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IntroductionThe somatostatin receptor (SSTR) standardized uptake value (SUVmax ) obtained by [ Ga]Ga-edotreotide positron emission tomography-computed tomography ([ Ga]Ga-SSTR PET/CT) helps recognize patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who are at a high risk for adverse outcomes. This observational cohort study was conducted to verify whether the SSTR representative tumor volume (RTV ) can provide incremental prognostic information over conventional PET/CT parameters in patients with metastatic disease.MethodsWe retrospectively evaluated patients (48% female) with metastatic GEP-NETs who underwent [ Ga]Ga-SSTR PET/CT between January 2022 and November 2023. The mean SUVmax , mean RTV (cm ; 42% threshold), and total RTV were recorded. Thereafter, patients were followed up for 22.9 (range: 8-42) months. The PET/CT results were compared to the progression free survival (PFS).ResultsSixty patients (59 ± 5 years) were enrolled. Only the mean and total RTV values were predictive in the multivariate analysis. Kaplan-Meier survival analysis for both the mean and total RTV demonstrated a significantly better PFS in patients presenting with lower than greater values ( = 0.001 and = 0.007, respectively; log-rank test). SUVmax was not appropriate for predicting PFS.ConclusionThe mean or total RTV represents a valuable volumetric parameter able to predict outcomes in patients with GEP-NETs that are metastatic at onset. The degree of the SSTR representative tumor burden, rather than the maximal SSTR representation at single voxel, has a predominant value for influencing the response to therapy in this cohort.

Background We retrospectively aimed to assess the prognostic significance of somatostatin receptor (SSTR) standardized uptake value (SUVmaxsstr), SSTR representative tumor volume (RTVsstr) and total lesion SSTR expression (TLsstr) obtained by [68Ga]Ga-edotreotide PET/CT ([68Ga]Ga-SSTR PET/CT) in patients with primary gastroenteropancreatic neuroendocrine tumors (GEP-NET) before surgery. Material and Methods We analyzed patients who underwent [68Ga]Ga-SSTR PET/CT 3-6 weeks before surgery from February 2020 to April 2022. The mean SUVmaxsstr value, the RTVsstr (cm3; 42% threshold) and the TLsstr (g) were registered. Thereafter the patients were followed up 10.3 months (range 3-27). The PET/CT results were compared to the event free survival (EFS). Results Forty-two patients (61 ± 13 years) have been enrolled. At multivariate analysis only RTVsstr values were predictive. The Kaplan-Meier survival analysis for RTVsstr showed a significant better EFS in patients presenting lower values as compared to those having greater (P = .003, log-rank test). SUVmaxsstr was not suitable for predicting EFS, TLsstr mildly. Conclusion RTVsstr represents a valuable volumetric parameter able to predict the outcome in GEP-NET patients who underwent surgery. The magnitude of the SSTR representative tumor burden holds a predominant value for determining the response to therapy in GEP-NET patients before surgery, rather than the maximal SSTR representation at single voxel.

Radium-223 dichloride is an alpha emitter approved for metastatic castration-resistant prostate cancer (mCRPC). Unfortunately, little data are available on the prognostic factors during radium-223-based therapy. Patients with histologically confirmed progressive CRPC with two or more bone metastases and symptomatic disease were eligible. Previous therapy with a novel hormonal therapy was allowed. The patients received six intravenous injections of radium-223 every 4 weeks. A visual analog scale (VAS) was adopted to evaluate patients' basal pain. A total of 25 patients were evaluated. Of these, 6 (24%) reported VAS <4. After a median follow-up of 8 months, all patients died with a median overall survival of 8.3 months (95% CI: 5.2-11.8 months), 12.6 months in the patients with VAS <4 vs 6.6 months in the patients with VAS ≥4 ( =0.03). The present study suggests that VAS could be prognostic of the survival of mCRPC treated with radium-223 irrespective of the limitations of a small number of patients and the retrospective nature of the data.

