a MEK inhibitor or temozolomide. In contrast to the glioma cell line SF188, combined ATRX knockout (KO) and TERC KO led to ALT-like properties and sensitized U251 glioma cells to ATR inhibition in vitro and in vivo. In addition, ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition, irrespective of ATRX level manipulation; whereas, the JHH-NF1-GBM1 cell line demonstrated sensitivity to ATR inhibition, but not temozolomide. Similar effects were noted using the MPNST cell line NF90.8 after combined ATRX knockdown and TERC KO; however, not in ST88-14. Taken together, our study supports the feasibility of targeting the ATR pathway in subsets of NF1-deficient and associated tumors. Full article

Two major concerns associated with cancer development in Paraná state, South Brazil, are environmental pollution and the germline TP53 p.R337H variant found in 0.27–0.30% of the population. We assessed breast cancer (BC) risk in rural (C1 and C2) and industrialized (C3) subregions, previously classified by geochemistry, agricultural productivity, and population density. C2 presents lower organochloride levels in rivers and lower agricultural outputs than C1, and lower levels of chlorine anions in rivers and lower industrial activities than C3. TP53 p.R337H status was assessed in 4658 women aged >30 years from C1, C2, and C3, subsequent to a genetic screening (Group 1, longitudinal study). BC risk in this group was 4.58 times higher among TP53 p.R337H carriers. BC prevalence and risk were significantly lower in C2 compared to that in C3. Mortality rate and risk associated with BC in women aged >30 years (n = 8181 deceased women; Group 2) were also lower in C2 than those in C3 and C1. These results suggest that environmental factors modulate BC risk and outcome in carriers and noncarriers. Full article

The balance between cellular proliferation and apoptosis and the regulation of cell differentiation must be established to maintain tissue homeostasis. These cellular responses involve the kinase cascade-mediated Hippo pathway as a crucial regulator. Hence, Hippo pathway dysregulation is implicated in diverse diseases, including cancer. O-GlcNAcylation is a non-canonical glycosylation that affects multiple signaling pathways through its interplay with phosphorylation in the nucleus and cytoplasm. An abnormal increase in the O-GlcNAcylation levels in various cancer cells is a potent factor in Hippo pathway dysregulation. Intriguingly, Hippo pathway dysregulation also disrupts O-GlcNAc homeostasis, leading to a persistent elevation of O-GlcNAcylation levels, which is potentially pathogenic in several diseases. Therefore, O-GlcNAcylation is gaining attention as a protein modification that regulates the Hippo pathway. This review presents a framework on how O-GlcNAcylation regulates the Hippo pathway and forms a self-perpetuating cycle with it. The pathological significance of this self-perpetuating cycle and clinical strategies for targeting O-GlcNAcylation that causes Hippo pathway dysregulation are also discussed. Full article

IDH1/2 mutations are common in acute myeloid leukemia (AML) and represent a therapeutic target. The GIMEMA AML1516 observational protocol was designed to study the prevalence of IDH1/2 mutations and associations with clinico-biological parameters in a cohort of Italian AML patients. We analyzed a cohort of 284 AML consecutive patients at diagnosis, 139 females and 145 males, of a median age of 65 years (range: 19–86). Of these, 38 (14%) harbored IDH1 and 51 (18%) IDH2 mutations. IDH1/2 mutations were significantly associated with WHO PS >2 (p < 0.001) and non-complex karyotype (p = 0.021) when compared to IDH1/2-WT. Furthermore, patients with IDH1 mutations were more frequently NPM1-mutated (p = 0.007) and had a higher platelet count (p = 0.036). At relapse, IDH1/2 mutations were detected in 6 (25%) patients. As per the outcome, 60.5% of IDH1/2-mutated patients achieved complete remission; overall survival and event-free survival at 2 years were 44.5% and 36.1%, respectively: these rates were similar to IDH1/2-WT. In IDH1/2-mutated patients, high WBC proved to be an independent prognostic factor for survival. In conclusion, the GIMEMA AML1516 confirms that IDH1/2 mutations are frequently detected at diagnosis and underlines the importance of recognizing IDH1/2-mutated cases up-front to offer the most appropriate therapeutic strategy, given the availability of IDH1/2 inhibitors. Full article

The prevalence of multiple lung cancers has been increasing recently. Molecular analysis of epidermal growth factor receptor (EGFR) mutations in individual tumors of multiple lung cancers is essential for devising an optimal therapeutic strategy. The EGFR mutation status in multiple lung cancers was evaluated to determine its therapeutic implications. In total, 208 tumors from 101 patients who underwent surgery for multiple lung cancers were analyzed. Individual tumors were subjected to histological evaluation and EGFR analysis using a real-time polymerase chain reaction. Additionally, EGFR-wildtype tumors were subjected to next-generation sequencing (NGS). EGFR mutations were detected in 113 tumors from 72 patients, predominantly in females (p < 0.001) and non-smokers (p < 0.001). Among patients with at least one EGFR-mutant tumor, approximately 72% of patients (52/72) had different EGFR mutations in individual tumors. NGS analysis of EGFR-wildtype tumors from 12 patients revealed four and eight cases with concordant and discordant molecular alterations, respectively. These findings revealed a high proportion of discordant EGFR mutations among multiple lung tumors. Hence, EGFR analysis of individual tumors of multiple lung tumors is essential for the evaluation of clonality and the development of an optimal treatment strategy. Full article

