Dual-Energy CT in Oncologic Imaging.

Dual-energy CT (DECT) is an innovative technology that is increasingly widespread in clinical practice. DECT allows for tissue characterization beyond that of conventional CT as imaging is performed using different energy spectra that can help differentiate tissues based on their specific attenuation properties at different X-ray energies. The most employed post-processing applications of DECT include virtual monoenergetic images (VMIs), iodine density maps, virtual non-contrast images (VNC), and virtual non-calcium (VNCa) for bone marrow edema (BME) detection. The diverse array of images obtained through DECT acquisitions offers numerous benefits, including enhanced lesion detection and characterization, precise determination of material composition, decreased iodine dose, and reduced artifacts. These versatile applications play an increasingly significant role in tumor assessment and oncologic imaging, encompassing the diagnosis of primary tumors, local and metastatic staging, post-therapy evaluation, and complication management. This article provides a comprehensive review of the principal applications and post-processing techniques of DECT, with a specific focus on its utility in managing oncologic patients.

Neoadjuvant Systemic Therapy in Early Breast Cancer: Results of a Prospective Observational Multicenter BRIDE Study.

To evaluate the rate of early breast cancer (EBC) patients treated with neoadjuvant systemic therapy (NAT) in Italy, criteria of patient selection and types of therapies delivered, an analysis of 1276 patients with stage I-II-III was conducted out of 1633 patients enrolled in the multicenter prospective observational BRIDE study. A total of 177 patients (13.9%) were treated with NAT and 1099 (85.9%) with surgery; in multivariate analysis, menopausal status, cT, cN, grade, HER2-positive and Triple negative (TN) subgroups were significantly associated with the decision to administer NAT. The type of NAT delivered was influenced by EBC subtype. NAT was administered to 53.2% of HER2+/HR-negative, 27.9% of HER2+/HR+, 7.1% of HER2-negative/HR+ and 30.3% of TN EBC patients. The pCR rates were similar to the ones reported in the literature: 74.2% in HER2+/HR-negative, 52.3% in HER2+/HR+, 17.2% in HER2-negative/HR+ and 37.9% in TN. In clinical practice, patient and tumor characteristics influenced oncologists in the decision to administer NAT in EBC and in the choice of the type of systemic therapy, according to ESMO and AIOM Guidelines. Currently, it is recommended always to evaluate the use of NAT in EBC, mainly in HER2+ and TN patients, considering that pCR is associated with significantly better survival of the patient and that effective therapies are now available for residual disease.

The Impact of NUTRItional Status at First Medical Oncology Visit on Clinical Outcomes: The NUTRIONCO Study.

Malnutrition affects up to 75% of cancer patients and results from a combination of anorexia and metabolic dysregulation. Metabolic and nutritional abnormalities in cancer patients can lead to cachexia, a multifactorial syndrome characterized by involuntary loss of skeletal muscle mass, systemic inflammation and increased protein catabolism. Cancer cachexia negatively affects patients' outcomes, response to anticancer treatments, quality of life, and survival. However, risk of malnutrition, and cachexia are still under-recognized in cancer patients. The Prevalence of Malnutrition in Oncology (PreMiO) study revealed that 51% of patients already had nutritional deficiencies at their first medical oncology visit. Here, we report the results of the subsequent retrospective, observational NUTRItional status at first medical oncology visit ON Clinical Outcomes (NUTRIONCO) study, aimed at assessing the impact of baseline nutritional and non-nutritional variables collected in the PreMiO study on the clinical outcomes of the same patients followed up from August 2019 to October 2021. We have highlighted a statistically significant association between baseline variables and patient death, rehospitalization, treatment toxicity, and disease progression at follow-up. We found a higher overall survival probability in the well-nourished general study population vs. malnourished patients (p < 0.001). Of major interest is the fact that patient stratification revealed that malnutrition decreased survival probability in non-metastatic patients but not in metastatic patients (p < 0.001). Multivariate analysis confirmed that baseline malnutrition (p = 0.004) and VAS score for appetite loss (p = 0.0104), in addition to albumin < 35 g/L (p < 0.0001) and neutrophil/lymphocyte ratio > 3 (p = 0.0007), were independently associated with the death of non-metastatic patients at follow-up. These findings highlight the importance of proactive, early management of malnutrition and cachexia in cancer patients, and in particular, in non-metastatic patients, from the perspective of a substantial improvement of their clinical outcomes.

Adherence to oral hormonal anticancer agents in breast cancer.

