Andrea Ardizzoni

(11)C-Choline PET/CT in castration-resistant prostate cancer patients treated with docetaxel.

PurposeTo investigate the role of 11C-choline PET/CT for evaluating the response to treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel in comparison with PSA response.MethodsInclusion criteria were (a) proven mCRPC, (b) docetaxel as first line of chemotherapy (docetaxel 75xa0mg/m2 + prednisone 5xa0mg), and (c) 11C-choline PET/CT and PSA values assessed before and after docetaxel administration. A total of 61 patients were retrospectively enrolled (mean age 68.9 years, range 57xa0–xa084 years). 11C-Choline PET/CT was performed at baseline before docetaxel treatment (PET1) and after the end of treatment (PET2). PSA values were measured before treatment (PSA1) and after treatment (PSA2). PET2 was reported as complete response (CR), partial response (PR) or stable disease (SD). Progressive disease (PD) was considered if a new lesion was seen. PSA trend was calculated from the change in absolute values between PSA1 and PSA2. A decrease of ≥50xa0% between PSA1 and PSA2 was considered a PSA response. Clinical, radiological and laboratory follow-up ranged from 6 to 53xa0months (mean 13.5xa0months).ResultsOf the 61 patients, 40 (65.5xa0%) showed PD on PET2, 13 (21.3xa0%) showed SD, 2 (3.4xa0%) showed PR, and 6 (9.8xa0%) showed CR. An increasing PSA trend was seen in 29 patients (47.5xa0%) and a decreasing PSA trend in 32 patients (52.5xa0%). A PSA response of ≥50xa0% was seen in 25 patients (41xa0%). Radiological PD was seen in 23 of the 29 patients (79.3xa0%) with an increasing PSA trend, in 16 of the 32 patients (50xa0%) with a decreasing PSA trend, and in 11 of the 25 patients (44xa0%) with a PSA response of ≥50xa0%. In the multivariate statistical analysis, the presence of more than ten bone lesions detected on PET1 was significantly associated with an increased probability of PD on PET2. No association was observed between PSA level and PD on PET2.ConclusionOur results suggest that an increasing PSA trend measured after docetaxel treatment could be considered predictive of PD. In patients with decreasing PSA values (decreasing PSA trend and a PSA response of ≥50xa0%), 11C-choline PET/CT may be useful to identify those with radiological progression despite a PSA response. Finally, the tumour burden, expressed as number of bone lesions on PET1, is significantly associated with an increased probability of PD on PET2.

(11)C-Choline PET/CT for restaging prostate cancer. Results from 4,426 scans in a single-centre patient series.

PurposeTo evaluate 11C-choline PET/CT as a diagnostic tool for restaging prostate cancer (PCa), in a large, homogeneous and clinically relevant population of patients with biochemical recurrence (BCR) of PCa after primary therapy. The secondary aim was to assess the best timing for performing 11C-choline PET/CT during BCR.MethodsWe retrospectively analysed 9,632 11C-choline PET/CT scans performed in our institution for restaging PCa from January 2007 to June 2015. The inclusion criteria were: (1) proven PCa radically treated with radical prostatectomy (RP) or with primary external beam radiotherapy (EBRT); (2) PSA serum values available; (3) proven BCR (PSA >0.2xa0ng/mL after RP or PSA >2xa0ng/mL above the nadir after primary EBRT with rising PSA levels). Finally, 3,203 patients with recurrent PCa matching all the inclusion criteria were retrospectively enrolled and 4,426 scans were analysed.ResultsOverall, 52.8xa0% of the 11C-choline PET/CT scans (2,337/4,426) and 54.8xa0% of the patients (1,755/3,203) were positive. In 29.4xa0% of the scans, at least one distant finding was observed. The mean and median PSA values were, respectively, 4.9 and 2.1xa0ng/mL at the time of the scan (range 0.2xa0–xa050xa0ng/mL). In our series, 995 scans were performed in patients with PSA levels between 1 and 2xa0ng/mL. In this subpopulation the positivity rate in the 995 scans was 44.7xa0%, with an incidence of distant findings of 19.2xa0% and an incidence of oligometastatic disease (one to three lesions) of 37.7xa0%. The absolute PSA value at the time of the scan and ongoing androgen deprivation therapy were associated with an increased probability of a positive 11C-choline PET/CT scan (pu2009<u20090.0001). In the ROC analysis, a PSA value of 1.16xa0ng/mL was the optimal cut-off value. In patients with a PSA value <1.16xa0ng/mL, 26.8xa0% of 1,426 11C-choline PET/CT scans were positive, with oligometastatic disease in 84.7xa0% of positive scans.ConclusionIn a large cohort of patients, the feasibility of 11C-choline PET/CT for detecting the sites of metastatic disease in PCa patients with BCR was confirmed. The PSA level was the main predictor of a positive scan with 1.16xa0ng/mL as the optimal cut-off value. In the majority of positive scans oligometastatic disease, potentially treatable with salvage therapies, was observed.