The present analysis compares the esthetics assessment by the BCCT.core software in relation to patients’ and physicians’ ratings, based on the IMRT-MC2 trial. Within this trial, breast cancer patients received breast-conserving surgery (BCS) and adjuvant radiotherapy. At the baseline, 6 weeks, and 2 years after radiotherapy, photos of the breasts were assessed by the software and patients’ and physicians’ assessments were performed. Agreement rates of the assessments and their correlation with breast asymmetry indices were evaluated. The assessments of the software and the physicians were significantly correlated with asymmetry indices. Before and 6 weeks after radiotherapy, the patients’ self-assessment was only correlated with the lower breast contour (LBC) and upward nipple retraction (UNR), while after 2 years, there was also a correlation with other indices. Only a slight agreement between the BCCT.core software and the physicians’ or patients’ assessment was seen, while a moderate and substantial agreement was detected between the physicians’ and the patients’ assessment after 6 weeks and 2 years, respectively. The BCCT.core software is a reliable tool to measure asymmetries, but may not sufficiently evaluate the esthetic outcome as perceived by patients. It may be more appropriate for a long-term follow-up, when symmetry appears to increase in importance. Full article

BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states. Full article

At the site of the tumor, myeloid derived suppressor cells (MDSCs) infiltrate and interact with elements of the tumor microenvironment in complex ways. Within the invading tumor, MDSCs are exposed to interstitial fluid flow (IFF) that exists within the chronic inflammatory tumor microenvironment at the tumor–lymphatic interface. As drivers of cell migration and invasion, the link between interstitial fluid flow, lymphatics, and MDSCs have not been clearly established. Here, we hypothesized that interstitial fluid flow and cells within the breast tumor microenvironment modulate migration of MDSCs. We developed a novel 3D model to mimic the breast tumor microenvironment and incorporated MDSCs harvested from 4T1-tumor bearing mice. Using live imaging, we found that sorted GR1+ splenocytes had reduced chemotactic index compared to the unsorted population, but their speed and displacement were similar. Using our adapted tissue culture insert assay, we show that interstitial fluid flow promotes MDSC invasion, regardless of absence or presence of tumor cells. Coordinating with lymphatic endothelial cells, interstitial fluid flow further enhanced invasion of MDSCs in the presence of 4T1 cells. We also show that VEGFR3 inhibition reduced both MDSC and 4T1 flow response. Together, these findings indicate a key role of interstitial fluid flow in MDSC migration as well as describe a tool to explore the immune microenvironment in breast cancer. Full article

Urothelial carcinomas (UCs) are a broad and heterogeneous group of malignancies, with the prevalence of upper tract urothelial carcinoma (UTUC) being rare, accounting for only 5–10% of total malignancies. There is a need for additional toolsets to assist the current clinical paradigm of care for patients with UTUC. As a non-invasive tool for the discovery of cancer-related biomarkers, the liquid biopsy has the potential to represent the complex process of tumorigenesis and metastasis. Herein, we show the efficacy of the liquid biopsy as a source of biomarkers for detecting UTUC. Using the third-generation high-definition single-cell assay (HDSCA3.0) workflow, we investigate liquid biopsy samples collected from patients with UTUC and normal donors (NDs) to provide critical information regarding the molecular and morphological characteristics of circulating rare events. We document several important findings from the liquid biopsy analysis of patients diagnosed with UTUC prior to surgery: (1) Large extracellular vesicles (LEVs) and circulating tumor cells (CTCs) are detectable in the peripheral blood. (2) The rare-event profile is highly heterogeneous. (3) Clinical data elements correlate with liquid biopsy analytes. Overall, this study provides evidence for the efficacy of the liquid biopsy in understanding the biology of UTUC with the future intent of informing clinical decision making, ultimately improving patient outcomes. Full article

The field of cancer research is famous for its incremental steps in improving therapy. The consistent but slow rate of improvement is greatly due to its meticulous use of consistent cancer biology models. However, as we enter an era of increasingly personalized cancer care, including chemo and radiotherapy, our cancer models must be equally able to be applied to all individuals. Patient-derived organoid (PDO) and organ-in-chip (OIC) models based on the micro-physiological bioengineered platform have already been considered key components for preclinical and translational studies. Accounting for patient variability is one of the greatest challenges in the crossover from preclinical development to clinical trials and patient derived organoids may offer a steppingstone between the two. In this review, we highlight how incorporating PDO’s and OIC’s into the development of cancer therapy promises to increase the efficiency of our therapeutics. Full article