Objectives: Preoperative chemoradiation is currently the standard of care in locally advanced rectal carcinoma, even though a subset of rectal tumors does not achieve major clinically meaningful responses upon neoadjuvant chemoradiation. At present, no molecular biomarkers are available to predict response to neoadjuvant chemoradiation and select resistant tumors willing more intense therapeutic strategies. Thus, BRAF mutational status was investigated for its role in favoring resistance to radiation in colorectal carcinoma cell lines and cyclin-dependent kinase 1 as a target to improve radiosensitivity in BRAF V600E colorectal tumor cells. Methods: Colony-forming assay and apoptotic rates were evaluated to compare the sensitivity of different colon carcinoma cell lines to ionizing radiation and their radiosensitivity upon exposure to BRAF and/or cyclin-dependent kinase 1 inhibitory/silencing strategies. Cyclin-dependent kinase 1 expression/subcellular distribution was studied by immunoblot analysis. Results: Colon carcinoma BRAF V600E HT29 cells exhibited poor response to radiation compared to BRAF wild-type COLO320 and HCT116 cells. Interestingly, neither radiosensitizing doses of 5-fluoruracil nor BRAF inhibition/silencing significantly improved radiosensitivity in HT29 cells. Of note, poor response to radiation correlated with upregulation/relocation of cyclin-dependent kinase 1 in mitochondria. Consistently, cyclin-dependent kinase 1 inhibition/silencing as well as its targeting, through inhibition of HSP90 quality control pathway, significantly inhibited the clonogenic ability and increased apoptotic rates in HT29 cells upon exposure to radiation. Conclusion: These data suggest that BRAF V600E colorectal carcinoma cells are poorly responsive to radiation, and cyclin-dependent kinase 1 represents a target to improve radiosensitivity in BRAF V600E colorectal tumor cells.

Lymphoproliferative disorders are a heterogeneous group of malignant clonal proliferations of lymphocytes whose diagnosis remains challenging, despite diagnostic criteria are now well established, due to their heterogeneity in clinical presentation and immunophenotypic profile. Lymphoid T-cell disorders are more rarely seen than B-cell entities and more difficult to diagnose for the absence of a specific immunophenotypic signature. Flow cytometry is a useful tool in diagnosing T-cell lymphoproliferative disorders since it is not only able to better characterize T-cell neoplasms but also to resolve some very complicated cases, in particular those in which a small size population of neoplastic cells is available for the analysis. Here, we report three patients with mature T-cell neoplasms with atypical clinical and biological features in which analysis of peripheral blood and bone marrow specimens by means of multicolor flow cytometry was very useful to identify and characterize three rare T-cell lymphoproliferative disorders, such as angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified and T-cell prolymphocytic leukemia. The aim of this case series report is not only to describe three rare cases of lymphoproliferative neoplasms but also to raise awareness that a fast, highly sensitive, and reproducible procedure, such as flow cytometry immunophenotyping, can have a determinant diagnostic role in these patients.Lymphoproliferative disorders are a heterogeneous group of malignant clonal proliferations of lymphocytes whose diagnosis remains challenging, despite diagnostic criteria are now well established, due to their heterogeneity in clinical presentation and immunophenotypic profile. Lymphoid T-cell disorders are more rarely seen than B-cell entities and more difficult to diagnose for the absence of a specific immunophenotypic signature. Flow cytometry is a useful tool in diagnosing T-cell lymphoproliferative disorders since it is not only able to better characterize T-cell neoplasms but also to resolve some very complicated cases, in particular those in which a small size population of neoplastic cells is available for the analysis. Here, we report three patients with mature T-cell neoplasms with atypical clinical and biological features in which analysis of peripheral blood and bone marrow specimens by means of multicolor flow cytometry was very useful to identify and characterize three rare T-cell lymphoproliferative disorders, such as angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified and T-cell prolymphocytic leukemia. The aim of this case series report is not only to describe three rare cases of lymphoproliferative neoplasms but also to raise awareness that a fast, highly sensitive, and reproducible procedure, such as flow cytometry immunophenotyping, can have a determinant diagnostic role in these patients.

Congenital adrenal hyperplasia (CAH) is a genetic disorder characterized by an impairment of steroid synthesis due to an altered production of 21-hydroxylase enzyme. Corticoid hormones are involved in the development and functioning of many organs. The aim of the present study was to review the international literature to collect data regarding oral manifestations of CAH. A review of the literature describing oral features of patients affected by CAH was performed using electronic databases (PubMed and Scopus). The data about number of patients, form of CAH, and oral findings were extracted and analyzed. Seven studies were included in the final analysis. The principal findings reported regarded an advanced dental development observed in patients with CAH. One paper reported amelogenesis imperfecta and periodontal issues. The dentist could be the first specialist involved in the CAH syndrome diagnosis, identifying the characteristic features described above, especially for the classical simple virilizing and non-classical form.

