Early stage breast cancer follow-up in real-world clinical practice: the added value of cell free circulating tumor DNA.

PURPOSE: Physical examinations and annual mammography (minimal follow-up) are as effective as laboratory/imaging tests (intensive follow-up) in detecting breast cancer (BC) recurrence. This statement is now challenged by the availability of new diagnostic tools for asymptomatic cases. Herein, we analyzed current practices and circulating tumor DNA (ctDNA) in monitoring high-risk BC patients treated with curative intent in a comprehensive cancer center. PATIENTS AND METHODS: Forty-two consecutive triple negative BC patients undergoing neoadjuvant therapy and surgery were prospectively enrolled. Data from plasma samples and surveillance procedures were analyzed to report the diagnostic pattern of relapsed cases, i.e., by symptoms, follow-up procedures and ctDNA. RESULTS: Besides minimal follow-up, 97% and 79% of patients had at least 1 non-recommended imaging and laboratory tests for surveillance purposes. During a median follow-up of 5.1(IQR, 4.1-5.9) years, 13 events occurred (1 contralateral BC, 1 loco-regional recurrence, 10 metastases, and 1 death). Five recurrent cases were diagnosed by intensive follow-up, 5 by symptoms, and 2 incidentally. ctDNA antedated disseminated disease in all evaluable cases excepted two with bone-only and single liver metastases. The mean time from ctDNA detection to suspicious findings at follow-up imaging was 3.81(SD, 2.68), and to definitive recurrence diagnosis 8(SD, 2.98) months. ctDNA was undetectable in the absence of disease and in two suspected cases not subsequently confirmed. CONCLUSIONS: Some relapses are still symptomatic despite the extensive use of intensive follow-up. ctDNA is a specific test, sensitive enough to detect recurrence before other methods, suitable for clarifying equivocal imaging, and exploitable for salvage therapy in asymptomatic BC survivors.

The hypothalamic-pituitary-adrenal and -thyroid axes activation lasting one year after an earthquake swarm: results from a big data analysis.

PURPOSE: To cope physical and/or psychological threats, the human body activates multiple processes, mediated by a close interconnection among brain, endocrine and inflammatory systems. The aim of the study was to assess the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes involvement after an acute stressful event (Emilia Romagna earthquake swarm) with a big data approach. METHODS: A retrospective, observational trial was performed, collecting all biochemical examinations regarding HPA and HPT axes performed in the same laboratory the year before and the year after the earthquake swarm (20-29 May 2012). RESULTS: Comparing 2576 pre-earthquake to 3021 post-earthquake measurements, a cortisol serum level increase was observed (p < 0.001). Similar increase was evident for urinary free cortisol (p = 0.016), but not for adrenocorticotropic hormone (p = 0.222). The biochemical hypercortisolism incidence increased from 7.6 to 10.3% after earthquakes (p = 0.001). Comparing 68,456 pre-earthquake to 116,521 post-earthquake measurements, a reduction in thyroid-stimulating hormone (TSH) levels was evident (p = 0.018), together with an increase in free triiodothyronine and free thyroxine levels (p < 0.001 and p < 0.001). Moreover, a significant increase in altered TSH after earthquakes was registered considering the epicenter-nearest measurements (p < 0.001). No clinically relevant alterations were observed considering thyroid-specific autoantibodies. CONCLUSION: A long-term HPA axis activation in the inhabitants of the earthquake-affected areas was highlighted for the first time. Moreover, an increased incidence of biochemical hypercortisolism emerged after earthquakes. We confirmed a recruitment of HPT axis after stressful events, together with increased incidence of altered TSH in the. Our big data study allowed to increase knowledge about the connection between external stressors and endocrine regulation.

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PURPOSE: To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. METHODS: A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. RESULTS: The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. CONCLUSIONS: The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Complementary therapy for severe Rh-alloimmunization.

PURPOSE OF INVESTIGATION: This report describes successful treatment, using invasive and noninvasive techniques, of a 36-year-old woman (gravida 10, para 0) referred to our center at 13 weeks' gestation for severe Rh alloimmunization. Pre-pregnancy indirect Coombs titers ranged from 1:1024-2048. All nine past pregnancies (conceived with three different partners) had ended in abortion, intrauterine death or neonatal death METHODS: The patient was treated with a single session of plasmapheresis (week 14) immediately followed by five days of immunoglobulin therapy and immunosuppressive therapy based on azathioprine and prednisone (weeks 15-22). Seven fetal transfusions (one intraperitoneal, six intravascular) were performed beginning at 16 weeks. RESULTS: The pregnancy, which was characterized by insulin-dependent gestational diabetes, spontaneously resolving polyhydramnios and peak indirect Coombs titers of 1:65,536, ended at 27 weeks with cesarean section delivery of a viable female weighing 1,000 g. In spite of numerous neonatal complications, the child is physically well at age 3, with normal intellectual and psychomotor development. CONCLUSION: In light of the negative outcomes of the patient's nine past pregnancies, our experience suggests that the early initiation of an integrated approach based on noninvasive and invasive techniques can play a potentially decisive role in the management of severe Rh-alloimmunization.

