Challenges in the diagnosis and management of tumor-induced osteomalacia: A case report.

The present case report is aimed to highlight the difficulty and the reason for the delayed diagnosis of phosphaturic mesenchymal tumors, emphasizing the need of standardized protocols for diagnosis, surgery and follow-up in high-volume hospitals. The clinical signs and symptoms, diagnostic and therapeutic procedures, immunohistological features were analyzed. Delayed diagnosis of phosphaturic mesenchymal tumor was primarily due to non-specific clinical symptoms such as fatigue, muscular and bone pain, and multiple fractures. This cryptic clinical picture made the diagnosis tricky that led to treatment of patient for non-specific pain and stress fractures before to consider the tumor-induced osteomalacia syndrome. Some well-documented studies were found in the literature in which the history of trauma is a critical trigger of glomus tumors. Extra-subungual tumors most frequently occur in the knee and ankle regions, particularly among young adults, and the diagnosis is typically made approximately 7.2 years after initial symptom onset. The difficult tumor localization represented an additional obstacle to the prompt treatment, leading to delayed curative surgery.

Lutetium [177Lu]-DOTA-TATE in gastroenteropancreatic-neuroendocrine tumours: rationale, design and baseline characteristics of the Italian prospective observational (REAL-LU) study.

PURPOSE: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [177Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein. METHODS: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [177Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [177Lu]Lu-DOTA-TATE for GEP-NETs in Italy. RESULTS: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [177Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry. CONCLUSION: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature. STUDY REGISTRATION: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1.

Challenging Axillary Lymph Nodes on PET/CT in Cancer Patients throughout COVID-19 Vaccination Era.

BACKGROUND: The unexpected detection of axillary lymphadenopathy (AxL) in cancer patients (pts) represents a real concern during the COVID-19 vaccination era. Benign reactions may take place after vaccine inoculation, which can mislead image interpretation in patients undergoing F-18-FDG, F-18-Choline, and Ga-68-DOTATOC PET/CT. They may also mimic loco-regional metastases or disease. We assessed PET/CT findings after COVID-19 first dose vaccination in cancer patients and the impact on their disease course management. METHODS: We evaluated 333 patients undergoing PET/CT (257 F-18-FDG, 54 F-18-Choline, and 23 Ga-68 DOTATOC) scans after the first vaccination with mRNA vaccine (Pfizer-BioNTech) (study group; SG). The uptake index (SUVmax) of suspected AxL was defined as significant when the ratio was > 1.5 as compared to the contralateral lymph nodes. Besides, co-registered CT (Co-CT) features of target lymph nodes were evaluated. Nodes with aggregate imaging positivity were further investigated. RESULTS: Overall, the prevalence of apparently positive lymph nodes on PET scans was 17.1% during the vaccination period. 107 pts of the same setting, who had undergone PET/CT before the COVID-19 pandemic, represented the control group (CG). Only 3 patients of CG showed reactive lymph nodes with a prevalence of 2.8% (p < 0.001 as compared to the vaccination period). 84.2% of SG patients exhibited benign characteristics on co-CT images and only 9 pts needed thorough appraisal. CONCLUSION: The correct interpretation of images is crucial to avoid unnecessary treatments and invasive procedures in vaccinated cancer pts. A detailed anamnestic interview and the analysis of lymph nodes' CT characteristics, after performing PET/CT, may help to clear any misleading diagnosis.

Can Baseline [18F]FDG PET/CT Predict Response to Immunotherapy After 6 Months and Overall Survival in Patients with Lung Cancer or Malignant Melanoma? A Multicenter Retrospective Study.