There is an increasing trend towards using oral antitumoral agents in oncological patients. Compared to parenteral therapy, oral treatment offers convenience for both the patient and the healthcare system, with similar efficacy. However, the benefit deriving from oral drugs will be obtained only if patients adhere strictly to the treatment. Medical oncologists must therefore seek to optimize patient adherence. Breast cancer patients, particularly, are often treated with oral hormonal anticancer agents. In this review, we summarized evidence about adherence of breast cancer patients to oral hormonal anticancer agents and the consequences of poor compliance, the barriers to oral treatment and strategies to overcome them.

Corrigendum: Results of the ECHO (Eating habits CHanges in Oncologic patients) Survey: An Italian Cross-Sectional Multicentric Study to Explore Dietary Changes and Dietary Supplement Use, in Breast Cancer Survivors.

[This corrects the article DOI: 10.3389/fonc.2021.705927.].

The predictive and prognostic role of metabolic and volume-based parameters of positron emission tomography/computed tomography as non-invasive dynamic biological markers in early breast cancer treated with preoperative systemic therapy.

Introduction: The role of fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in early breast cancer treated with preoperative systemic therapy (PST) is not yet established in clinical practice. PET parameters have aroused great interest in the recent years, as non-invasive dynamic biological markers for predicting response to PST. Methods: In this retrospective study, we included 141 patients with stage II-III breast cancer who underwent surgery after PST. Using ROC analysis, we set optimal cutoff of FDG-PET/CT parameters predictive for pathological complete response (pCR). We investigated the correlation between FDG-PET/CT parameters and pCR, median disease-free survival (DFS), and median overall survival (mOS). Results: At multivariable analysis, baseline SUVmax (high vs low: OR 9.00, CI 1.85 - 61.9, p=0.012) and Delta SUVmax (high vs low: OR 9.64, CI 1.84, 69.2, p=0.012) were significantly associated with pCR rates. Interestingly, we found that a combined analysis of the metabolic parameter Delta SUVmax with the volume-based parameter Delta MTV, may help to identify patients with pCR, especially in the subgroup of hormone receptor positive breast cancer. Delta SUVmax was also an independent predictive marker for both mDFS (high vs low: HR 0.17, 95%CI 0.05-0.58, p=0.004) and mOS (high vs. low: HR 0.19, 95%CI 0.04-0.95, p=0.029). Discussion: Our results suggest that Delta SUVmax may predict survival of early BC patients treated with PST.

"OPERATION PHALCO"-Adapted Physical Activity for Breast Cancer Survivors: Is It Time for a Multidisciplinary Approach?

The international literature emphasizes the importance of physical activity (PA) in the first steps after cancer surgery. The regular practice of physical exercise causes positive adaptations on several functional capacities, with positive consequences on patients' quality of life. This project aims to evaluate the effect of a post-operative training protocol, structured by taking into account both cancer-related issues and the presence of comorbidities, on functional capacities and quality of life of breast cancer survivors. Therefore, it was necessary to create a synergy between oncologists (referring physicians), sport medicine physicians (risk stratification and exercise prescription) and kinesiologists (trainers). Thirty-five post-surgery BC patients decided on a voluntary basis to attend an online Adapted PA (APA) protocol for 4 months, twice a week (APA Group) or Usual Care Group (UC Group). Functional capacity of the APA Group significantly increased, by 13.1% (p = 0.000), whereas perceived exertion decreased by 19.7% (p = 0.020). In the same group, the general health evaluated through the questionnaire EORTC-QLQ-C30 increased (p = 0.050). No differences were found in the UC Group. Operation Phalco, creating a network between oncologists, sports medicine physicians and kinesiologists, confirms the importance of structuring a post-operative path where APA should be included as early as possible in the cancer patient care.

Results of the ECHO (Eating habits CHanges in Oncologic patients) Survey: An Italian Cross-Sectional Multicentric Study to Explore Dietary Changes and Dietary Supplement Use, in Breast Cancer Survivors.