Recombinant erythropoietin in the prevention of late anaemia in intrauterine transfused neonates with Rh-haemolytic disease.

OBJECTIVE: To evaluate the efficacy of recombinant human erythropoietin (rHuEPO) in prevention of late anaemia due to Rh-haemolytic disease in neonates subjected to one or more intrauterine transfusions (IUTs). STUDY DESIGN: Six neonates (GA 28-38 weeks, BW 980-3,360 g), subjected to one or more IUTs for Rh-haemolytic disease, were treated for 3 weeks with rHuEPO (200 U/kg/day, s.c.) after the second week of life to prevent late anaemia and consequently reduce the need for blood transfusions. All treated neonates were supplemented weekly with iron, vitamin E and folinic acid, intramuscularly. RESULTS: Of the 6 patients studied, 4 preterm neonates, after commencement of rHuEPO treatment, showed a decrease in Hct values with persistent reticulocytopenia, and consequent need for one or more transfusions with packed and filtered red cells (PFRC). These 4 neonates had received a greater blood volume with IUTs than the 2 other term neonates, who, after starting rHuEPO treatment, showed an increase in Hct values and in reticulocyte count, with no transfusion requirements after birth (247 +/- 47 vs. 84 +/- 76 ml). CONCLUSIONS: Our results seem to correlate the efficacy of erythropoietin treatment in prevention of late anaemia resulting from Rh-haemolytic disease to the severity of intrauterine anaemia and to gestational age. Erythropoietin, in fact, was less effective in cases of severe intrauterine anaemia requiring a high volume of PFRC; it was also less effective in the preterm babies, because of the simultaneous presence of anaemia of prematurity and other major diseases.

[Diagnostic imaging and interventional therapy in hepatocarcinoma. Multicenter study of 290 cases]. / La diagnostica mediante immagini e la terapia interventistica dell'epatocarcinoma. Studio multicentrico su 290 casi.

We report the results of a multicenter study on the diagnosis and interventional therapy of hepatocellular carcinoma (HCC). The first aim--diagnosis--was to evaluate the sensitivity of 4 imaging techniques, namely ultrasonography (US), Computed Tomography (CT), digital arteriography (DSA) and Lipiodol CT (LCT), in HCC detection. The accuracy of these techniques was also investigated in tumor staging, which is important for treatment planning. Two hundred ninety patients underwent this imaging protocol. The patients were classified by tumor spread into three groups, namely group 1 (single HCCs < 5 cm), group 2 (multifocal HCCs with max. 3 nodules or tumor volume < 80 cc), group 3 (multifocal HCCs with more than 3 nodules and/or tumor volume > 80 cc). US and CT diagnosed more cases as group 1 and fewer cases as group 3 than DSA and LCT; the latter two techniques gave a similar classification. With LCT as the gold standard, US and CT understaged 27.9% and 26.5% of cases, respectively. Even though LCT is known to have 53% sensitivity, it is currently the most sensitive preoperative investigation and therefore the best tool for treatment planning. In surgical patients, however, intraoperative US, with its nearly 100% sensitivity, is suggested. The second aim--treatment--consisted in assessing the therapeutic efficacy of intraarterial chemoembolization (CEAT) versus percutaneous ethanol injection (PEI) in non advanced HCC and of CEAT versus no treatment (NT) in advanced HCC. Treatment efficacy was evaluated with the following randomized protocols: PEI versus CEAT in group 1, PEI versus CEAT in group 2 and CEAT versus NT in group 3. The data were analyzed relative to 215 patients for 6 to 30 months. The Kaplan-Meier method was used to calculate survival rates, which were, at 24 and 30 months, 72% and 72% for PEI and 72% and 52% for CEAT in group 1, 52% and 28% for PEI and 70% and 50% for CEAT in group 2 and finally 30% and 20% for NT and 45% and 30% for CEAT in group 3. In group 1, PEI appeared markedly superior to CEAT. In group 2, the difference between PEI and CEAT was not statistically significant; the results in this group indicate that CEAT should be considered when three nodules are present because of PEI invasiveness in these cases. In group 3, CEAT results were definitely better in the first two years, but there was no difference with NT patients at the end of the third year. Therefore, CEAT is indicated in advanced HCC because it improves the survival rate in the first 24 months. After this period, the survival time is not modified by treatment.