Aim: To assess the role of baseline 18F-fluorodeoxyglucose ([18F]FDG)-positron emission tomography/computed tomography (PET/CT) in predicting response to immunotherapy after 6 months and overall survival (OS) in patients with lung cancer (LC) or malignant melanoma (MM). Materials and Methods: Data from a multicenter, retrospective study conducted between March and November 2021 were analyzed. Patients >18 years old with a confirmed diagnosis of LC or MM, who underwent a baseline [18F]FDG-PET/CT within 1-2 months before starting immunotherapy and had a follow-up of at least 12 months were included. PET scans were examined visually and semiquantitatively by physicians at peripheral centers. The metabolic tumor burden (number of lesions with [18F]FDG-uptake) and other parameters were recorded. Clinical response was assessed at 3 and 6 months after starting immunotherapy, and OS was calculated as the time elapsing between the PET scan and death or latest follow-up. Results: The study concerned 177 patients with LC and 101 with MM. Baseline PET/CT was positive in primary or local recurrent lesions in 78.5% and 9.9% of cases, in local/distant lymph nodes in 71.8% and 36.6%, in distant metastases in 58.8% and 84%, respectively, in LC and in MM patients. Among patients with LC, [18F]FDG-uptake in primary/recurrent lung lesions was more often associated with no clinical response to immunotherapy after 6 months than in cases without any tracer uptake. After a mean 21 months, 46.5% of patients with LC and 37.1% with MM had died. A significant correlation emerged between the site/number of [18F]FDG foci and death among patients with LC, but not among those with MM. Conclusions: In patients with LC who are candidates for immunotherapy, baseline [18F]FDG-PET/CT can help to predict response to this therapy after 6 months, and to identify those with a poor prognosis based on their metabolic parameters. For patients with MM, there was only a weak correlation between baseline PET/CT parameters, response to therapy, and survival.

ITA-IMMUNO-PET: The Role of [18F]FDG PET/CT for Assessing Response to Immunotherapy in Patients with Some Solid Tumors.

AIM: To examine the role of [18F]FDG PET/CT for assessing response to immunotherapy in patients with some solid tumors. METHODS: Data recorded in a multicenter (n = 17), retrospective database between March and November 2021 were analyzed. The sample included patients with a confirmed diagnosis of a solid tumor who underwent serial [18F]FDG PET/CT (before and after one or more cycles of immunotherapy), who were >18 years of age, and had a follow-up of at least 12 months after their first PET/CT scan. Patients enrolled in clinical trials or without a confirmed diagnosis of cancer were excluded. The authors classified cases as having a complete or partial metabolic response to immunotherapy, or stable or progressive metabolic disease, based on a visual and semiquantitative analysis according to the EORTC criteria. Clinical response to immunotherapy was assessed at much the same time points as the serial PET scans, and both the obtained responses were compared. RESULTS: The study concerned 311 patients (median age: 67; range: 31-89 years) in all. The most common neoplasm was lung cancer (56.9%), followed by malignant melanoma (32.5%). Nivolumab was administered in 46.3%, and pembrolizumab in 40.5% of patients. Baseline PET and a first PET scan performed at a median 3 months after starting immunotherapy were available for all 311 patients, while subsequent PET scans were obtained after a median 6, 12, 16, and 21 months for 199 (64%), 102 (33%), 46 (15%), and 23 (7%) patients, respectively. Clinical response to therapy was recorded at around the same time points after starting immunotherapy for 252 (81%), 173 (56%), 85 (27%), 40 (13%), and 22 (7%) patients, respectively. After a median 18 (1-137) months, 113 (36.3%) patients had died. On Kaplan-Meier analysis, metabolic responders on the first two serial PET scans showed a better prognosis than non-responders, while clinical response became prognostically informative from the second assessment after starting immunotherapy onwards. CONCLUSIONS: [18F]FDG PET/CT could have a role in the assessment of response to immunotherapy in patients with some solid tumors. It can provide prognostic information and thus contribute to a patient's appropriate treatment. Prospective randomized controlled trials are mandatory.

Ga-68-Edotreotide Positron Emission Tomography/Computed Tomography Somatostatin Receptors Tumor Volume Predicts Outcome in Patients With Primary Gastroenteropancreatic Neuroendocrine Tumors.

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.

Congenital adrenal hyperplasia. Role of dentist in early diagnosis.

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.

Prognostic Value of Hybrid PET/MR Imaging in Patients with Differentiated Thyroid Cancer.