The role of a healthy diet in cancer prevention is well recognized. Recent data indicate that following the same advices can also improve cancer survivors' quality of life. Breast cancer (BC) patients are commonly concerned about diet and nutrition and frequently express the need to obtain health-related information and the will to change their diet and lifestyle. Hence, be aware of survivors' dietary changes and information needs is crucial for healthcare professionals to guide them toward optimal lifestyle choices. In order to investigate eating habits changes in a BC survivors' population, we conceived the cross-sectional multicentric study ECHO (Eating habits CHanges in Oncologic patients) Survey. Data were collected from 684 patients, diagnosed with invasive breast cancer, in order to investigate their changes in food consumption, use of supplements, or the beginning of a specific diet, after BC diagnosis. We also examined the sources of information used and if any modification in their diets was reported to the oncologist. We primarily observed that patients increased their consumption of vegetables, pulses, nuts, fruits, wholemeal bread/pasta, grains and fish; while decreasing red and processed meat, refined bread/pasta, baked good and animal fat consumption. Survivors also reported the use of dietary supplements, mainly vitamins, aimed at counteracting therapies' side effects. Changes in nutritional habits were often adopted without asking or informing the oncologist. Despite BC survivors made some positive changes in their nutritional habits, those modifications were mostly pursued by less than half of them, while the majority of patients consumed nutritional supplements after diagnosis. These results, as well as the failure to communicate with the physicians, reinforce the need to both improve the patient-healthcare professional relationship and to develop tailored nutrition counselling and intervention programs for cancer survivors.

When and how to treat women with HER2-positive, small (pT1a-b), node-negative breast cancer?

Small (pT1a-b), node-negative (pN0) breast cancer generally has a good prognosis. However, HER2-positive status is associated with an increased risk of relapse and decreased survival even in these tumors. Although there are only few data from prospective randomized trials, results of retrospective studies suggest adjuvant chemotherapy plus trastuzumab may improve outcomes of patients with pT1a-b pN0 HER2-positive breast cancer. On the other hand, trastuzumab is potentially associated with increased cardiac toxicity, especially when combined with anthracycline-based chemotherapy. A valid strategy for improving cardiac safety is the addition of trastuzumab to non-anthracycline chemotherapy, whereas a shorter duration of trastuzumab should be not routinely considered although might represent an option for selected patients at low risk of relapse and very high risk of cardiac events. Therefore, the choice of adjuvant treatment for patients with pT1a-b pN0 HER2-positive breast cancer should be done on individual basis, carefully weighing benefits and risks.

The evolving landscape of criteria for evaluating tumor response in the era of cancer immunotherapy: From Karnofsky to iRECIST.

The objective response is an important endpoint to evaluate clinical activity of new anticancer drugs. Standardized criteria for evaluating response are needed for comparing results of different trials and represent the basis for advances in cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 are the most used in clinical practice and in clinical trials; however, they are not able to capture atypical responses seen with immunotherapy drugs. We describe the evolution of response criteria with a special focus on the immune-related criteria.

The incidence and relative risk of pulmonary toxicity in patients treated with anti-PD1/PD-L1 therapy for solid tumors: a meta-analysis of current studies.

AIM: Monoclonal antibodies (mAbs) directed against PD-1/PD-L1 have recently entered the therapeutic algorithm of several solid tumors. Among treatment-related adverse events pulmonary toxicity (PT) is of particular interest. We assess the incidence and relative risk (RR) of PT in patients treated with anti-PD1/PD-L1 mAbs. RESULTS: 11 articles were selected. The incidence of any- and high-grade PT was low (2.9 and 1.0%, respectively). Compared with standard therapies, anti-PD-1 mAbs do not significantly increase the risk of both any-grade (RR: 2.65; p = 0.06) and high-grade PT (RR: 1.40; p = 0.25). Of note, the RR: of developing any-grade (RR: 3.13; p < 0.0001) and high-grade (RR: 2.42; p = 0.03) PT significantly increased when excluding the Checkmate-025 trial, with everolimus as control therapy. No differences were identified between the type of mAbs, the tumor type and treatment duration for both any-grade and high-grade PT.

Cathepsin K expression in castration-resistant prostate carcinoma: a therapeutical target for patients at risk for bone metastases.

