PARP Inhibitors in Metastatic Prostate Cancer: A Comprehensive Systematic Review and Meta-analysis of Existing Evidence.

Poly (ADP-ribose) polymerase inhibitors (PARPi) represent an option in selected cases of metastatic castration-resistant prostate cancer (mCRPC). The aim of the present systematic review and meta-analysis is to evaluate the efficacy and safety of approved (Olaparib, Rucaparib) and investigational (Talazoparib, Niraparib, Veliparib) PARPi in mCRPC patients. Three databases were queried for studies analyzing oncological outcomes and adverse events of mCRPC patients receiving PARPi. Primary outcome was a PSA decline ≥ 50% from baseline. Secondary outcomes were objective response rate, progression-free survival (PFS), radiological PFS, overall survival (OS), conversion of circulating tumor cell count, and time to PSA progression. The number and rate of any grade adverse events (AEs), grade ≥ 3 AEs, and most common grade ≥ 3 AEs were registered. A subanalysis of outcomes per mutation type, prospective trials, and studies adopting combination therapies was performed. Overall, 31 studies were included in this systematic review, 28 of which are available for meta-analysis. The most frequently investigated drug was Olaparib. The most frequent mutation was BRCA2. A PSA decline rate of 43% (95% CI 0.32-0.54) was observed in the overall population. Mean OS was 15.9 (95% CI 12.9-19.0) months. In BRCA2 patients, PSA decline rate was 66% (95% CI 0.57-0.7) and OS 23.4 months (95% CI 22.8-24.1). Half of the patients suffered from grade 3 and 4 AEs (0.50 [95% CI 0.39-0.60]). Most common AEs were hematological, the most frequent being anemia (21.5%). PARP inhibitors represent a viable option for mCRPC patients. Current evidence suggests an increased effectiveness in homologous recombination repair (HRR) gene mutation carriers, especially BRCA2.

Radiofrequency echographic multi-spectrometry and DXA for the evaluation of bone mineral density in a peritoneal dialysis setting.

BACKGROUND: The aim of this real-life cross-sectional explorative study was to compare radiofrequency echographic multi-spectrometry (REMS) with dual-energy X-rays absorptiometry (DXA) in the BMD assessment of patients receiving peritoneal dialysis (PD). Furthermore, we investigated the relationship between lumbar aortic calcifications (AOCs) and the DXA lumbar measurements. METHODS: Consecutive patients referring to the PD clinic of our hospital were included. Lumbar spine and femur scans were acquired with both techniques (including lumbar laterolateral DXA scans). The risk assessment of two fracture risk algorithms (FRAX® and DeFRA®) were compared. Cohen's k coefficients were used to assess the inter-technique agreement in the classification of patients as osteoporotic. Lumbar AOCs were estimated semi-quantitatively on laterolateral DXA scans. RESULTS: 41 patients were enrolled. No significant differences were documented between the BMD T-scores measured through DXA or REMS at the femur. At the lumbar spine, the DXA anteroposterior mean T-score (- 0.49 ± 1.98) was significantly higher than both the laterolateral DXA (- 1.66 ± 0.99) and the REMS (- 2.00 ± 1.94) measurements (p < 0.01 vs both). No significant differences were found between the DXA and REMS fracture risk estimates with both algorithms. The inter-technique Cohen's k coefficient (for the worst T-score, any site) was 0.421, p < 0.001. The discrepancy between the DXA laterolateral and anteroposterior lumbar T-score was positively associated with the AOCs extent and severity (r = 0.402, p < 0.01). CONCLUSIONS: Our data showed a promising agreement, in a real-life PD setting, between DXA and REMS BMD assessment and in the consequent fracture risk estimation and confirm the AOCs interference on the diagnostic accuracy of lumbar DXA.

Diffuse Idiopathic Skeletal Hyperostosis (DISH) in Type 2 Diabetes: A New Imaging Possibility and a New Biomarker.

