[18F]Fluorocholine PET/CT-guided stereotactic body radiotherapy in patients with recurrent oligometastatic prostate cancer.

BACKGROUND: In the last years, functional imaging has given a significant contribution to the clinical decision-making of biochemically relapsed prostate cancer (PCa). Hereby, we present a prospective study aiming to validate the role of [18F]Fluoro-Methyl Choline ([18F]FMCH) PET/CT in the selection of PCa patients suitable for stereotactic body radiotherapy (SBRT). METHODS: Patients with biochemical recurrence limited up to three lesions revealed by [18F]FMCH PET/CT were enrolled in the present study and treated with SBRT on all active lesions. Systemic therapy-free survival since the [18F]FMCH PET/CT was considered as the primary endpoint. RESULTS: Forty-six patients were evaluated, and a total of 67 lesions were treated. After a median follow-up of 28.9 months, systemic therapy was started in 30 patients (65.2%) and median systemic therapy-free survival was 39.1 months (95% CI 6.5-68.6); 6, 12, and 24-month ratios were 93.5%, 73.9%, and 63.1%, respectively. At univariate Cox regression analysis, Delta PSA demonstrated an impact on systemic therapy-free survival (p < 0.001). CONCLUSIONS: Based on our findings, [18F]FMCH PET/CT can identify oligometastatic prostate cancer patients suitable for SBRT, resulting in a systemic therapy-free survival of 39.1 months.

Pilot, Open, Randomized, Prospective Trial for Normothermic Machine Perfusion Evaluation in Liver Transplantation From Older Donors.

Ex situ normothermic machine perfusion (NMP) might minimize ischemia/reperfusion injury (IRI) of liver grafts. In this study, 20 primary liver transplantation recipients of older grafts (≥70 years) were randomized 1:1 to NMP or cold storage (CS) groups. The primary study endpoint was to evaluate graft and patient survival at 6 months posttransplantation. The secondary endpoint was to evaluate liver and bile duct biopsies; IRI by means of peak transaminases within 7 days after surgery; and incidence of biliary complications at month 6. Liver and bile duct biopsies were collected at bench surgery, end of ex situ NMP, and end of transplant surgery. Interleukin (IL) 6, IL10, and tumor necrosis factor α (TNF-α) perfusate concentrations were tested during NMP. All grafts were successfully transplanted. Median (interquartile range) posttransplant aspartate aminotransferase peak was 709 (371-1575) IU/L for NMP and 574 (377-1162) IU/L for CS (P = 0.597). There was 1 hepatic artery thrombosis in the NMP group and 1 death in the CS group. In NMP, we observed high TNF-α perfusate levels, and these were inversely correlated with lactate (P < 0.001). Electron microscopy showed decreased mitochondrial volume density and steatosis and an increased volume density of autophagic vacuoles at the end of transplantation in NMP versus CS patients (P < 0.001). Use of NMP with older liver grafts is associated with histological evidence of reduced IRI, although the clinical benefit remains to be demonstrated.

DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients.

Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.

Patterns of Failures and Clinical Outcome of Patients with Early-Stage, High-Risk, Node-Negative Endometrial Cancer Treated with Surgery Followed by Adjuvant Platinum-Based Chemotherapy and Vaginal Brachytherapy.

OBJECTIVE: To assess the clinical outcome of patients with high-risk early-stage endometrial cancer and negative pelvic nodes who received adjuvant platinum-based chemotherapy plus vaginal brachytherapy (VBT). METHODS: This investigation assessed 80 patients who underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy for stage Ib-II, grade 2-3 endometrioid (n = 43) or stage Ia-II nonendometrioid (n = 37) endometrial cancer. RESULTS: Five-year local control rate, 5-year disease-free survival, and 5-year overall survival were 97, 87, and 97%, respectively, for endometrioid carcinoma, and 66, 50, and 72%, respectively, for nonendometrioid carcinoma. CONCLUSIONS: This retrospective study appears to show that adjuvant platinum-based chemotherapy plus VBT achieve very good results in endometrioid carcinoma. This combined treatment seems to be less effective in nonendometrioid carcinoma.