Contribution of KRAS mutations and c.2369C > T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA.

Introduction KRAS oncogene mutations (MUTKRAS) drive resistance to EGFR inhibition by providing alternative signaling as demonstrated in colo-rectal cancer. In non-small cell lung cancer (NSCLC), the efficacy of treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) depends on activating EGFR mutations (MUTEGFR). However, inhibition of EGFR may select resistant cells displaying alternative signaling, i.e., KRAS, or restoration of EGFR activity due to additional MUTEGFR, i.e., the c.2369C > T (p.T790MEGFR). Aim The aim of this study was to investigate the appearance of MUTKRAS during EGFR-TKI treatment and their contribution to drug resistance. Methods This study used cell-free circulating tumor DNA (cftDNA) to evaluate the appearance of codon 12 MUTKRAS and p.T790MEGFR mutations in 33 advanced NSCLC patients progressing after an EGFR-TKI. Results p.T790MEGFR was detected in 11 (33.3%) patients, MUTKRAS at codon 12 in 3 (9.1%) while both p.T790MEGFR and MUTKRAS codon 12 were found in 13 (39.4%) patients. Six patients (18.2%) were KRAS wild-type (WTKRAS) and negative for p.T790MEGFR. In 8 subjects paired tumor re-biopsy/plasma samples were available; the percent concordance of tissue/plasma was 62.5% for p.T790MEGFR and 37.5% for MUTKRAS. The analysis of time to progression (TTP) and overall survival (OS) in WTKRAS vs. MUTKRAS were not statistically different, even if there was a better survival with WTKRAS vs. MUTKRAS, i.e., TTP 14.4 vs. 11.4 months (p = 0.97) and OS 40.2 vs. 35.0 months (p = 0.56), respectively. Conclusions MUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance.

Enhancement of the anti-tumor activity of FGFR1 inhibition in squamous cell lung cancer by targeting downstream signaling involved in glucose metabolism

Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated in clinical setting. We determined whether targeting downstream signaling implicated in FGFR1 effects on glucose metabolism potentiates the anti-tumor activity of FGFR1 inhibition in SQCLC. In FGFR1 amplified/over-expressing SQCLC cell lines, FGF2-mediated stimulation of FGFR1 under serum-deprivation activated both MAPK and AKT/mTOR pathways and increased glucose uptake, glycolysis, and lactate production, through AKT/mTOR-dependent HIF-1α accumulation and up-regulation of GLUT-1 glucose transporter. These effects were hindered by PD173074 and NVP-BGJ398, selective FGFR inhibitors, as well as by dovitinib, a multi-kinase inhibitor. Glucose metabolism was hampered by the FGFR inhibitors also under hypoxic conditions, with consequent inhibition of cell proliferation and viability. In presence of serum, glucose metabolism was impaired only in cell models in which FGFR1 inhibition was associated with AKT/mTOR down-regulation. When the activation of the AKT/mTOR pathway persisted despite FGFR1 down-regulation, the efficacy of NVP-BGJ398 could be significantly improved by the combination with NVP-BEZ235 or other inhibitors of this signaling cascade, both in vitro and in xenotransplanted nude mice. Collectively our results indicate that inhibition of FGFR1 signaling impacts on cancer cell growth also by affecting glucose energy metabolism. In addition, this study strongly suggests that the therapeutic efficacy of FGFR1 targeting molecules in SQCLC may be implemented by combined treatments tackling on glucose metabolism.Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated in clinical setting. We determined whether targeting downstream signaling implicated in FGFR1 effects on glucose metabolism potentiates the anti-tumor activity of FGFR1 inhibition in SQCLC. In FGFR1 amplified/over-expressing SQCLC cell lines, FGF2-mediated stimulation of FGFR1 under serum-deprivation activated both MAPK and AKT/mTOR pathways and increased glucose uptake, glycolysis, and lactate production, through AKT/mTOR-dependent HIF-1α accumulation and up-regulation of GLUT-1 glucose transporter. These effects were hindered by PD173074 and NVP-BGJ398, selective FGFR inhibitors, as well as by dovitinib, a multi-kinase inhibitor. Glucose metabolism was hampered by the FGFR inhibitors also under hypoxic conditions, with consequent inhibition of cell proliferation and viability. In presence of serum, glucose metabolism was impaired only in cell models in which FGFR1 inhibition was associated with AKT/mTOR down-regulation. When the activation of the AKT/mTOR pathway persisted despite FGFR1 down-regulation, the efficacy of NVP-BGJ398 could be significantly improved by the combination with NVP-BEZ235 or other inhibitors of this signaling cascade, both in vitro and in xenotransplanted nude mice. Collectively our results indicate that inhibition of FGFR1 signaling impacts on cancer cell growth also by affecting glucose energy metabolism. In addition, this study strongly suggests that the therapeutic efficacy of FGFR1 targeting molecules in SQCLC may be implemented by combined treatments tackling on glucose metabolism.

Clinical outcome of patients who reduced sunitinib or pazopanib during first-line treatment for advanced kidney cancer

OBJECTIVESnTo investigate the different outcomes in patients with metastatic renal cell carcinoma (mRCC) who receive a reduced first-line dose of sunitinib or pazopanib compared to those who continue at the standard dose.nnnPATIENTS AND METHODSnAll the patients treated in 11 oncological centers in Italy for mRCC who started first-line treatment with sunitinib or pazopanib at the standard dose. Descriptive statistical tests were used to highlight differences among groups. Survival was estimated by the Kaplan-Meier method and compared across the groups using log-rank tests, the Cox proportional hazards model adjusted for statistically significant variables was also done.nnnRESULTSnA total of 591 patients were included in the study. Of these, 45.7% received a reduced dose of sunitinib or pazopanib after a median treatment time of 3.6 months at the standard dose. The median overall survival in the patients who continued to receive the standard dose was 24.0 months compared to 49.4 months for those who received a reduced dose (hazard ratio = 1.80; 95% CI: 1.42-2.29; P<0.001). Only 45% of the patients received second-line therapy: 42.5% had an mTOR and 54.1% a tyrosine kinase inhibitor. Second-line overall survival was 19.8 and 11.8 months, respectively, in the patients who received, or did not, a reduced dose during first-line therapy (P = 0.007).nnnCONCLUSIONSnToxicity-related dose reduction is a common event in mRCC patients who have started first-line therapy with either sunitinib or pazopanib. This is positively related to the outcomes of both first- and second-line therapy.

A case of nivolumab-related cholangitis and literature review: how to look for the right tools for a correct diagnosis of this rare immune-related adverse event

SummaryAnti-programmed cell death-1 (PD-1) monoclonal antibodies, such as nivolumab, used for the treatment of several tumors, can trigger effector T-cells against tumor- and self-antigens, leading to the occurrence of different immune-related adverse events. Among them, liver injuries are rare and usually transient. To date, only four cases of immune-related cholangitis in non-small cell lung cancer (NSCLC) patients have been described during nivolumab treatment. Here, we describe laboratory tests, imaging and liver biopsy features that confirm this diagnosis as opposed to other forms of autoimmune liver disease; nevertheless, we also provide evidence of the presence of different clinical-pathological patterns of immune-related cholangitis.

