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PURPOSE Biomarkers for treatment personalization in metastatic castration-resistant prostate cancer (mCRPC) could help improve patient outcomes. Multiple tests on blood have reported associations with poorer outcome, including serum lactate dehydrogenase (LDH), chromogranin A (CGA), neutrophil:lymphocyte ratio (NLR), and, recently, copy number (CN) of androgen receptor (AR) in plasma DNA. Biologic data suggest an association between choline uptake and AR signaling. We aimed to integrate 18F-fluorocholine (FCH) uptake on positron emission tomography/computed tomography (PET/CT) scanning with plasma AR CN and other routinely obtained circulating biomarkers to evaluate their association with outcome. MATERIALS AND METHODS We determined plasma AR CN by digital droplet polymerase chain reaction from 105 mCRPC samples collected before abiraterone (n = 65) or enzalutamide (n = 40) therapy in the before (n = 26) and after (n = 79) chemotherapy settings. Pretreatment serum LDH, CGA, and NLR were also measured. FCH-PET/CT scan was performed at baseline, and maximum standardized uptake value (SUVmax), total lesion activity (TLA), and metabolic tumor volume (MTV) were calculated. Main end points were the correlation of FCH-PET/CT parameters with circulating biomarkers and their impact on outcome. RESULTS Plasma AR CN gain was observed in 27 patients (25.7%), and it correlated significantly with higher median SUVmax, TLA, and MTV values ( P < .001). Kaplan-Meier curves showed significantly worse progression-free survival and overall survival in patients with plasma AR gain and higher SUVmax, TLA, and MTV values ( P < .001 in each prognostic group). Conversely, no association was reported for prostate-specific antigen response. On multivariable analysis of overall survival, we showed as independent factors AR gain (hazard ratio [HR], 1.92; 95% CI, 1.07 to 3.47; P = .029), presence of visceral metastasis (HR, 3.04; 95% CI, 1.66 to 5.58; P = < .001), LDH (HR, 2.95; 95% CI, 1.72 to 5.05; P < .001), NLR (HR, 3.51; 95% CI, 2.14 to 5.74; P < .001), serum CGA (HR, 3.36; 95% CI, 1.99 to 5.67; P < .001), and MTV (HR, 2.09; 95% CI, 1.25 to 3.50; P = .005). CONCLUSION Our results indicate the potential usefulness of integrating functional imaging with plasma DNA analysis and other noninvasive biomarkers as a tool to improve treatment selection for CRPC. A larger prospective evaluation is warranted.

Given a complex analytic germ $(X, 0)$ in $(\mathbb C^n, 0)$, the standard Hermitian metric of $\mathbb C^n$ induces a natural arc-length metric on $(X, 0)$, called the inner metric. We study the inner metric structure of the germ of an isolated complex surface singularity $(X,0)$ by means of an infinite family of numerical analytic invariants, called inner rates. Our main result is a formula for the Laplacian of the inner rate function on a space of valuations, the non-archimedean link of $(X,0)$. We deduce in particular that the global data consisting of the topology of $(X,0)$, together with the configuration of a generic hyperplane section and of the polar curve of a generic plane projection of $(X,0)$, completely determine all the inner rates on $(X,0)$, and hence the local metric structure of the germ. Several other applications of our formula are discussed in the paper., Comment: Proposition 5.3 strengthened, exposition improved, some typos corrected, references updated. 42 pages and 10 figures. To appear in Geometry & Topology

Purpose The objective of this study was to evaluate a set of radiomics-based advanced textural features extracted from 18F-FLT-PET/CT images to predict tumor response to neoadjuvant chemotherapy (NCT) in patients with locally advanced breast cancer (BC). Materials and Methods Patients with operable (T2-T3, N0-N2, M0) or locally advanced (T4, N0-N2, M0) BC were enrolled. All patients underwent chemotherapy (six cycles every 3 weeks). Surgery was performed within 4 weeks of the end of NCT. The MD Anderson Residual Cancer Burden calculator was used to evaluate the pathological response. 18F-FLT-PET/CT was performed 2 weeks before the start of NCT and approximately 3 weeks after the first cycle. The evaluation of PET response was based on EORTC criteria. Standard uptake value (SUV) statistics (SUVmax, SUVpeak, SUVmean), together with 148 textural features, were extracted from each lesion. Indices that are robust against contour variability (ICC test) were used as independent variables to logistically model tumor response. LASSO analysis was used for variable selection. Results Twenty patients were included in the study. Lesions from 15 patients were evaluable and analyzed: 9 with pathological complete response (pCR) and 6 with pathological partial response (pPR). Concordance between PET response and histological examination was found in 13/15 patients. LASSO logistic modelling identified a combination of SUVmax and the textural feature index IVH_VolumeIntFract_90 as the most useful to classify PET response, and a combination of PET response, ID range, and ID_Coefficient of Variation as the most useful to classify pathological response. Conclusions Our study suggests the potential usefulness of FLT-PET for early monitoring of response to NCT. A model based on PET radiomic characteristics could have good discriminatory capacity of early response before the end of treatment.