Damaging and protective interactions of lichens and biofilms on ceramic dolia and sculptures of the International Museum of Ceramics, Faenza, Italy.

Although ceramic objects are an important part of the worldwide cultural heritage, few investigations on the effects of lithobiontic growth on their outdoor conservation are available in the literature. Many aspects of the interaction between lithobionts and stones are still unknown or strongly debated, as in the case of equilibria between biodeterioration and bioprotection. This paper describes research on the colonization by lithobionts on outdoor ceramic Roman dolia and contemporary sculptures of the International Museum of Ceramics, Faenza (Italy). Accordingly, the study i) characterized the mineralogical composition and petrographic structure of the artworks, ii) performed porosimetric measurements, iii) identified lichen and microbial diversity, iv) elucidated the interaction of the lithobionts with the substrates. Moreover, v) the measurements of variability in stone surface hardness and in water absorption of colonized and uncolonized areas were collected to assess damaging and/or protective effects by the lithobionts. The investigation showed how the biological colonization depends on physical properties of the substrates as well on climatic conditions of environments in which the ceramic artworks are located. The results indicated that lichens Protoparmeliopsis muralis and Lecanora campestris may have a bioprotective effect on ceramics with high total porosity and pores with very small diameters, as they poorly penetrate the substrate, do not negatively affect surface hardness and are able to reduce the amount of absorbed water limiting the water ingress. By contrast, Verrucaria nigrescens, here widely found in association with rock-dwelling fungi, deeply penetrate terracotta causing substrate disaggregation, with negative consequences on surface hardness and water absorption. Accordingly, a careful evaluation of the negative and positive effects of lichens must be carried out before deciding their removal. Regarding biofilms, their barrier efficacy is related to their thickness and composition. Even if thin, they can impact negatively on substrates enhancing the water absorption in comparison to uncolonized parts.

Surgical management of follicular thyroid carcinoma in children and adolescents: A study of 30 cases.

BACKGROUND/PURPOSE: The purpose of the study is to describe the anatomoclinical, diagnostic, therapeutic and prognostic aspects of pediatric follicular thyroid carcinoma (FTC) in order to choose the best therapeutic strategy. METHODS: Our study includes patients ≤18 years old surgically treated for FTC in four Italian Pediatric Surgery Centers from January 2000 to March 2017. The collected data were compared with those of 132 patients matched for age with a histological diagnosis of papillary thyroid carcinoma (PTC) surgically treated in the same institutions during the same period and with the data of patients diagnosed with FTC found in the literature; p-values <0.05 were considered significant. RESULTS: 21 (70%) of the 30 patients with a histological diagnosis of FTC underwent hemithyroidectomy while 9 (30%) underwent total thyroidectomy. 11 (55%) out of 21 patients were subjected to a completion of thyroidectomy. All patients are alive (OS = 100%) without recurrence or relapse of the disease. Compared with PTC, FTC is significant for capsule infiltration (p < 0.0001), vascular invasion (p = 0.0014) and T-stage T3-T4 (p = 0.013). However, multifocality (p < 0.001), extrathyroid extension (p < 0.0001) and lymph node metastasis (p < 0.0001) are more evident in PTC. CONCLUSION: The conservative approach seems to be a valid surgical treatment for pediatric patients diagnosed with MI-FTC. For patients with wide vascular invasion and/or a tumor >4 cm, especially with high after-surgery Tg rate, a completion of thyroidectomy is recommended. In patients with multifocal neoplasia, and/or tumor size ≥4 cm, and/or extrathyroid extension, and/or lymph node metastasis, and/or distant metastasis, total thyroidectomy followed by radioiodine therapy is generally indicated. LEVELS OF EVIDENCE: II.

Definitive radiotherapy for recurrent vulvar carcinoma after primary surgery: a two-institutional Italian experience.

