Aromatase inhibitors (AIs) have radically changed the prognosis of hormone receptor positive breast cancer (BC) in post-menopausal women, and are a mainstay of the adjuvant therapy for BC after surgery in place of, or following, Tamoxifen. However, AIs aren’t side effect-free; frequent adverse events involve the musculoskeletal system, in the form of bone loss, AI-associated arthralgia (AIA) syndrome and autoimmune rheumatic diseases. In this narrative review, we reported the main clinical features of these three detrimental conditions, their influence on therapy adherence, the possible underlying molecular mechanisms and the available pharmacological and non-pharmacological treatments. The best-known form is the AIs-induced osteoporosis, whose molecular pathway and therapeutic possibilities were extensively investigated in the last decade. AIA syndrome is a high prevalent joint pain disorder which often determines a premature discontinuation of the therapy. Several points still need to be clarified, as a universally accepted diagnostic definition, the pathogenetic mechanisms and satisfactory management strategies. The association of AIs therapy with autoimmune diseases is of the utmost interest. The related literature has been recently expanded, but many issues remain to be explored, the first being the molecular mechanisms.

Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either PD-1 or PD-L1 are active agents for these patients; however, their use may be complicated by unpredictable immune-related adverse events (irAEs), including immune-related pneumonitis (IRP). We carried out a retrospective multi-institutional statistical analysis to investigate clinical and biological parameters correlated with IRP rate on a cohort of 256 patients who received real-world treatment with PD-1/PD-L1 blocking mAbs. An independent radiological review board detected IRP in 29 patients. We did not find statistical IRP rate correlation with gender, tumor type, specific PD-1 or PD-L1 blocking mAbs, radiation therapy, inflammatory profile, or different irAEs. A higher IRP risk was detected only in mNSCLC patients who received metronomic chemotherapy +/− bevacizumab compared with other treatments prior PD-1/PD-L1 blockade. Moreover, we detected a strong correlation among the IRP rate and germinal expression of HLA-B*35 and DRB1*11, alleles associated to autoimmune diseases. Our findings may have relevant implications in predicting the IRP rate in mNSCLC patients receiving PD-1/PD-L1 blockade and need to be validated on a larger patient series.

The expanding clinical application of CDK4- and CDK6-inhibiting drugs in the managements of breast cancer has raised a great interest in testing these drugs in other neoplasms. The potential of combining these drugs with other therapeutic approaches seems to be an interesting work-ground to explore. Even though a potential integration of CDK4 and CDK6 inhibitors with radiotherapy (RT) has been hypothesized, this kind of approach has not been sufficiently pursued, neither in preclinical nor in clinical studies. Similarly, the most recent discoveries focusing on autophagy, as a possible target pathway able to enhance the antitumor efficacy of CDK4 and CDK6 inhibitors is promising but needs more investigations. The aim of this review is to discuss the recent literature on the field in order to infer a rational combination strategy including cyclin-D1/CDK4-CDK6 inhibitors, RT, and/or other anticancer agents targeting G1-S phase cell cycle transition.

Background. We hypothesized that texture analysis (TA) from the preoperative MRI can predict early disease progression (ePD), defined as the percentage of patients who relapsed or showed distant metastasis within three months from the radical surgery, in patients with locally advanced rectal cancer (LARC, stage II and III, AJCC) undergoing neoadjuvant chemoradiotherapy (C-RT). Methods. This retrospective monoinstitutional cohort study included 49 consecutive patients in total with a newly diagnosed rectal cancer. All the patients underwent baseline abdominal MRI and CT scan of the chest and abdomen to exclude distant metastasis before C-RT. Texture parameters were extracted from MRI performed before C-RT (T1, DWI, and ADC sequences) using LifeX Software, a dedicated software for extracting texture parameters from radiological imaging. We divided the cohort in a training set of 34 patients and a validation set of 15 patients, and we tested the data sets for homogeneity, considering the clinical variables. Then we performed univariate and multivariate analysis, and a ROC curve was also generated. Results. Thirteen patients (26.5%) showed an ePD, three of whom with lung metastases and ten with liver relapse. The model was validated based on the prediction accuracy calculated in a previously unseen set of 15 patients. The prediction accuracy of the generated model was 82% (AUC=0.853) in the training and 80% (AUC=0.833) in the validation cohort. The only significant features at multivariate analysis was DWI GLCM Correlation (OR: 0.239, p<0.001). Conclusion. Our results suggest that TA could be useful to identify patients that may develop early progression.

We performed a pilot study to evaluate the use of MRI delta texture analysis (D-TA) as a methodological item able to predict the frequency of complete pathological responses and, consequently, the outcome of patients with locally advanced rectal cancer addressed to neoadjuvant chemoradiotherapy (C-RT) and subsequently, to radical surgery. In particular, we carried out a retrospective analysis including 100 patients with locally advanced rectal adenocarcinoma who received C-RT and then radical surgery in three different oncological institutions between January 2013 and December 2019. Our experimental design was focused on the evaluation of the gross tumor volume (GTV) at baseline and after C-RT by means of MRI, which was contoured on T2, DWI, and ADC sequences. Multiple texture parameters were extracted by using a LifeX Software, while D-TA was calculated as percentage of variations in the two time points. Both univariate and multivariate analysis (logistic regression) were, therefore, carried out in order to correlate the above-mentioned TA parameters with the frequency of pathological responses in the examined patients’ population focusing on the detection of complete pathological response (pCR, with no viable cancer cells: TRG 1) as main statistical endpoint. ROC curves were performed on three different datasets considering that on the 21 patients, only 21% achieved an actual pCR. In our training dataset series, pCR frequency significantly correlated with ADC GLCM-Entropy only, when univariate and binary logistic analysis were performed (AUC for pCR was 0.87). A confirmative binary logistic regression analysis was then repeated in the two remaining validation datasets (AUC for pCR was 0.92 and 0.88, respectively). Overall, these results support the hypothesis that D-TA may have a significant predictive value in detecting the occurrence of pCR in our patient series. If confirmed in prospective and multicenter trials, these results may have a critical role in the selection of patients with locally advanced rectal cancer who may benefit form radical surgery after neoadjuvant chemoradiotherapy.

MicroRNAs (miRNA), are short regulatory RNA molecules that regulate gene expression by binding specific sequences within target messenger RNA (mRNA)