We performed a cross-sectional study to investigate the prevalence of Diffuse Idiopathic Skeletal Hyperostosis (DISH) through Dual-Energy X-ray absorptiometry (DXA) Vertebral Fracture Assessment (VFA) in a group of post-menopausal women with Type 2 Diabetes Mellitus (T2DM). We also explored several biomarkers of bone turnover metabolism, including Wnt pathway modulators. DXA-VFA was performed to detect the presence of DISH. Serum samples were collected from all patients at the time of study recruitment. 16 different serum biomarkers were tested between the two subgroups. Given the exploratory nature of the study, we did not adjust for multiplicity. At VFA analysis, among 96 individuals enrolled in the study 20 (20.8%) showed features of DISH. No statistically significant difference was found for BMD values, between the DISH and NO-DISH subgroups. Concerning blood biomarkers, DISH patients showed a significant difference only in the sclerostin serum levels (32 vs 35.5 pmol/L, for the DISH and NO-DISH subgroup, respectively; p = 0.010). After adjustment for confounding factors, sclerostin serum levels remained significantly lower in DISH group (p = 0.002). We demonstrated a non-negligible prevalence of DISH in a population of post-menopausal women affected by T2DM and suggested low serum sclerostin as a possible key feature associated with DISH presence. In addition, we propose DXA-VFA analysis, whose radiation dose is considerably lower than conventional radiography, as a viable diagnostic and prognostic mean to obtain data not only on bone health, but also for the screening for DISH in subjects at risk.

Type 1 and Type 2 Autoimmune Pancreatitis: Distinctive Clinical and Pathological Features, But Are There Any Differences at Magnetic Resonance? Experience From a Referral Center.

OBJECTIVES: This study aimed to evaluate magnetic resonance imaging findings of autoimmune pancreatitis (AIP) and to find radiological patterns that could differentiate type 1 and type 2 AIP. METHODS: Eighty-four patients with diagnosis of AIP were enrolled. Image analysis included pancreatic signal intensity abnormalities, enhancement pattern, extrapancreatic involvement, and main pancreatic duct alterations. RESULTS: Pancreatic parenchyma resulted in hypointensity on T1-weighted images in 65 (98.5%) of 66 cases in type 1 and in 17 (94.5%) of 18 in type 2 (P > 0.05) and in hyperintensity on T2-weighted images in 41 (62%) of 66 and in 15 (83.4%) of 18, respectively (P > 0.05). Lesions were hypovascular in 64 (97%) of 66 cases in type 1 and in 16 (88.9%) of 18 in type 2 with delayed contrast retention in 56 (84.8%) of 66 and in 17 (94.5%) of 18, respectively (P > 0.05). Autoimmune cholangitis was found in 29 (43.9%) of 66 patients with type 1 and in 3 (16.7%) of 18 with type 2 (P = 0.02); renal involvement was observed in 20 (30.3%) of 66 and 1 (5.5%) of 18, respectively (P = 0.02). Both subtypes presented with multiple stenoses (P > 0.05). Dilation of upstream duct was more frequent in type 1 (P = 0.02). CONCLUSIONS: Magnetic resonance imaging is useful in detecting extrapancreatic involvement, typically seen in type 1. Dilation of the upstream duct suggests type 1 AIP.

Surgery after FOLFIRINOX treatment for locally advanced and borderline resectable pancreatic cancer: increase in tumour attenuation on CT correlates with R0 resection.

