In this work, we introduced an automated diagnostic system for Gleason system grading and grade groups (GG) classification using whole slide images (WSIs) of digitized prostate biopsy specimens (PBSs). Our system first classifies the Gleason pattern (GP) from PBSs and then identifies the Gleason score (GS) and GG. We developed a comprehensive DL-based approach to develop a grading pipeline system for the digitized PBSs and consider GP as a classification problem (not segmentation) compared to current research studies (deals with as a segmentation problem). A multilevel binary classification was implemented to enhance the segmentation accuracy for GP. Also, we created three levels of analysis (pyramidal levels) to extract different types of features. Each level has four shallow binary CNN to classify five GP labels. A majority fusion is applied for each pixel that has a total of 39 labeled images to create the final output for GP. The proposed framework is trained, validated, and tested on 3080 WSIs of PBS. The overall diagnostic accuracy for each CNN is evaluated using several metrics: precision (PR), recall (RE), and accuracy, which are documented by the confusion matrices.The results proved our system’s potential for classifying all five GP and, thus, GG. The overall accuracy for the GG is evaluated using two metrics, PR and RE. The grade GG results are between 50% to 92% for RE and 50% to 92% for PR. Also, a comparison between our CNN architecture and the standard CNN (ResNet50) highlights our system’s advantage. Finally, our deep-learning system achieved an agreement with the consensus grade groups. Full article

The long-chain fatty acyl CoA synthetase (ACSLs) family of enzymes contributes significantly to lipid metabolism and produces acyl-coenzyme A by catalyzing fatty acid oxidation. The dysregulation of ACSL3 and ACSL4, which belong to the five isoforms of ACSLs, plays a key role in cancer initiation, development, metastasis, and tumor immunity and may provide several possible therapeutic strategies. Moreover, ACSL3 and ACSL4 are crucial for ferroptosis, a non-apoptotic cell death triggered by the accumulation of membrane lipid peroxides due to iron overload. Here, we present a summary of the current knowledge on ACSL3 and ACSL4 and their functions in various cancers. Research on the molecular mechanisms involved in the regulation of ferroptosis is critical to developing targeted therapies for cancer. Full article

Resistance to treatments is one of the leading causes of cancer therapy failure. Oxaliplatin is a standard chemotherapy used to treat metastatic colorectal cancer. However, its efficacy is greatly reduced by the development of resistances. In a previous study, we deciphered the mechanisms leading to oxaliplatin resistance and highlighted the roles played by ROS production and the p38 MAPK pathway in this phenomenon. In this report, we studied the effects of different chemotherapy molecules on our oxaliplatin-resistant cells to identify alternative treatments. Among all the studied molecules, gemcitabine was the only one to present a major cytotoxic effect on oxaliplatin-resistant cancer cells both in vivo and in vitro. However, the combination of oxaliplatin and gemcitabine did not present any major interest. Indeed, the study of combination efficiency using Chou and Talalay’s method showed no synergy between oxaliplatin and gemcitabine. Using PamGene technology to decipher gemcitabine’s effects on oxaliplatin-resistant cells, we were able to show that gemcitabine counteracts chemoresistance by strongly inhibiting the Akt and src/p38 MAPK pathways, leading to apoptosis induction and cell death. In view of these results, gemcitabine could be an interesting alternative therapy for patients with colorectal cancer not responding to oxaliplatin-based protocols such as FOLFOX. Full article

This research addresses the problem of interobserver variability (IOV), in which different oncologists manually delineate varying primary gross tumor volume (pGTV) contours, adding risk to targeted radiation treatments. Thus, a method of IOV reduction is urgently needed. Hypothesizing that the radiation oncologist’s IOV may shrink with the aid of IOV maps, we propose IOV prediction network (IOV-Net), a deep-learning model that uses the fuzzy membership function to produce high-quality maps based on computed tomography (CT) images. To test the prediction accuracy, a ground-truth pGTV IOV map was created using the manual contour delineations of radiation therapy structures provided by five expert oncologists. Then, we tasked IOV-Net with producing a map of its own. The mean squared error (prediction vs. ground truth) and its standard deviation were 0.0038 and 0.0005, respectively. To test the clinical feasibility of our method, CT images were divided into two groups, and oncologists from our institution created manual contours with and without IOV map guidance. The Dice similarity coefficient and Jaccard index increased by ~6 and 7%, respectively, and the Hausdorff distance decreased by 2.5 mm, indicating a statistically significant IOV reduction (p < 0.05). Hence, IOV-net and its resultant IOV maps have the potential to improve radiation therapy efficacy worldwide. Full article