We evaluated the pain response and daily discomfort in patients suffering from a borderline degree of bone pain due to breast or lung cancer bone metastases, who had undergone early palliative radionuclide treatment. The results were compared with those from patients who had received standard analgesic therapy. Twenty-one patients (65.7 ± 3 years; 17 women) with metastatic bone cancer underwent samarium-153 (Sm-153) ethylene diamine tetramethylene phosphonate (EDTMP) administration (group A) and 18 patients (64.3 ± 8 years; 16 women) continued to receive standard analgesics (group B; control group). The patients kept a daily pain diary assessing both their discomfort and the pain at specific sites by means of a visual analog scale, rating from 0 (no discomfort–no pain) to 10 (worst discomfort–pain). These diaries were reviewed weekly for 2 months and three physicians rated the pain response on a scale from −2 (considerable deterioration) to +2 (considerable improvement). Baseline characteristics were similar in both groups. The reduction of total discomfort and of bone pain in group A was significantly greater compared to group B ( p  < 0.0001). A significant improvement of clinical conditions was observed in group A, where the physician rate changed from −1 to 1, compared to group B in which the rate changed from −1 to 0. Sm-153 EDTMP therapy can be considered for patients with bone pain from breast and lung cancer in advance, i.e., before the establishment of severe pain syndrome.

We evaluated the prognostic significance of standardized uptake value (SUVmax), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) in [F-18] FDG PET/CT findings in patients with inoperable non-small-cell lung cancer (NSCLC). One hundred and three patients (mean age, 65.6 ± 16 years) underwent [F-18] FDG PET/CT before the chemotherapy. The SUVmax value, the MTV (cm ; 42% threshold) and the TLG (g) were registered. The patients were followed up to 18 months thereafter (range 12-55 months). Failure to respond without progression, progression and/or disease-related death constituted surrogate end-points. The optimal SUVmax, MTV and TLG cut-off to predict the patients’ outcome were estimated. PET/CT results were then related to disease outcome (progression free survival; PFS). The Kaplan-Meier survival analysis for SUVmax showed a significant shorter PFS in patients presenting with lower values as compared to those with higher (p < 0.05, log-rank test). MTV and TLG were not suitable for predicting PFS apart from the subset of patients with mediastinal nodal involvement. Despite the availability of new tools for the quantitative assessment of disease activity on PET/CT, the SUVmax rather than MTV and TLG remains the only predictor for PFS in NSCLC patients. MTV holds a value only when concomitant nodal involvement occurs.

The quantitative assessment of coronary flow reserve (CFR) may be useful for the functional evaluation of coronary artery disease (CAD), allowing judgment of its severity, tracking of disease progression, and evaluation of the anti-ischemic efficacy of therapeutic strategies. Invasive techniques, such as intracoronary Doppler ultrasound and the pressure-derived method, which directly assess CFR velocity and fractional flow reserve, have been used for the evaluation of the physiologic significance of coronary lesions. Considerable progress has been made in the improvement of technologies directed toward the noninvasive quantification of myocardial blood flow and CFR. Positron emission tomography has emerged as an accurate technique to quantify CFR. The absolute measurements obtained with this noninvasive approach have been widely validated. Nevertheless, it has not been applied to routine studies because of its high cost and complexity. On the other hand, technetium 99m–labeled tracers have been largely used for the evaluation of myocardial perfusion with single photon emission computed tomography (SPECT) imaging in patients with suspected or known CAD. Recently, attempts to estimate CFR with SPECT tracers have been made to obtain, with noninvasive methods, data for quantitative functional assessment of CAD. This review analyzes the relative merit and limitations of CFR measurements by cardiac SPECT imaging with Tc-99m–labeled tracers and describes the potential clinical applications of this technique.

The Kirsten rat sarcoma viral oncogene homolog (RAS)/v-raf-1 murine leukemia viral oncogene homolog 1 (RAF)/mitogen-activated protein kinase 1 (MAPK) signaling cascade is the most important oncogenic pathway in human cancers. Tumors leading mutations in the gene encoding for v-raf murine sarcoma viral oncogene homolog B (BRAF) serine-threonine kinase are reliant on the MAPK signaling pathway for their growth and survival. Indeed, the constitutive activation of MAPK pathway results in continuous stimulation of cell proliferation, enhancement of the apoptotic threshold and induction of a migratory and metastatic phenotype. In a clinical perspective, this scenario opens to the possibility of targeting BRAF pathway for therapy. Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 29–83% of human thyroid malignancies and, differently from melanomas, are less sensitive to BRAF inhibitors and develop primary or acquired resistance due to mutational events or activation of alternative signaling pathways able to reactivate ERK signaling. In this review, we provide an overview on the current knowledge concerning the mechanisms leading to resistance to BRAF inhibitors in human thyroid carcinomas and discuss the potential therapeutic strategies, including combinations of BRAF inhibitors with other targeted agents, which might be employed to overcome drug resistance and potentiate the activity of single agent BRAF inhibitors.