OBJECTIVES: To assess factors associated with radical resection (R0) of pancreatic ductal adenocarcinoma (PDAC) after induction treatment with FOLFIRINOX. METHODS: Patients with either locally advanced (LA) and borderline resectable (BR) PDAC undergoing surgical exploration after FOLFIRINOX were retrospectively enrolled. Two pancreatic radiologists reviewed the CT blinded to the final outcome and assessed chemotherapy response and resectability. Patients were then divided into R0 resected (group A) and not resected/R1 resected (group B), which were compared. RESULTS: Of 59 patients included, 19 were defined as unresectable (32%), 33 borderline resectable (56%) and 7 resectable (12%) during the blind radiological evaluation after FOLFIRINOX. Once in a surgical setting, 27% were non-resectable, whereas 73% received surgical resection with a 70% R0 rate. Consequent sensitivity and specificity were 86% and 29%. At imaging review, significant decreases in longest tumour dimension were observed in both groups: from 32 mm (95% CI 15-55) to 21 (10-44) in group A and from 34 (18-70) to 26 (7-60) in group B, p < 0.05. However, a significant increase in tumour attenuation in all phases was only observed for R0 resected, from 52 HU (26-75) to 65 (35-92) in arterial phase (p < 0.001) and from 62 (36-96) to 78 (40-120) in the venous (p = 0.001). CONCLUSION: After neoadjuvant FOLFIRINOX, CT predicted resectability with acceptable sensitivity but low specificity. The observation of increased tumour attenuation at CT scan after FOLFIRINOX treatment might represent a reliable predictor of R0 resection. KEY POINTS: • CT drives the assessment of PDAC resectability after FOLFIRINOX • CT predicts resectability with acceptable sensitivity but low specificity • Significant increase in tumour attenuation was only observed for R0 resected PDAC • Tumour attenuation after FOLFIRINOX represents a reliable predictor of R0 resection.

Paraduodenal pancreatitis as a mimicker of pancreatic adenocarcinoma: MRI evaluation.

PURPOSE: To evaluate the MRI features of paraduodenal pancreatitis (PDP) and to define useful signs to differentiate PDP from pancreatic ductal adenocarcinoma (PDAC). MATERIAL AND METHODS: We reviewed the MRI scans of 56 patients, 28 affected by PDP and 28 by PDAC, all pathologically proven. The following parameters were evaluated: signal intensity of the lesion on T1-, T2-WI, DWI (b800) and after contrast medium administration; presence of cysts; dilation of common hepatic duct and main pancreatic duct; focal thickening of the second portion of the duodenum; maximum diameter and volume of the lesion. RESULTS: Both PDPs and PDACs were more frequently hypointense on T1-WI, iso-hyperintense on T2-WI, hypointense in the pancreatic phase and iso-hypointense in the venous phase (p>0.05); in the delayed phase most PDP were hyperintense (p=0.0031); on DWI 71.4% PDPs were isointense and all PDACs were hyperintense (p=0.0041). Cystic components were present in 85.7% PDPs (p=0.0011); double duct sign was present in 50% PDACs (p=0.0048); focal thickening of the duodenum was depicted in 89.3 PDPs (p=0.0012). PDPs were larger than PDACs (p=0.0003). CONCLUSION: The most suggestive signs of PDP are: signal hyperintensity in the delayed phase, isointensity on DWI, presence of cysts, focal thickening of the duodenum and large size of the lesion.

Clinical and Morphological Features of Paraduodenal Pancreatitis: An Italian Experience With 120 Patients.

OBJECTIVES: This study aimed to evaluate the clinical and radiological features and clinical outcomes of paraduodenal pancreatitis (PP). METHODS: A final diagnosis of PP was based on surgical specimens in resected patients and on imaging in nonoperated patients. Clinical, radiological, and pathological data were collected and reevaluated. RESULTS: We studied 120 patients, 97.5% of whom were drinkers and 97.5% were smokers. Symptoms at clinical onset were acute pancreatitis in 78 patients (65%) and continuous pain in 68 patients (55.8%). Other symptoms were vomiting (36.7%), weight loss (25.8%), and jaundice (11.7%). Cystic variant was diagnosed in 82 patients (68.0%), and solid variant was diagnosed in 38 patients (32.0%). Pure and diffuse forms were observed in 22 (18.3%) and 98 (81.7%) patients, respectively. Pancreatic calcifications were present at clinical onset in 5.0% of the patients and in 61.0% at the end of follow-up. Somatostatin analogs were used in 13 patients (10.8%), and 81 patients (67.0%) underwent surgery. CONCLUSIONS: The clinical profile of PP was found to be middle-aged men who were heavy drinkers and smokers with painful pancreatitis and was associated with vomiting and weight loss. In nonresponders, alcohol withdrawal and medical therapy can be proposed as a first-line treatment, and surgery as a second-line treatment.