In this paper we use motivic integration and non-archimedean analytic geometry to study the singularities at infinity of the fibers of a polynomial map $f\colon \mathbb A^d_\mathbb C \to \mathbb A^1_\mathbb C$. We show that the motive $S_{f,a}^{\infty}$ of the motivic nearby cycles at infinity of $f$ for a value $a$ is a motivic generalization of the classical invariant $\lambda_f(a)$, an integer that measures a lack of equisingularity at infinity in the fiber $f^{-1}(a)$. We then introduce a non-archimedean analytic nearby fiber at infinity $\mathcal F_{f,a}^{\infty}$ whose motivic volume recovers the motive $S_{f,a}^{\infty}$. With each of $S_{f,a}^{\infty}$ and $\mathcal F_{f,a}^{\infty}$ can be naturally associated a bifurcation set; we show that the first one always contains the second one, and that both contain the classical topological bifurcation set of $f$ whenever $f$ has isolated singularities at infinity.

Evidence supporting rechallenge in patients responding to first exposure to trabectedin is limited. We report on a 39-year-old woman with advanced high-grade undifferentiated sarcoma (US) retreated twice with trabectedin after first response. The patient presented in June 2006 with an abdominal mass originating from the rear fascia of the rectus abdominis. Staging examinations did not indicate metastases and she underwent surgery; pathology showed a high-grade (FNCLCC G3) US. Subsequently, the patient received five cycles of adjuvant chemotherapy with epirubicin and ifosfamide. In February 2009 a computed tomography (CT) scan showed an abdominal mass involving the transverse mesocolon. R0 surgery was performed. In September 2009, peritoneal lesions appeared. Trabectedin was initiated at a dose of 1.5 mg/m2 by a 24 h intravenous infusion every 3 weeks, without relevant toxicity. After six cycles (March 2010), CT and PET-CT scans showed complete disappearance of metastases. In February 2012, new secondary lesions in the subdiaphragmatic region and a peritoneal lesion appeared. We rechallenged the patient with the same schedule of trabectedin; a complete response was achieved after two cycles. In October 2013, new secondary lesions in the subdiaphragmatic region and a retroperitoneal lesion were found. We rechallenged with the same schedule of trabectedin; PET-CT scans after two cycles showed complete response on the subdiaphragmatic lesion. Radiotherapy on the retroperitoneal lesion was performed. The patient underwent a total of 18 cycles and remains free from radiologically detectable disease. We report complete radiological remission after two rechallenges with trabectedin in a patient with previously responding high-grade US.

We characterize sandwiched singularities in terms of their link in two different settings. We first prove that such singularities are precisely the normal surface singularities having self-similar non-archimedean links. We describe this self-similarity both in terms of Berkovich analytic geometry and of the combinatorics of weighted dual graphs. We then show that a complex surface singularity is sandwiched if and only if its complex link can be embedded in a Kato surface in such a way that its complement remains connected., 35 pages

We study the Galois descent of semi-affinoid non-archimedean analytic spaces. These are the non-archimedean analytic spaces which admit an affine special formal scheme as model over a complete discrete valuation ring, such as for example open or closed polydiscs or polyannuli. Using Weil restrictions and Galois fixed loci for semi-affinoid spaces and their formal models, we describe a formal model of a $K$-analytic space $X$, provided that $X\otimes_KL$ is semi-affinoid for some finite tamely ramified extension $L$ of $K$. As an application, we study the forms of analytic annuli that are trivialized by a wide class of Galois extensions that includes totally tamely ramified extensions. In order to do so, we first establish a Weierstrass preparation result for analytic functions on annuli, and use it to linearize finite order automorphisms of annuli. Finally, we explain how from these results one can deduce a non-archimedean analytic proof of the existence of resolutions of singularities of surfaces in characteristic zero., Comment: Exposition improved and minor modifications. 37 pages. To appear in Math. Z

We define a non-Archimedean analytic version of the link of a singularity, and we use it to study surfaces over an algebraically closed field. This yields a characterization of log essential valuations.

We define normalized versions of Berkovich spaces over a trivially valued field $k$, obtained as quotients by the action of $\mathbb R_{>0}$ defined by rescaling semivaluations. We associate such a normalized space to any special formal $k$-scheme and prove an analogue of Raynaud's theorem, characterizing categorically the spaces obtained in this way. This construction yields a locally ringed $G$-topological space, which we prove to be $G$-locally isomorphic to a Berkovich space over the field $k((t))$ with a $t$-adic valuation. These spaces can be interpreted as non-archimedean models for the links of the singularities of $k$-varieties, and allow to study the birational geometry of $k$-varieties using techniques of non-archimedean geometry available only when working over a field with non-trivial valuation. In particular, we prove that the structure of the normalized non-archimedean links of surface singularities over an algebraically closed field $k$ is analogous to the structure of non-archimedean analytic curves over $k((t))$, and deduce characterizations of the essential and of the log essential valuations, i.e. those valuations whose center on every resolution (respectively log resolution) of the given surface is a divisor., Several corrections and improvements. New result added, Theorem 10.8, proving a characterization of essential valuations. 51 pages. To appear in Transactions of the AMS