BACKGROUND: The lysosomal cysteine protease cathepsin K is involved in bone remodeling and is also expressed in the peritumoral stroma of carcinomas arising from different organs. A new generation of cathepsin K inhibitors blocking the RANKL/RANK pathway are being developed. We sought to investigate cathepsin K expression in a cohort of castration-resistant prostate carcinomas. METHODS: Sixteen cases of castration-resistant disease with at least 5 years of follow-up were selected from a cohort of 280 patients who underwent surgery. Cathepsin K was evaluated on formalin-fixed and paraffin-embedded tissue microarrays with 5 tissue spots per case. These were scored as high 2+ (≥30% of cells), low 1+ (<30% of cells) or zero (absence), distinguishing tumor cells and peritumoral stroma cells. Low (1+) and absence (0) of scoring were interpreted as negative, and high (2+) as positive. RESULTS: The castration-resistant group was composed of 15 acinar adenocarcinomas and 1 neuroendocrine carcinoma, and all showed at least Gleason score 8 at prostatectomy. Two out of 16 cases (12%) scored positive for cathepsin K in tumor cells; and 5 of 16 cases (31%) scored positive in peritumoral stroma cells. The neuroendocrine and acinar subtypes of carcinoma with positive immunoexpression in neoplastic cells developed bone metastases after 4 and 5 years, respectively, and subsequently died. CONCLUSIONS: Patients affected by castration-resistant prostate carcinoma may be tested for cathepsin K, and a positive strong expression (2+) could be a useful predictive biomarker of response to targeted agents, aiding in the selection of patients eligible for these treatments.

Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma.

Losses of chromosomes 9p and 14q are associated with worse outcomes in patients affected by clear-cell renal cell carcinoma (RCC) and are helpful for prognostic risk stratification. Both chromosomal loci harbor several hot-spot molecular pathways suitable for targeted therapeutic interventions. Intratumor heterogeneity may foster tumor adaptation and therapeutic failure. We sought to investigate the presence of losses of the hot spots of chromosomal loci 9p and 14q in primary clear-cell RCC and matched metastatic tissues. CD10 and CD13 were performed on 7 cases of clear-cell RCC with hematogenous tissue metastases. Cytogenetic fluorescence in situ hybridization analysis was performed on primary and matched metastatic tissues using specific probes mapping the 9p and the 14q loci. The loss of chromosome 9p was observed in 85% of both primary clear-cell RCCs and in matched metastases; 14% showed discordance between primary and matched metastases showing gains. The loss of chromosome 14q was observed in 58% of both primary and matched metastases. Only 3/7 (42%) did show an equal status of loss of chromosome 14q. Heterogeneity of the cytogenetic status between metastatic and primary clear-cell RCCs is observed for the loss of chromosome 14q rather than chromosome 9p. The impact of chromosome 14q cytogenetic status, harboring the HIF1 gene, a major driver for the angiogenenic switch, may drive the efficacy of targeted inhibitors, whereas the loss of chromosome 9p, harboring other hot-spot genes, seems to be related to the metastatic behavior per se, without cytogenetic modulation. Reprofiling the metastatic tissue, as compared with the primary tumor, in patients affected by metastatic RCC could be a novel approach to overcome resistance to VEGF(Rs)-targeting agents.

Immune Checkpoint Inhibitors and Prostate Cancer: A New Frontier?

Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), agents that provide durable disease control and long-term survival are still needed. It is a fact that a tumor-induced immunosuppressive status (mediated by aberrant activation of inhibitory immune checkpoint pathways as a mechanism to evade host immune surveillance) plays a crucial role in the pathogenesis of cancer, including prostate cancer (PC), making CRPC patients suitable candidates for immunotherapy. Therefore, growing interest of anticancer research aims at blocking immune checkpoints (mainly targeting CTLA-4 and PD1/PD-L1 pathways) to restore and enhance cellular-mediated antitumor immunity and achieve durable tumor regression. In this review, we describe the current knowledge regarding the role of immune checkpoints in mediating PC progression, focusing on CTLA-4 and PD1 pathways. We also provide current clinical data available, an update on ongoing trials of immune checkpoint inhibitors in PC. Finally, we discuss the necessity to identify prognostic and predictive biomarkers of immune activity, and we analyze new immune checkpoints with a role as promising targets for PC therapy.

Investigating BRCA Mutations: A Breakthrough in Precision Medicine of Castration-Resistant Prostate Cancer.

Despite the development of novel effective therapeutic strategies, metastatic castration-resistant prostate cancer (mCRPC) remains a disease with a lethal course and a high biological and molecular heterogeneity. To date, germline mutations in the BRCA gene represent one of the main risk factors for developing prostate cancer, with a strong association with aggressive phenotype and poor clinical outcomes. A better understanding of the genomic landscape of prostate cancer has strengthened the idea that "synthetic lethality" of this disease might be useful in cancer-drug discovery, focusing on agents such as platinum compounds and poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi). In this review, we summarize the main data available on BRCA mutations and discuss the clinical implications of these genomic aberrations in the management of prostate cancer, stressing the need to identify prognostic and predictive biomarkers and to deeply understand the mechanisms of treatment resistance, in order to maximize personalized medicine protocols and therefore clinical benefit.

Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: 'Game Over'?

Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an important role in prostate cancer progression and pathological bone turnover, representing potential targets for improving clinical outcomes in mCRPC. Studies evaluating agents that target one or both these pathways have demonstrated modest activity but no improvement in overall survival. Nevertheless, this therapeutic strategy seems to still be a promising and engaging area of prostate cancer research and the interest in better understanding the MET/VEGFR axis and the mechanism of action of these inhibitors is growing. This review describes the rationale for targeting MET and VEGFR pathway in mCRPC and provides the clinical data available to date and an update on ongoing trials.

AR-V7 and prostate cancer: The watershed for treatment selection?

The androgen receptor (AR) plays a key role in progression to metastatic castration-resistant prostate cancer (mCRPC). Despite the recent progress in targeting persistent AR activity with the next-generation hormonal therapies (abiraterone acetate and enzalutamide), resistance to these agents limits therapeutic efficacy for many patients. Several explanations for response and/or resistance to abiraterone acetate and enzalutamide are emerging, but growing interest is focusing on importance of AR splice variants (AR-Vs) and in particular of AR-V7. Increasing evidences highlight the concept that variant expression could be used as a potential predictive biomarker and a therapeutic target in advanced prostate cancer. Therefore, understanding the mechanisms of treatment resistance or sensitivity can help to achieve a more effective management of mCRPC, increasing clinical outcomes and representing a promising and engaging area of prostate cancer research.

State of the art of chemotherapy for the treatment of central nervous system metastases from non-small cell lung cancer.

Chemotherapy is the mainstay of treatment of advanced non-small cell lung cancer (NSCLC) without molecular drivers. Despite a low penetration of central nervous system (CNS), chemotherapy drugs demonstrated encouraging activity against CNS metastases from NSCLC. Based on the available data, chemotherapy should be considered as an important part of the multidisciplinary treatment of CNS metastases. Particularly, platinum-based regimens represent the most active combinations and pemetrexed is associated with a meaningful clinical benefit for patients with non-squamous histology. How to integrate chemotherapy and radiotherapy for newly diagnosed brain metastases (BMs) is still debated. Although flawed by some limitations, the available evidence suggests a role for upfront chemotherapy for the treatment of NSCLC patients with synchronous, asymptomatic BMs, thus allowing a delay of radiotherapy. Despite the introduction of modern and more effective chemotherapy, however, the prognosis of NSCLC patients with CNS metastases remains poor, especially for those with progressive BMs or leptomeningeal carcinomatosis (LC).

Metabolic Alterations in Renal and Prostate Cancer.

BACKGROUND: Cancer metabolism is emerging as a promising research area in genitourinary tumors. Both renal cell carcinoma (RCC) and prostate cancer (PCa) cells exhibit marked alterations of their metabolism. These changes include increased aerobic glycolysis (the Warburg effect), increased protein and DNA synthesis and de novo fatty acid (FA) synthesis. OBJECTIVE: Understanding the molecular mechanisms underlying such alterations will represent a major step forward in cancer research. Indeed, reprogramming cancer cell energy metabolism represents a promising hallmark of cancer and may pave the way for novel personalized approaches. METHOD: PubMed databases were searched for articles published about cancer metabolism in genitourinary tumors. RESULTS AND CONCLUSION: This review is focused on the metabolic alterations that occur in RCC and PCa and describes the mechanisms underlying such metabolic changes.

Addressing the expected survival benefit for clinical trial design in metastatic castration-resistant prostate cancer: Sensitivity analysis of randomized trials.

We performed a sensitivity analysis, cumulating all randomized clinical trials (RCTs) in which patients with metastatic castration-resistant prostate cancer (mCRPC) received systemic therapy, to evaluate if the comparison of RCTs may drive to biased survival estimations. An overall survival (OS) significant difference according to therapeutic strategy was more likely be determined in RCTs evaluating hormonal drugs versus those studies testing immunotherapy, chemotherapy or other strategies. With regard to control arm, an OS significant effect was found for placebo-controlled trials versus studies comparing experimental treatment with active therapies. Finally, regarding to docetaxel (DOC) timing, the OS benefit was more likely to be proved in Post-DOC setting in comparison with DOC and Pre-DOC. These data suggest that clinical trial design should take into account new benchmarks such as the type of treatment strategy, the choice of the comparator and the phase of the disease in relation to the administration of standard chemotherapy.