Pancreatic duct stenosis: Differential diagnosis between malignant and benign conditions at secretin-enhanced MRCP.

PURPOSE: To define imaging criteria of benign and malignant nature in patients with main pancreatic duct (MPD) stenosis. MATERIALS-METHODS: S-MRCPs of 35 patients with pancreatitis and 14 with adenocarcinoma were evaluated. RESULTS: Adenocarcinoma caused higher prevalence of complete stenosis (14/14-100% vs 17/35-49%), dilated side-branches (14/14-100% vs 18/35-51%) and lower prevalence of duct-penetrating sign (0/14-0% vs 31/35-89%). The number of stenoses was higher in benign conditions (mean 1.4 Vs 1). Upstream MPD diameter was higher in cancer-induced stenoses (4.5 vs 2.9mm). CONCLUSIONS: Single complete stenosis with dilated side branches, increased MPD caliber and absent duct-penetrating sign are suggestive of malignancy.

Santorinicele: secretin-enhanced magnetic resonance cholangiopancreatography findings before and after minor papilla sphincterotomy.

OBJECTIVES: To evaluate secretin-enhanced MRCP (S-MRCP) findings of patients with pancreas divisum and Santorinicele, before and after minor papilla sphincterotomy. METHODS: S-MRCP examinations of 519 patients with suspected pancreatic disease were included. Size of the main pancreatic duct, presence and calibre of Santorinicele were evaluated. Duodenal filling was assessed on dynamic images. After sphincterotomy the same parameters and the clinical findings were re-evaluated. RESULTS: Pancreas divisum was depicted in 55/519 patients (11 %) by MRCP and an additional 26/519 by S-MRCP (total 81/519, 16 %). Santorinicele was detected in 7/81 patients (8.6 %) with pancreas divisum by MRCP and an additional 20/81 by S-MRCP (total 27/81, 33 %). Dorsal duct in patients with Santorinicele was significantly larger in the head compared with patients with only pancreas divisum (p < 0.01), in basal conditions (average 2.4 versus 1.9 mm) and after secretin administration (average 3.0 versus 2.4 mm). Duodenal filling was impaired in 11/27 patients (41 %) with Santorinicele. After sphincterotomy significant reduction in size of Santorinicele (-33 %) and dorsal duct (-17 %), increase of pancreatic juice and symptoms improvement were observed. CONCLUSION: Secretin administration increases the accuracy of MRCP in detecting Santorinicele and demonstrates the impaired duodenal filling. S-MRCP is useful to assess results of sphincterotomy. KEY POINTS: • Secretin-enhanced MRCP gives anatomical and functional information on pancreatic outflow dynamics. • Santorinicele is a cystic dilatation of the termination of the Santorini duct. • S-MRCP images are the most useful to recognize the presence of Santorinicele. • Minor papilla sphincterotomy during ERCP is indicated in patients with Santorinicele.

Pancreatic duct abnormalities in focal autoimmune pancreatitis: MR/MRCP imaging findings.