Effects of lipiodol retention on MRI signal intensity from hepatocellular carcinoma and surrounding liver treated by chemoembolization.

Opinion is divided regarding the influence of iodized oil on MRI signal intensity of hepatic tumours treated with transcatheter arterial chemoembolization (TACE), in which lipiodol deposits. The aim of our study was to ascertain whether or not lipiodol directly influences the MRI signal intensity of hepatocellular carcinoma (HCC) treated by TACE and that of the surrounding liver. Thirteen patients with HCC were studied retrospectively. CT and MRI scans were performed both before and 3 months after TACE. The CT scan was performed to check whether embolized nodules contained lipiodol and how lipiodol was distributed within them. In addition, eight patients were examined prospectively within 7 days after TACE. In these patients a CT scan was performed to see how lipiodol was distributed in the neoplastic nodules and in normal hepatic parenchyma. In the first group of patients the contrast-to-noise (C/N) ratio on T1-weighted (T1W) images and the T2 relaxation time on T2-weighted (T2W) images were calculated for both neoplasm and surrounding liver. In the second group of patients we also measured the signal intensity of non-neoplastic liver that was either permeated or not permeated by lipiodol. The data were analysed with Wilcoxon's test. On T1W images we observed that the retention of lipiodol increased the C/N ratio in all the tumours studied within 1 week after TACE. In the patients studied 3 months after TACE the C/N ratio was not significantly increased. On T2W images lipiodol retention did not change tumour signal intensity. The iodized oil did not change the signal intensity of the liver surrounding the tumour, in comparison with the liver not permeated by lipiodol, on either T1W or T2W images. The results indicate that lipiodol does not modify the signal intensity in non-neoplastic hepatic parenchyma in which it is deposited; after 3 months it does not significantly affect the signal of the tumours that accumulated it. Lipiodol produces a high signal on T1W images over the first few days following TACE in those tumours in which it is deposited.

Combined modality follow-up and postoperative recurrence in rectal cancer.

Rectal cancer patients are at high risk for disease progression even after radical surgery for cure. Prognosis depends on a timely diagnosis for effective, curative therapies. In resected patients, an accurate follow-up especially within the first two years of surgery, is required. Clinical and radiologic follow-up is based on periodical, timed physical and instrumental exams (rectal exploration, neoplastic markers, rectoscopy, colonic enema, CT MRI, TRUS) which supply information on locoregional (liver, lymph nodes, peritoneum, chest) recurrence. Rectal exploration, endoscopy, colonic enema and TRUS enable the control of anastomosis and the identification of possible metachronous tumors. CT and MRI as liver US and chest X-ray, detect recurrence in other sites (pelvic perianastomotic recurrence, peritoneal carcinomatosis, lymph node or liver locations). A diagnostic problem is represented by the difficult differentiation of local recurrence from postoperative fibrosis. In this case, surveillance in the course of time with exams more reliable in tissue differentiation (MRI, though with some limitations) and US- or CT-guided biopsy, is required.

[Comparative evaluation of ultrasonography, computerized tomography, angiography and lipiodol CT in defining extent of hepatocarcinoma. A multicenter study]. / Valutazione comparativa dell'ecografia, della Tomografia Computerizzata, dell'angiografia, della Lipiodol TC nel bilancio di estensione dell'epatocarcinoma. Studio multicentrico.

The authors report the results of a multicentric trial on hepatocellular carcinoma (HCC) patients, whose lesions were confirmed with biopsy or by high (> 400 ng/ml) alpha-fetoprotein levels. The series consisted of 149 patients examined in 8 different centers and submitted to ultrasonography (US), Computed Tomography (CT) before and after contrast agent administration, angiography and Lipiodol CT. According to lesion size and number, the patients were divided with each imaging modality into three groups: a) group 1: unifocal HCC < 5 cm diameter; b) group 2: multifocal HCC with 2-3 nodules and/or tumor mass < 80 ml; c) multifocal HCC with more than 3 nodules (with total tumor mass not exceeding 40% of liver volume) or with total tumor mass > 80 ml. In 77 patients all the examinations were available for comparison. US and CT diagnosed more patients as belonging to group 1 than angiography and Lipiodol CT, while more patients were classified as groups 2 and 3 with angiography and Lipiodol CT, meaning that US and CT may understage some HCC cases (about 15%) because they show a lower number of nodules. This observation was confirmed by the direct comparison between US and Lipiodol CT (in 114 patients), CT and Lipiodol CT (in 103 patients) and angiography and Lipiodol CT (in 116 patients). US and Lipiodol CT were in disagreement in 18 cases, CT and Lipiodol CT in 16 cases and angiography and Lipiodol CT in 13 cases. In most of these cases, Lipiodol CT showed more lesions than the other techniques. The size of the undetected lesions was small, ranging few mm to 2 cm in nearly all cases. To conclude, the results of this multicentric trial show that Lipiodol CT is a fundamental tool to evaluate HCC extent. In contrast, conventional CT appeared not to add any significant piece of information and can therefore be excluded from the diagnostic protocol of HCC.