Introduction: Delays in the diagnosis and treatment of endometrial cancer negatively impact patient survival. The aim of this study was to establish whether rapid evaporative ionisation mass spectrometry using the iKnife can accurately distinguish between normal and malignant endometrial biopsy tissue samples in real time, enabling point-of-care (POC) diagnoses. Methods: Pipelle biopsy samples were obtained from consecutive women needing biopsies for clinical reasons. A Waters G2-XS Xevo Q-Tof mass spectrometer was used in conjunction with a modified handheld diathermy (collectively called the ‘iKnife’). Each tissue sample was processed with diathermy, and the resultant surgical aerosol containing ionic lipid species was then analysed, producing spectra. Principal component analyses and linear discriminant analyses were performed to determine variance in spectral signatures. Leave-one-patient-out cross-validation was used to test the diagnostic accuracy. Results: One hundred and fifty patients provided Pipelle biopsy samples (85 normal, 59 malignant, 4 hyperplasia and 2 insufficient), yielding 453 spectra. The iKnife differentiated between normal and malignant endometrial tissues on the basis of differential phospholipid spectra. Cross-validation revealed a diagnostic accuracy of 89% with sensitivity, specificity, positive predictive value and negative predictive value of 85%, 93%, 94% and 85%, respectively. Conclusions: This study is the first to use the iKnife to identify cancer in endometrial Pipelle biopsy samples. These results are highly encouraging and suggest that the iKnife could be used in the clinic to provide a POC diagnosis. Full article

Background: The prognosis of patients with stage II and stage III colon cancer is heterogeneous. Clinical and pathological characteristics, such as tumor budding, may help to further refine the recurrence risk. Methods: We included all the patients with localized colon cancer at Hospital Universitario La Paz from October 2016 to October 2021. We built a prognostic score for recurrence in the training cohort based on multivariate cox regression analysis and categorized the patients into two risk groups. Results: A total of 440 patients were included in the training cohort. After a median follow-up of 45 months, 81 (18%) patients had a first tumor recurrence. T4, N2, and high tumor budding remained with a p value <0.05 at the last step of the multivariate cox regression model for time to recurrence (TTR). We assigned 2 points to T4 and 1 point to N2 and high tumor budding. Forty-five percent of the patients were assigned to the low-risk group (score = 0). Compared to the high-risk group (score 1–4), patients in the low-risk group had a significantly longer TTR (hazard ratio for disease recurrence of 0.14 (95%CI: 0.00 to 0.90; p < 0.045)). The results were confirmed in the validation cohort. Conclusions: In our study, we built a simple score to predict tumor recurrence based on T4, N2, and high tumor budding. Patients in the low-risk group, that comprised 44% of the cohort, had an excellent prognosis. Full article

Retinoic acid (RA) and its synthetic derivatives, retinoids, have been established as promising anticancer agents based on their ability to regulate cell proliferation and survival. Clinical trials, however, have revealed that cancer cells often acquire resistance to retinoid therapy. Therefore, elucidation of underlying mechanisms of retinoid resistance has been considered key to developing more effective use of retinoids in cancer treatment. In this study, we show that constitutive activation of ERK MAP kinase signaling, which is often caused by oncogenic mutations in RAS or RAF genes, suppresses RA receptor (RAR) signaling in breast cancer cells. We show that activation of the ERK pathway suppresses, whereas its inhibition promotes, RA-induced transcriptional activation of RAR and the resultant upregulation of RAR-target genes in breast cancer cells. Importantly, ERK inhibition potentiates the tumor-suppressive activity of RA in breast cancer cells. Moreover, we also reveal that suppression of RAR signaling and activation of ERK signaling are associated with poor prognoses in breast cancer patients and represent hallmarks of specific subtypes of breast cancers, such as basal-like, HER2-enriched and luminal B. These results indicate that ERK-dependent suppression of RAR activity underlies retinoid resistance and is associated with cancer subtypes and patient prognosis in breast cancers. Full article