OBJECTIVE: To assess the clinical outcome of patients treated with radiotherapy (RT) for recurrent squamous cell carcinoma of the vulva after primary surgery. METHODS: Fifty-six patients developed recurrent disease after surgery, consisting of deep total vulvectomy with inguino-femoral lymphadenectomy in 44 (78.6%) and deep partial vulvectomy with inguino-femoral lymphadenectomy in 12 (21.4%). All patients underwent RT at the Divisions of Radiotherapy, University of Pisa and ASST Cremona, between 1992 and 2016. Forty-three patients (76.8%) underwent external beam RT and 13 (23.2%) were treated with exclusive high-dose rate brachytherapy. RESULTS: Five-year progression-free survival (PFS) and overall survival (OS) were 19% and 43%, respectively. Primary tumor size ⩽4 cm, early FIGO stage, and negative lymph node status were significantly associated with better PFS (p = .005, p = .020 and p = .036, respectively) and OS (p < .0001, p = .023 and p = .008, respectively). Patients with more than 1 positive lymph node at primary surgery had significantly worse PFS (p = .028) and OS (p = .001). Patients with local recurrence had significantly better PFS and OS (p = .022, p = .002, respectively). RT total dose >54 Gy was associated with a lower risk of recurrence. CONCLUSIONS: Primary tumor size, FIGO stage, nodal status, and site of recurrent disease were significant predictors of clinical outcome in patients treated with RT for recurrent squamous cell carcinoma of the vulva.

An individual reference limit of the serum CEA-TPA-CA 15-3 tumor marker panel in the surveillance of asymptomatic women following surgery for primary breast cancer.

PURPOSE: The purpose of this study was to evaluate the combined measurement of serum CEA, TPA, and CA 15-3, using an individual reference limit (IRL), for predicting distant metastases in asymptomatic women following a diagnosis of primary breast cancer. METHODS: A total of 231 patients were followed up for a mean of 5.5±1.6 years. An IRL for defining critical changes (CCs) in marker levels was used as a warning signal of pending distant metastases. RESULTS: Sensitivity, specificity, and accuracy of the combined CEA-TPA-CA 15-3 marker panel for predicting patient outcome were 95.2%, 97.8%, and 97.9%, respectively. In all, 19 (8.3%) patients relapsed with a mean lead time to radiological evidence of metastases of 11.7±13.8 months. CONCLUSION: We concluded that the combined measurement of CA 15-3, CEA, and TPA using an IRL for determining the CC in markers levels is an accurate strategy for predicting outcome during postoperative monitoring of asymptomatic breast cancer patients. Whether the early prediction of metastasis and subsequent administration of therapy impacts on patient outcome should now be the objective of a prospective clinical trial. The marker panel described here could serve as the basis for such a trial.

High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ naïve lymphocytes and prevents TTV reactivation.

INTRODUCTION: Zinc plays an important role in thymic function and immune homeostasis. We performed a prospective clinical trial using a high-dose zinc oral supplementation to improve the immune reconstitution after hematopoietic stem cell transplant (HSCT). PATIENTS AND METHODS: We enrolled 18 patients undergoing autologous HSCT for multiple myeloma. Nine patients were randomized to receive only a standard antimicrobial prophylaxis; whereas, nine patients received in addition 150 mg/day of zinc from day +5 to day +100 after transplant. RESULTS: CD4+ naïve lymphocytes and TRECs showed a significant increase from day +30 until day +100 only in the zinc-treated group. Moreover, the load of Torquetenovirus, a harmless virus that replicates in course of immunedepression, increased at day +100 only in the control group. No severe adverse events were reported during the zinc consumption. CONCLUSION: First data from the ZENITH trial suggest that high-dose zinc supplementation is safe and may enhance the thymic reconstitution after HSCT. Registered: http://Clinicaltrials.gov (NCT03159845); and EUDRACT: 2014-28 004499-47.

Different Timing to Use Bevacizumab in Patients with Recurrent Glioblastoma: Early Versus Delayed Administration.