Circulating tumor cells in genitourinary tumors

Management of advanced urogenital malignancies has profoundly changed in recent years due to the development of novel targeted drugs that have significantly improved patient’s clinical outcomes. This process has been made possible mainly thanks to better knowledge of tumor genetic alterations and molecular altered pathways. Despite these remarkable results, several issues such as early detection of the disease as well as the research into early markers of recurrence or disease progression still remain an open challenge for clinical research. The detection of circulating tumor cells and circulating DNA appears an attractive option since it is a minimally invasive approach potentially able to allow clinicians an accurate diagnosis and maybe lead to more customized treatment strategies. This review focuses on the current techniques adopted for the detection and isolation of circulating tumor cells in genitourinary tumors highlighting their present and possible future application in clinical practice.

The Tumor Entity Denominated “clear cell-papillary renal cell carcinoma” According to the WHO 2016 new Classification, have the Clinical Characters of a Renal Cell Adenoma as does Harbor a Benign Outcome

The new WHO 2016 classification of renal neoplasia encounters the new entity called “clear cell papillary renal cell carcinoma” (ccpRCC). The ccpRCC has been long included as a subtype of clear cell RCC histotype and it actually ranges from 2 to 9% in different routinely available cohort of renal carcinomas. Of important note, ccpRCC does not show any recurrences or metastases or lymph-node invasion and the outcome is always good. We reviewed twenty-four publications with available follow-up for patients (no. 362) affected by clear cell papillary RCCs/renal adenomatoid tumours and notably ccpRCC harbors an indolent clinical behavior after a mean of 38xa0months (3,5xa0years) of follow-up. This paper reviews the histological, molecular and clinical features characterizing ccpRCC, with the goal of focusing the knowledge of the benign fashion of this new tumour entity, supporting the idea of a new renal cell adenoma recruited morphologically from ex conventional clear cell RCC tumours.

Immune-mediated cholangitis: is it always nivolumab’s fault?

We read with much interest the article published by Kashima and colleagues on “Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small cell lung cancer: a case report” [1]. Immune-related AEs (irAEs) affecting the biliary system on treatment with immune-oncology (I-O) agents, such PD-1/PD-L1 mAbs, are considered rare and their management remains unclear. Recently, four cases of nivolumab-related cholangitis have been reported in the literature, including three cases of “large-duct cholangitis” [2] and one case of “small-duct cholangitis” [3]. None of the patients had a history of autoimmune disorders or IgG4-related disease and all showed a predominant elevation of alkaline phosphatase and gammaglutamyltranspeptidase enzymes. The three Japanese patients with “large-duct cholangitis” developed an extensive extrahepatic biliary tract dilation without obstruction that progressed during drug administration. However, a diagnosis of primitive sclerosing cholangitis could not be definitively ruled out due to lack of data on perinuclear antineutrophil cytoplasmic antibodies (pANCA). Our case referred to as “small-duct cholangitis” did not show either intrahepatic or extrahepatic bile duct dilation and a complete serological autoimmune panel excluded any other diagnosis. However, histological findings on liver biopsies were similar in all four cases reporting a significant T cell infiltrate with a predominant CD8-positive cluster. We first speculated on the presence of different patterns of nivolumab-related cholangitis. In our opinion, the case described by Kashima and colleagues presents several aspects that differ from those previously reported (Table 1) and make a diagnosis of nivolumab-related cholangitis unlikely. Radiological imaging from a 64-year-old Japanese patient who received nivolumab for the treatment of advanced NSCLC was suggestive of cholecystitis without gallstones associated with an obstruction at the lower tract of the common bile duct. A significant rise in cholestatic enzymes and clinical symptoms also supported this diagnosis. Initially, the patient underwent several endoscopic procedures and was given empirical antibiotic therapy. Later, he presented with fever and bacteria were isolated from bile cultures. After antibiotic therapy, liver function tests initially improved, but later a new deterioration in biliary enzyme levels occurred. The authors then assumed that this event was to be considered as an immune-related toxicity and the patient was treated with high doses of corticosteroid. There was a rapid improvement in biliary enzyme levels and subsequent normalization of radiological imaging over the following months. The patient provided several bile duct biopsies/cytological smears at three different time points. The histological findings were always consistent with the presence of interstitial fibrosis and neutrophil infiltration into the bile duct. These findings were different from those reported in the other cases of immunotherapy-related cholangitis in which a CD8-positive T cell infiltrate into the liver was predominant. Furthermore, histological evidence of fibrosis would suggest a chronic disease, while the presence of a neutrophil infiltrate, associated with the detection of positive bile cultures, could be more consistent with a diagnosis of infectious disease. Finally, the presence of fibrosis and the lack of any information on serum IgG4 and pANCA levels do not rule out other forms of classic autoimmune cholangitis, such as IgG4-related disease and primitive sclerosing cholangitis. Several reports of IgG4-related disease have been described in the Japanese population, all with an excellent response to corticosteroids, as for the reported case with regression of bile strictures. This comment refers to the article available at https ://doi. org/10.1007/s0026 2-017-2062-3