AIM: To evaluate the magnetic resonance (MR) imaging-MR cholangiopancreatographic (MRCP) findings of focal forms of autoimmune pancreatitis (AIP) to describe ductal involvement at diagnosis. METHODS: MR examinations of 123 patients affected by AIP were analysed. We included 26 patients who satisfied International Consensus Diagnostic Criteria and were suffering from focal AIP. Image analysis included: site of parenchymal enlargement, main pancreatic duct (MPD) diameter, MPD stenosis, stricture length, presence of upstream dilation within the stricture, signal intensity, and pancreatic enhancement. RESULTS: Signal intensity abnormalities were localized in the head in 10/26 (38.5%) and in the body-tail in 16/26 (61.5%) patients. MRCP showed a single MPD stenosis in 12/26 (46.1%) and multiple MPD stenosis in 14/26 (53.8%) patients, without a dilation of the upstream MPD (mean: 3.83 mm). Lesions showed hypointensity on T1-weighted images in all patients, and hyperintensity on T2-weighted images in 22/26 (84.6%) patients. The affected parenchyma was hypovascular during the arterial phase in 25/26 (96.2%) patients with contrast retention. CONCLUSIONS: MR-MRCP are effective techniques for the diagnosis of AIP showing the loss of the physiological lobulation and the typical contrastographic appearance. The presence of multiple, long stenoses without an upstream MPD dilation at MRCP suggests the diagnosis of AIP, and can be useful in differential diagnosis of pancreatic adenocarcinoma. KEY POINTS: • MRI represents the gold standard in the diagnosis of AIP. • MRCP is an increasingly useful technique in the diagnosis of focal AIP. • MRCP could be a problem-solving tool in the differential diagnosis of AIP.

MRI features of solid pseudopapillary neoplasm of the pancreas.

PURPOSE: To evaluate the magnetic resonance imaging (MRI) findings of solid pseudopapillary neoplasm (SPN) of the pancreas. METHODS AND MATERIALS: From January 2006 to December 2013, 41 patients with SPN of the pancreas were retrospectively evaluated. Inclusion criteria were the execution of an MR examination and tumor resection with an histopathological evaluation at our Institute. Exclusion criteria were the execution of an MR examination at other centers (14/41) and the execution of CT or ultrasonography (10/41) at our Institute. The qualitative analysis evaluated: location (head/body-tail), shape (round/oval/lobulated), margins (regular/irregular), and signal intensity on T1- and T2-weighted images compared to the surrounding pancreas (hypo-, iso-, or hyperintense and homogeneous or heterogeneous), appearance of MPD and the secondary ducts, and the presence of metastases and/or vascular involvement. The quantitative analysis included: maximum size of the lesion, wall thickness, and maximum diameter of the main pancreatic duct (MPD). RESULTS: The population comprised 17 women (median age: 31 year) with a median tumor size of 50.6 mm, a median wall thickness of 2 mm and median diameter of the MPD of 1.8 mm. 9/17 were at the head; 8/17 on the body/tail: respectively, 8/17 round, 6/17 oval, and 3/17 lobulated. All showed regular margins. On T1-weighted images 8/17 appeared homogeneously hypointense, 7/17 heterogeneously hypointense, and 2/17 heterogeneously hyperintense. On T2-weighted images 1/17 appeared homogeneously hyperintense and 16/17 heterogeneously hyperintense. No secondary ducts dilatations were detected. During the follow-up, one patient presented disease recurrence 48 months after surgery. CONCLUSIONS: MR imaging features can be highly suggestive for the diagnosis of SPN.

Retrospective comparison between preoperative diagnosis by International Consensus Diagnostic Criteria and histological diagnosis in patients with focal autoimmune pancreatitis who underwent surgery with suspicion of cancer.

OBJECTIVE: The objective of this study was to compare the preoperative diagnosis by International Consensus Diagnostic Criteria (ICDC) with histological diagnosis in patients with focal autoimmune pancreatitis (AIP) who underwent surgery. METHODS: Thirty patients (type 1 AIP in 23 and type 2 AIP in 7) with a diagnosis of AIP based on histology of surgical specimens were classified according to ICDC based on their preoperative data. RESULTS: Pancreatic core biopsies and diagnostic steroid trial were not preoperatively performed in any of the patients. Based on preoperative data, ICDC diagnosed 6 patients (20%) as having type 1 AIP and 24 (80%) as probable AIP. Assuming all patients had responded to a steroid trial preoperatively, ICDC would have diagnosed 8 patients (27%) as having type 1 AIP, 4 (13%) as type 2 AIP, 10 as AIP-not otherwise specified (33%), and 8 (27%) as probable AIP. In the hypothetical situation, 7 of 8 type 1 AIP patients and 3 of 3 type 2 AIP patients would have been classified into the correct subtype of AIP. CONCLUSIONS: A steroid trial enhances the possibility of correctly diagnosing AIP by ICDC despite the lack of histology. However, some patients cannot be diagnosed as having AIP or be classified into the correct subtype without histology.