Background: Hybrid positron emission tomography (PET)/magnetic resonance (MR) is an emerging imaging modality with great potential to provide complementary data acquired at the same time, under the same physiological conditions. The aim of this study was to evaluate the prognostic value of hybrid 18F-fluorodeoxyglucose (FDG) PET/MR in patients with differentiated thyroid cancer (DTC) who underwent total thyroidectomy and radioactive iodine therapy for suspicion of disease relapse. Methods: Between November 2015 and February 2017, 55 patients underwent hybrid 18F-FDG PET/MR. Assessment of positive MR was made considering all sequences in terms of malignancy based on the morphological T2-weighted features and the presence of restricted diffusivity on diffusion-weighted imaging images and both needed to be positive on the same lesion. Both foci with abnormal 18F-FDG uptake, which corresponded to tissue abnormalities on the MR, and tracer accumulation, which did not correspond to normal morphological structures, were considered positive. Results: During follow-up (mean 42 ± 27 months), 29 patients (53%) had disease recurrence. In the Cox univariate regression analysis age, serum Tg level ≥ 2 ng/mL, positive short tau inversion recovery (STIR), and positive PET were significant predictors of DTC recurrence. Kaplan−Meier survival analyses showed that patients with Tg ≥ 2 ng/mL had poorer outcomes compared to those with serum Tg level < 2 ng/mL (p < 0.05). Similarly, patients with positive STIR and positive PET had a worst outcome compared to those with negative STIR (p < 0.05) and negative PET (p < 0.005). Survival analysis performed in the subgroup of 36 subjects with Tg level ≥ 2 ng/mL revealed that patients with positive PET had a worst outcome compared to those with negative PET (p < 0.05). Conclusions: Age, serum Tg level ≥ 2 ng/mL, positive STIR, and positive 18F-FDG PET were significant predictors of DTC recurrence. However, the serum Tg level was the only independent predictor of DTC. Hybrid PET/MR imaging may have the potential to improve the information content of one modality with the other and would offer new opportunities in patients with DTC. Thus, further studies in a larger patient population are needed to understand the additional value of 18F-FDG PET/MR in patients with DTC.

Combined bone scintigraphy and fluorocholine PET/computed tomography predicts response to radium-223 therapy in patients with prostate cancer.

AIM: To assess the value of bone scintigraphy and 18F-fluorocholine PET/computed tomography (CT) in predicting outcome in patients with prostate cancer and bone metastases treated with 223radium. MATERIALS & METHODS: Retrospective analysis of 48 patients that underwent 223radium therapy. End points were pain relief and overall survival. RESULTS: After therapy, pain relief was observed in 27 patients. Patients without pain relief had more bone lesions at PET/CT than at bone scintigraphy (pretherapy imaging mismatch). In 39 patients who completed treatment protocol, post-therapy alkaline phosphatase and pretherapy imaging mismatch were independent predictors of poor overall survival. CONCLUSION: Patients with more lesions at 18F-fluorocholine PET/CT than at bone scintigraphy had a poor prognosis. The combined imaging approach could be useful to predict outcome after 223radium therapy.

TRAP1 enhances Warburg metabolism through modulation of PFK1 expression/activity and favors resistance to EGFR inhibitors in human colorectal carcinomas.

Metabolic rewiring is a mechanism of adaptation to unfavorable environmental conditions and tumor progression. TRAP1 is an HSP90 molecular chaperone upregulated in human colorectal carcinomas (CRCs) and responsible for downregulation of oxidative phosphorylation (OXPHOS) and adaptation to metabolic stress. The mechanism by which TRAP1 regulates glycolytic metabolism and the relevance of this regulation in resistance to EGFR inhibitors were investigated in patient-derived CRC spheres, human CRC cells, samples, and patients. A linear correlation was observed between TRAP1 levels and 18 F-fluoro-2-deoxy-glucose (18 F-FDG) uptake upon PET scan or GLUT1 expression in human CRCs. Consistently, TRAP1 enhances GLUT1 expression, glucose uptake, and lactate production and downregulates OXPHOS in CRC patient-derived spheroids and cell lines. Mechanistically, TRAP1 maximizes lactate production to balance low OXPHOS through the regulation of the glycolytic enzyme phosphofructokinase-1 (PFK1); this depends on the interaction between TRAP1 and PFK1, which favors PFK1 glycolytic activity and prevents its ubiquitination/degradation. By contrast, TRAP1/PFK1 interaction is lost in conditions of enhanced OXPHOS, which results in loss of TRAP1 regulation of PFK1 activity and lactate production. Notably, TRAP1 regulation of glycolysis is involved in resistance of RAS-wild-type CRCs to EGFR monoclonals. Indeed, either TRAP1 upregulation or high glycolytic metabolism impairs cetuximab activity in vitro, whereas TRAP1 targeting and/or inhibition of glycolytic pathway enhances cell response to cetuximab. Finally, a linear correlation between 18 F-FDG PET uptake and poor response to cetuximab in first-line therapy in human metastatic CRCs was observed. These results suggest that TRAP1 is a key determinant of CRC metabolic rewiring and favors resistance to EGFR inhibitors through regulation of glycolytic metabolism.