Elevated cancer-specific mortality in PWH has been demonstrated for non-AIDS-defining malignancies. However, additional clinical endpoints of interest, including patient-reported outcomes (PROs), have not been systematically examined in PWH and cancer. We evaluated differences in patient-reported symptomology between cancer patients with versus without HIV using data from 12,529 patients at the Moffitt Cancer Center, including 55 with HIV. The symptoms were assessed using the Edmonton Symptom Assessment Scale (ESAS), which asks patients to rank 12 symptoms on a scale of 1–10, with scores ≥7 considered severe. The responses across all questions were summed to create a composite score. Vital status through t July 2021 was determined through linkage to the electronic health record. PWH reported a higher composite ESAS score on average (44.4) compared to HIV-uninfected cancer patients (30.7, p-value < 0.01). In zero-inflated negative binomial regression models adjusted for cancer site, sex, and race, the composite ESAS scores and the count of severe symptoms were 1.41 times (95% CI: 1.13–1.77) and 1.45 times (95% CI: 1.09–1.93) higher, respectively, in cancer patients with HIV. Among PWH, higher ESAS scores were associated with mortality (p-value = 0.02). This is the first demonstration of uniquely poor PROs in PWH and cancer and suggests that patient symptom monitoring to improve clinical endpoints deserves further study. Full article

It remains a challenge to preoperatively forecast whether lung pure ground-glass nodules (pGGNs) have invasive components. We aimed to construct a radiomic model using tumor characteristics to predict the histologic subtype associated with pGGNs. We retrospectively reviewed clinicopathologic features of pGGNs resected in 338 patients with lung adenocarcinoma between 2011–2016 at a single institution. A radiomic prediction model based on forward sequential selection and logistic regression was constructed to differentiate adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma (MIA) from invasive adenocarcinoma. The study cohort included 133 (39.4%), 128 (37.9%), and 77 (22.8%) patients with AIS, MIA, and invasive adenocarcinoma (acinar 55.8%, lepidic 33.8%, papillary 10.4%), respectively. The majority (83.7%) underwent sublobar resection. There were no nodal metastases or tumor recurrence during a mean follow-up period of 78 months. Three radiomic features—cluster shade, homogeneity, and run-length variance—were identified as predictors of histologic subtype and were selected to construct a prediction model to classify the AIS/MIA and invasive adenocarcinoma groups. The model achieved accuracy, sensitivity, specificity, and AUC of 70.6%, 75.0%, 70.0%, and 0.7676, respectively. Applying the developed radiomic feature model to predict the histologic subtypes of pGGNs observed on CT scans can help clinically in the treatment selection process. Full article

Supratentorial non-skull base meningiomas are the most common primary central nervous system tumor subtype. An understanding of their pathophysiology, imaging characteristics, and clinical management options will prove of substantial value to the multi-disciplinary team which may be involved in their care. Extensive review of the broad literature on the topic is conducted. Narrowing the scope to meningiomas located in the supratentorial non-skull base anatomic location highlights nuances specific to this tumor subtype. Advances in our understanding of the natural history of the disease and how findings from both molecular pathology and neuroimaging have impacted our understanding are discussed. Clinical management and the rationale underlying specific approaches including observation, surgery, radiation, and investigational systemic therapies is covered in detail. Future directions for probable advances in the near and intermediate term are reviewed. Full article