[The magnetic resonance of small hepatocarcinoma. A comparison with echography, computed tomography, digital angiography and computed tomography with lipiodol]. / La risonanza magnetica del piccolo epatocarcinoma. Confronti con ecografia tomografia computerizzata, angiografia digitale e tomografia computerizzata con Lipiodol.

Diagnostic techniques as a whole and periodic ultrasonography (US) in particular frequently allows tumors < 3 cm (small hepatocellular carcinomas) to be detected in patients suffering from liver cirrhosis. Multifocal diseases are a major limitation to surgery. Recently, MR imaging has shown its capabilities in the diagnosis of small hepatocellular carcinomas. In our study the diagnostic value of MR imaging was compared with that of US, of pre- and post-contrast CT, of digital angiography and of CT after lipiodol injection (Lipiodol CT). The morphologic and signal intensity MR features of small hepatocellular carcinomas were investigated. Fifteen cirrhotic patients with 31 nodules of hepatocellular carcinoma < 3 cm were examined. All patients were studied with US, MR imaging, angiography and Lipiodol CT; 12/15 patients underwent CT. Histologic confirmation was obtained in 12 nodules (2 at surgery and 10 by means of percutaneous biopsy); in the extant 19 cases the diagnosis was made by combining US, CT, MR, angiographic and lipiodol-CT findings; in 9 tumors < 1 cm Lipiodol retention one month after angiography was considered as diagnostic. MR imaging detected 21/31 nodules (63%), US 22/31 (66.6%), CT 12/24 (50%), angiography 24/31 (74%), lipiodol CT 29/31 (92.5%). Mc Nemar test showed no difference in sensitivity between MR imaging and CT, MR and angiography, MR and US, lipiodol CT and angiography; however, the differences between the detection rates of MR imaging and Lipiodol CT and CT and lipiodol CT and US were statistically significant (p < 0.05). The difference in sensitivity between the detection rates of lipiodol CT and US was just above the threshold value which is usually considered significant (p = 0.065). One false positive was observed on US and none with MR, CT, angiography and lipiodol CT. On Se T1-weighted images 18 nodules were hyperintense, 2 isointense and 2 hypointense; on proton-density images 14 nodules were hyperintense, 7 isointense and none hypointense. On SE T2-weighted images 18 nodules were hyperintense, 3 isointense and none hypointense. A pseudocapsule was seen in 10/17 nodules (58%), especially on T1-weighted images. Accuracy and limitations of each technique and morphologic and signal intensity MR findings of small hepatocellular carcinoma are discussed. We believe that US is still the best diagnostic technique for the screening of hepatocellular carcinomas in cirrhotic livers.(ABSTRACT TRUNCATED AT 400 WORDS)

MRI of small hepatocellular carcinoma: comparison with US, CT, DSA, and Lipiodol-CT.

Thirteen cirrhotic patients with 27 nodules of hepatocellular carcinoma less than 3 cm (small HCC) were examined with ultrasonography (US), MR, pre- and postcontrast CT, digital subtraction angiography (DSA), and CT after injection of Lipiodol (Lipiodol-CT). The accuracy of MR was compared with other diagnostic modalities and MR morphologic and the signal intensity features of HCC were investigated. The detection rate by MR was 63%, by US 67%, by CT 50%, by DSA 74%, and by Lipiodol-CT 93%. The Mc Nemar test showed no difference between the detection rates of MR and CT, MR and DSA, MR and US, and Lipiodol-CT and DSA; however, the differences between the detection rates of MR and Lipiodol-CT and CT and Lipiodol-CT were statistically significant (p less than or equal to 0.05). The difference in sensitivity between the detection rates of Lipiodol-CT and US was just above the level considered significant (P less than or equal to 0.065). On T1- and T2-weighted spin echo images 83% of small HCC were hyperintense relative to the surrounding liver parenchyma. Pseudocapsule was observed in 58% of lesions on T1-weighted images in particular. We believe that US is still the best diagnostic technique for the screening of HCC. We prefer MR to CT as a second level examination to support US in noninvasive diagnosis of small HCC, since MR gives the same or slightly better results than CT without the need of ionizing radiation and large amounts of iodized contrast medium. In our opinion, more invasive examinations, such as DSA and Lipiodol-CT, cannot be avoided in cases where an exact knowledge of the number of lesions is essential for the choice of therapy.