Atypical Mature T-Cell Neoplasms: The Relevance of the Role of Flow Cytometry.

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.

Exploring the Molecular Crosstalk between Pancreatic Bud and Mesenchyme in Embryogenesis: Novel Signals Involved.

Pancreatic organogenesis is a multistep process that requires the cooperation of several signaling pathways. In this context, the role of pancreatic mesenchyme is important to define the epithelium development; nevertheless, the precise space-temporal signaling activation still needs to be clarified. This study reports a dissection of the pancreatic embryogenesis, highlighting the molecular network surrounding the epithelium-mesenchyme interaction. To investigate this crosstalk, pancreatic epithelium and surrounding mesenchyme, at embryonic day 10.5, were collected through laser capture microdissection (LCM) and characterized based on their global gene expression. We performed a bioinformatic analysis to hypothesize crosstalk interactions, validating the most promising genes and verifying the precise localization of their expression in the compartments, by RNA in situ hybridization (ISH). Our analyses pointed out also the c-Met gene, a very well-known factor involved in stimulating motility, morphogenesis, and organ regeneration. We also highlighted the potential crosstalk between Versican (Vcan) and Syndecan4 (Sdc4) since these genes are involved in pancreatic tissue repair, strengthening the concept that the same signaling pathways required during pancreatic embryogenesis are also involved in tissue repair. This finding leads to novel strategies for obtaining functional pancreatic stem cells for cell replacement therapies.

BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives.

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.

Colorectal cancer: Parametric evaluation of morphological, functional and molecular tomographic imaging.

Colorectal cancer (CRC) represents one of the leading causes of tumor-related deaths worldwide. Among the various tools at physicians' disposal for the diagnostic management of the disease, tomographic imaging (e.g., CT, MRI, and hybrid PET imaging) is considered essential. The qualitative and subjective evaluation of tomographic images is the main approach used to obtain valuable clinical information, although this strategy suffers from both intrinsic and operator-dependent limitations. More recently, advanced imaging techniques have been developed with the aim of overcoming these issues. Such techniques, such as diffusion-weighted MRI and perfusion imaging, were designed for the "in vivo" evaluation of specific biological tissue features in order to describe them in terms of quantitative parameters, which could answer questions difficult to address with conventional imaging alone (e.g., questions related to tissue characterization and prognosis). Furthermore, it has been observed that a large amount of numerical and statistical information is buried inside tomographic images, resulting in their invisibility during conventional assessment. This information can be extracted and represented in terms of quantitative parameters through different processes (e.g., texture analysis). Numerous researchers have focused their work on the significance of these quantitative imaging parameters for the management of CRC patients. In this review, we aimed to focus on evidence reported in the academic literature regarding the application of parametric imaging to the diagnosis, staging and prognosis of CRC while discussing future perspectives and present limitations. While the transition from purely anatomical to quantitative tomographic imaging appears achievable for CRC diagnostics, some essential milestones, such as scanning and analysis standardization and the definition of robust cut-off values, must be achieved before quantitative tomographic imaging can be incorporated into daily clinical practice.

Adapting and Surviving: Intra and Extra-Cellular Remodeling in Drug-Resistant Gastric Cancer Cells.

Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating evidence that a plethora of cellular and molecular factors is implicated in drug-induced phenotypical switching of GC cells. Among them, epithelial-mesenchymal transition (EMT), autophagy, drug detoxification, DNA damage response and drug target alterations, have been reported as major determinants. Intriguingly, resistant GC phenotype may be the result of GC cell-induced tumor microenvironment (TME) remodeling, which is currently emerging as a key player in promoting drug resistance and overcoming cytotoxic effects of drugs. In this review, we discuss the possible mechanisms of drug resistance and their involvement in determining current GC therapies failure.

Radium-223 for the treatment of bone metastases in castration-resistant prostate cancer: when and why.

Radium-223 dichloride (223Ra) is the first, recently approved, α-particle-emitting radiopharmaceutical for the treatment of patients with bone metastases in castration-resistant prostate cancer (CRPC) and no evidence of visceral metastases. We explored MEDLINE, relevant congresses, and websites for data on 223Ra and prostate cancer therapies, focusing on therapeutic strategies and timing, bone metastases, and diagnostic assessment. 223Ra represents the only bone-targeting agent that has significantly extended patients' overall survival while reducing pain and symptomatic skeletal events. Unlike other radiopharmaceuticals, such as strontium-89 and samarium-153 EDTMP, 223Ra (11.4-days half-life) has shown a high biological efficiency mainly due to its short penetration range. These features potentially allow reduced bone marrow toxicity and limit undue exposure. 223Ra has been validated under the product name Xofigo® by the US Food and Drug Administration and the European Medicines Agency. Patient selection, management, and treatment sequencing is recommended to be discussed in the context of a multidisciplinary environment, including oncology, urology, nuclear medicine, and radiation therapy physicians. No consensus has been achieved regarding the optimal timing and its administration as single agent or in combination with zoledronic acid or chemotherapy, so far. This review aims to provide a rationale for the use of 223Ra in treating metastases from CRPC, highlighting the crucial role of a multidisciplinary approach, the disputed inclusion and exclusion criteria on the basis of agencies regulations, and the value of diagnostics for therapy assessment.

Pain predicts overall survival in men with metastatic castration-resistant prostate cancer treated with radium-223.

BACKGROUND: 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 AND METHODS: 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. RESULTS: 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 (P=0.03). CONCLUSION: 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.

Risk-related 18F-FDG PET/CT and new diagnostic strategies in patients with solitary pulmonary nodule: the ITALIAN multicenter trial.

PURPOSE: Diagnosis of solitary pulmonary nodule (SPN) is an important public health issue and 18F-FDG PET/CT has proven to be more effective than CT alone. Pre-test risk stratification and clinical presentation of SPN could affect the diagnostic strategy. A relevant issue is whether thoracic segmental (s)-PET/CT could be implemented in patients with SPN. This retrospective multicenter study compared the results of FDG whole-body (wb)-PET/CT to those of s-PET/CT. METHODS: 18F-FDG PET/CT of 502 patients, stratified for pre-test cancer risk, were retrospectively analyzed. The thoracic part of wb-PET/CT, considered s-PET/CT, was compared to wb-PET/CT. Clinical and PET/CT variables were investigated for SPN characterization as well as for identification of patients in whom s-PET/CT could be performed. Histopathology or follow-up data were used as a reference. RESULTS: In the study population, 36% had malignant, 35% benign, and 29% indeterminate SPN. 18F-FDG uptake indicative of thoracic and extra-thoracic lesions was detectable in 13% and 3% of the patients. All patients with extra-thoracic metastases (n = 13) had thoracic lymph node involvement and highest 18F-FDG uptake at level of SPN (negative predictive value 100%). Compared to wb-PET/CT, s-PET/CT could save about 2/3 of 18F-FDG dose, radiation exposure or scan-time, without affecting the clinical impact of PET/CT. CONCLUSION: Pre-test probability of malignancy can guide the diagnostic strategy of 18FDG-PET/CT in patients with SPN. In subjects with low-intermediate pretest probability s-PET/CT imaging might be planned in advance, while in those at high risk and with thoracic lymph node involvement a wb-PET/CT is necessary.

Cyclin-dependent kinase 1 targeting improves sensitivity to radiation in BRAF V600E colorectal carcinoma cells.

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.