The growing incidence of skin cancer, with its associated mortality and morbidity, has in recent years led to the developing of new non-invasive technologies, which allow an earlier and more accurate diagnosis. Some of these, such as digital photography, 2D and 3D total-body photography and dermoscopy are now widely used and others, such as reflectance confocal microscopy and optical coherence tomography, are limited to a few academic and referral skin cancer centers because of their cost or the long training period required. Health care professionals involved in the treatment of patients with skin cancer need to know the implications and benefits of new non-invasive technologies for dermatological oncology. In this article we review the characteristics and usability of the main diagnostic imaging methods available today. Full article

Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 167 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-matched cancer-AID incidence rate sex bias data pairs, we find that, indeed, the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are positively correlated across human tissues. The common key factor whose levels across human tissues are most strongly associated with these incidence rate sex biases is the sex bias in the expression of the 37 genes encoded in the mitochondrial genome. Full article

Previous research has demonstrated the antitumoral effects of melatonin on breast cancer in both in vitro and in vivo studies. The aim of the present study was to investigate whether melatonin has a favorable effect on the survival of patients diagnosed with early breast cancer. This retrospective registry-based study included all patients diagnosed with breast cancer in Sweden between 2005 and 2015. Data were linked to the Swedish Prescribed Drug Registry and the Swedish Cause of Death Registry. A multivariate Cox regression model, including patient age, tumor size, tumor grade, ER status, HER2 status, nodal status and defined daily doses (DDDs) of melatonin, was used to analyze breast-cancer-specific survival as well as overall survival. Of the 37,075 included patients, 926 (2.5%) were prescribed melatonin, with a median DDD of 30. Melatonin was found to have a protective effect on breast-cancer-specific survival (BCSS) in the univariate analysis (HR: 0.736, 95% CI: 0.548–0.989, p = 0.042), but when adjusting for known prognostic factors in the multivariate analysis, this beneficial effect disappeared (HR: 1.037, 95% CI: 0.648–1.659, p = 0.879). Melatonin was not proven to have a favorable effect on the survival of patients diagnosed with early breast cancer in this retrospective registry study. Full article

Predicting the survival outcomes of patients with colorectal cancer (CRC) remains challenging. We investigated the prognostic significance of the transcriptome and tumour-infiltrating lymphocyte T-cell receptor (TIL/Tc-TCR) repertoire and analysed TIL/Tc-TCR sequences of The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) CRC cohorts. Using a multivariate Cox regression, we tested whether TIL/Tc-TCR repertoire, patient and tumour characteristics (stage, sidedness, total non-synonymous mutations, microsatellite instability (MSI) and transcriptional signatures) correlated with patient overall survival (OS) and designed a prognostic nomogram. A multivariate analysis (C-index = 0.75) showed that only patient age, disease stage, TIL/Tc degree of infiltration and clonality were independent prognostic factors for OS. The cut-offs for patients’ allocation to TIL/Tc abundance subgroups were determined using a strategy of maximally selected rank statistics with the OptimalCutpoints R package. These were “high”, “low” and “very high” (90 th percentile) TIL/Tc infiltration-stratified OS (median not reached, 67 and 44.3 months; p < 0.001); the results were validated in the CPTAC cohort. TIL/Tc clonality was prognostic (median OS in “high” vs. “low” clonality not reached and 67.3 months; p = 0.041) and independent of TIL/Tc infiltration. Whilst tumour sidedness was not prognostic, the “very highly” infiltrated tumours were prevalent among right-sided CRCs (p = 0.039) and showed distinct immunological features, with lower Th1 signature (p = 0.004), higher PD-L1 expression (p < 0.001) and likely enrichment in highly suppressory IL1R1⁺ Tregs (FoxP3 and IL1R1 overexpression, p < 0.001). TIL/Tc abundance and clonality are independent prognosticators in CRC and, combined with clinical variables, refine risk stratification. We identified a subset of CRCs with “very high” TIL/Tc infiltration, poor prognosis and distinct genetic and immunologic features, which may benefit from alternative therapeutic approaches. These results need validation in prospective patient cohorts. Full article