Liver metastases from prostate cancer at 11C-Choline PET/CT: a multicenter, retrospective analysis

AimDuring our daily clinical practice using 11C-Choline PET/CT for restaging patients affected by relapsing prostate cancer (rPCa) we noticed an unusual but significant occurrence of hypodense hepatic lesions with a different tracer uptake. Thus, we decided to evaluate the possible correlation between rPCa and these lesions as possible hepatic metastases.Materials and methodsWe retrospectively enrolled 542 patients diagnosed with rPCa in biochemical relapse after a radical treatment (surgery and/or radiotherapy). Among these, patients with a second tumor or other benign hepatic diseases were excluded. All patients underwent 11C-Choline PET/CT during the standard restaging workup of their disease. We analyzed CT images to evaluate the presence of hypodense lesions and PET images to identify the relative tracer uptake. In accordance to the subsequent oncological history, five clinical scenarios were recognized [Table 1]: normal low dose CT (ldCT) and normal tracer distribution (Group A); evidence of previously unknown hepatic round hypodense areas at ldCT with normal rim uptake (Group B); evidence of previously known hepatic round hypodense areas at ldCT stable over time and with normal rim uptake (Group C); evidence of previously known hepatic round hypodense areas at ldCT, in a previous PET/CT scan, with or without rim uptake and significantly changing over time in terms of size and/or uptake (Group D); evidence of hepatic round hypodense areas at ldCT with or without rim uptake confirmed as prostate liver metastases by histopathology, triple phase ceCT, ce-ultra sound (CEUS) and clinical/biochemical evaluation (Group E). We evaluated the correlation with PSA level at time of scan, rim SUVmax and association with local relapse or non-hepatic metastases (lymph nodes, bone, other parenchyma).ResultsFive hundred and forty-two consecutive patients were retrospectively enrolled. In 140 of the 542 patients more than one 11C-choline PET/CT had been performed. A total of 742 11C-Choline PET/CT scans were analyzed. Of the 542 patients enrolled, 456 (84.1%) had a normal appearance of the liver both at ldCT and PET (Group A). 19/542 (3,5%) belonged to Group B, 13/542 (2.4%) to Group C, 37/542 (6.8%) to Group D and 18/542 (3.3%) to Group E. Mean SUVmax of the rim was: 4.5 for Group B; 4.2 for Group C; 4.8 for Group D; 5.9 for Group E. Mean PSA level was 5.27 for Group A, 7.9 for Group B, 10.04 for Group C, 10.01 for Group D, 9.36 for Group E. Presence of positive findings at 11C-Choline PET/CT in any further anatomical area (local relapse, lymph node, bone, other extra hepatic sites) correlated with an higher PSA (pu2009=u20090.0285). In both the univariate and multivariate binary logistic regression analyses. PSA, SUVmax of the rim, local relapse, positive nodes were not associated to liver mets (Groups D-E) (pu2009>u20090.05). On the contrary, a significant correlation was found between the presence of liver metG (group D-E) and bone lesions (p= 0.00193).ConclusionOur results indicate that liver metastases in relapsing prostate cancer may occur frequently. The real incidence evaluation needs more investigations. In this case and despite technical limitations, Choline PET/CT shows alterations of tracer distribution within the liver that could eventually be mistaken for simple cysts but can be suspected when associated to high trigger PSA, concomitant bone lesions or modification over time. In this clinical setting an accurate analysis of liver tracer distribution (increased or decreased uptake) by the nuclear medicine physician is, therefore, mandatory.