Multifocal branch-duct intraductal papillary mucinous neoplasms (IPMNs) of the pancreas: magnetic resonance (MR) imaging pattern and evolution over time.

PURPOSE: The aim of our study was to follow the evolution over time of multifocal intraductal papillary mucinous neoplasms (IPMN) of the pancreatic duct side branches by means of magnetic resonance imaging (MRI). MATERIALS AND METHODS: A total of 155 patients with multifocal IPMN of the side branches were examined with MRI and MR cholangiopancreatography (MRI/MRCP). Inclusion criteria were patients with ≥2 dilated side branches involving any site of the parenchyma; presence of communication with the main pancreatic duct and previous investigations by MRI/MRCP within at least six months. Median follow-up was 25.8 months (range, 12-217). Patients with a follow-up period shorter than 12 months (n=33) and those with a diagnosis of multifocal IPMN of the side branches without any follow-up (n=14) were excluded from the study. The final study population thus comprised 108 patients. A double, quantitative and qualitative, analysis was carried out. The quantitative image analysis included: number of dilated side branches in the head-uncinate process and body-tail; maximum diameter of lesions in the head-uncinate process; maximum diameter in the body-tail; maximum diameter of the main pancreatic duct in the head and body-tail. The qualitative image analysis included: presence of malformations or anatomical variants of the pancreatic ductal system; site of the lesions (head-uncinate process, body-tail, ubiquitous, bridge morphology); presence of gravity-dependent intraluminal filling defects; presence of enhancing mural nodules. RESULTS: At diagnosis, the mean number of cystic lesions of the side branches was 7.09. The mean diameter of the cystic lesions was 13.7 mm. The mean diameter of the main pancreatic duct was 3.6 mm. At follow-up, the mean number of cystic lesions was 7.76. The mean diameter of the cystic lesions was 13.9 mm. The mean diameter of the main pancreatic duct was 3.7 mm. Intraluminal filling defects in the side branches were seen in 18/108 patients (16.6%); enhancing mural nodules were seen in 3/108 patients (2.7%). CONCLUSIONS: Multifocal IPMN of the branch ducts shows a very slow growth and evolution over time. In our study, only 3/108 patients showed mural nodules which, however, did not require any surgical procedure, indicating that careful nonoperative management may be safe and effective in asymptomatic patients.

Application of international consensus diagnostic criteria to an Italian series of autoimmune pancreatitis.

BACKGROUND: International consensus diagnostic criteria (ICDC) have been proposed to classify autoimmune pancreatitis (AIP) in type 1, type 2, or not otherwise specified. OBJECTIVE: Aim was to apply the ICDC to an Italian series of patients to evaluate the incidence and clinical profiles among different subtypes of AIP. METHODS: we re-evaluated and classified 92 patients diagnosed by Verona criteria, according to the ICDC. RESULTS: Out of 92 patients, 59 (64%) were diagnosed as type 1, 17 (18%) as type 2, and 15 (16%) as not otherwise specified according to the ICDC. A significant difference between type 1 and type 2 were found for age (54.5 ± 14.5 vs. 34.4 ± 13.9 respectively; p < 0.0001), male sex (76 vs. 47%; p = 0.007), jaundice (66 vs. 18%; p = 0.002) and acute pancreatitis (9 vs. 47%; p < 0.0001), elevated serum IgG4 levels (85 vs. 7%; p < 0.0001), inflammatory bowel disease (8 vs. 82%; < 0.0001), and relapse of the disease (34 vs. 6%; p = 0.058). Imaging and response to steroids in the not-otherwise-specified group were similar to type 1 and 2. CONCLUSIONS: Type 1 has a different clinical profile from type 2 autoimmune pancreatitis. The not-otherwise-specified group has peculiar clinical features which are shared both with type 1 or type 2 groups.