BACKGROUND/AIM: In patients with recurrent glioblastoma, the best timing to administer bevacizumab is not well addressed yet. In this study, we reported the results of a monocentric experience comparing the early use of bevacizumab (following the first GBM recurrence) with the delayed administration (following the second or even further GBM recurrences). MATERIALS AND METHODS: This analysis included 129 glioblastoma patients with a median follow-up of 22.4 months (range=5.26-192 months). RESULTS: The median time lapse from diagnosis of glioblastoma to disease recurrence was 11.6 months; 13.1 for patients treated with deferred administration of bevacizumab and 9.9 for patients with early administration (p=0.047). Bevacizumab progression-free survival with early and delayed use was 3.45 and 2.92 months, respectively (p=0.504). Survival time from the start of bevacizumab was 6.18 months in patients with early administration, and 6.47 in the delayed administration one (p=0.318). CONCLUSION: Delayed administration of bevacizumab can be considered in selected patients with less aggressive recurrent glioblastoma.

Image-guided Stereotactic Body Radiotherapy in Metastatic Prostate Cancer.

BACKGROUND/AIM: In the last years, the use of Image Guided Stereotactic Radiotherapy (IG-SBRT) in patients with metastatic prostate cancer has increased. In this study, we aimed to assess the role of IG-SBRT in terms of local control and safety in patients with metastatic prostate cancer. MATERIALS AND METHODS: Primary and secondary endpoints of this prospective observational study were local control and safety related to IG-SBRT. All lesions were treated with 24 Gy as a single fraction or 27 Gy in 3 fractions. After SBRT, Systemic therapies were administered only after the occurrence of more than three synchronous active lesions in oligometastatic patients (patients with less than 4 active synchronous lesions) or new lesions occurrence in patients with more than 3 synchronous lesions. RESULTS: From April 2011 to June 2017, 78 metastatic lesions (32 bone and 46 node) from 51 patients with prostate cancer were treated. After a median follow-up of 18.5 months (range=3-103 months), only 2 lesions (4%) relapsed inside the radiation field. All local recurrences were located on the bone. Estimated 12 and 24 months local control ratios were 98.7 and 97.4%, respectively. Except for one case, toxicity greater than G2 was not recorded. CONCLUSION: IG-SBRT is safe and can be considered as a valid therapy in patients with metastatic prostate cancer requiring a long-lasting metastases control.

Stereotactic body radiotherapy of bone metastases in oligometastatic disease: prognostic factors of oncologic outcomes.

BACKGROUND: To evaluate the safety of stereotactic body radiotherapy (SBRT) of bone metastases in oligometastatic disease and to investigate prognostic factors of local control (LC), progression/disease-free survival (PDFS), and overall survival (OS). METHODS: Eligibility criteria were number of metastates ≤5, controlled primary tumor without evidence of progression under systemic therapy, exclusion of surgery, and no previous radiotherapy of the lesion of interest. Oligometastatic status was classified into only bone (BOD) and outside bone disease (OBOD), whereas SBRT was delivered to bone lesions using 2 different schedules: 24 Gy/1 fraction or 27 Gy/3 fractions. A positron emission tomography study of the lesion of interest was performed at baseline and at 3 months after SBRT to evaluate metabolic response according to European Organization for Research and Treatment of Cancer (EORTC) criteria. A Cox regression model was used for univariate and multivariate analysis. RESULTS: Between January 2010 and December 2013, 40 patients were enrolled. Only 1 patient experienced severe late toxicity (radiation-related fracture). Local control was longer among responders' than nonresponders' lesions (94.2% and 91.2% versus 63% and 35% at 1 and 2 years, respectively) (p = 0.004; hazard ratio = 9.958). The multivariate analysis of PDFS showed a significant correlation with planning target volume (PTV) size (p = 0.003) and oligometastatic status (p = 0.002). The multivariate analysis of OS confirmed a statistically significant value of the oligometastatic status (p = 0.002) and a significant trend for PTV size (p = 0.065). CONCLUSIONS: Stereotactic body radiotherapy is safe with a low incidence of severe toxicity. Positron emission tomography response was a strong prognostic factor of LC whereas BOD status and small PTV size could identify a subset of oligometastatic patients at better prognosis.