We study whether a given tropical curve $\Gamma$ in $\mathbb{R}^n$ can be realized as the tropicalization of an algebraic curve whose non-archimedean skeleton is faithfully represented by $\Gamma$. We give an affirmative answer to this question for a large class of tropical curves that includes all trivalent tropical curves, but also many tropical curves of higher valence. We then deduce that for every metric graph $G$ with rational edge lengths there exists a smooth algebraic curve in a toric variety whose analytification has skeleton $G$, and the corresponding tropicalization is faithful. Our approach is based on a combination of the theory of toric schemes over discrete valuation rings and logarithmically smooth deformation theory, expanding on a framework introduced by Nishinou and Siebert., Comment: 16 pages, introduction improved and other minor modifications, to appear in IMRN, comments very welcome!

The aim of this work was to preliminarily evaluate the sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of 68Ga-citrate PET/CT in a population of patients with suspected bone infections. Methods: We enrolled 31 patients with suspected osteomyelitis or diskitis who underwent a total of forty 68Ga-citrate PET/CT scans. The results were compared with different combinations of diagnostic procedures (MRI, radiography, CT, or white blood cell scintigraphy), biopsy (when diagnostic), and follow-up data (at least 1 y) to determine the performance of 68Ga-citrate PET/CT. Results: We found a sensitivity of 100%, a specificity of 76%, a positive predictive value of 85%, a negative predictive value of 100%, and an overall accuracy of 90%. Conclusion: Although preliminary, these data confirm a possible role for 68Ga-citrate in the diagnosis of bone infections, especially in consideration of its favorable characteristics.

The aim of this paper was to review the data existing in the English literature on the quality of life in patients who undergo surgical resection of the pancreatic gland either for benign or for malignant diseases. MEDLINE, Web of Science, and ScienceDirect were browsed in order to select the data existing in the literature on quality of life and pancreatic surgery. Alerts received by e-mail were also taken into account. Only full text papers were selected. Of the 161 papers found, only 13 papers were evaluated for the purpose of this study: 11 focused on surgical resective procedures in chronic pancreatitis and two focused their interest on assessing the quality of life related to resective procedures in pancreatic neoplasms. Despite the scarcity of studies assessing the quality of life in patients who underwent pancreatic surgery, there is the need to routinely assess well-being in patients who have been operated on.

The only potentially radical treatment for pancreatic cancer is the removal of the tumor which can be performed by total or subtotal surgical resection of the pancreas; this is possible in the early stages of the disease when the tumor is confined to the pancreatic gland without metastasis to the liver, lymph nodes and/or the peritoneum, or involvement of the vascular system such as the celiac trunk and its branches and the superior mesenteric artery. In this paper, we describe the accuracy of computed tomography and positron emission tomography in the diagnosis of exocrine pancreatic cancer.

In recent years, a number of articles have been published on the treatment of acute pancreatitis in experimental models and most of them were published about animals with mild disease. However, it is difficult to translate these results into clinical practice. For example, infliximab, a monoclonal TNF antibody, was experimentally tested in rats and it was able to significantly reduce the pathologic score and serum amylase activity, and also alleviate alveolar edema and acute respiratory distress syndrome; no studies are available in clinical human acute pancreatitis. Another substance, such as interleukin 10, was efficacious in decreasing the severity and mortality of lethal pancreatitis in rats, but seems to have no effect on human severe acute pancreatitis. Thus, the main problem in acute pancreatitis, especially in the severe form of the disease, is the difficulty of planning clinical studies capable of giving hard statistically significant answers regarding the benefits of the various proposed therapeutic agents previously tested in experimental settings. According to the pathophysiology of acute pancreatitis, we may re-evaluate the efficacy of the drugs already available, such as gabexate mesilate, lexipafant and somatostatin which should be probably administered in a different manner. Of course, also in this case, we need large studies to test this hypothesis. Another great problem is prevention of the infection of pancreatic necrosis. A randomized study has been published to test the hypothesis that probiotics and specific fibres used as supplements in early enteral nutrition may be effective in reducing pancreatic sepsis and the number of surgical interventions. A study named PROPATRIA (Probiotic Prophylaxis in Patients with Predicted Severe Acute Pancreatitis) has been planned to give a more robust confirmation to the previous study. Furthermore, the open question of the prevention of the fungal infection of necrosis is still being debated. Finally, the prevention of pain relapse after oral feeding in patients with mild or severe acute pancreatitis should be explored. Even if some studies exist on this issue, the question of optimal treatment is still unanswered. As in other diseases, obtaining results when treating patients with acute pancreatitis is difficult and will take continuous small steps.

In recent years, a number of articles have been published on the treatment of acute pancreatitis in experimental models and most of them concerned animals with mild disease. However, it is difficult to translate these results into clinical practice. For example, infliximab, a monoclonal TNF antibody, was experimentally tested in rats and it was found to significantly reduce the pathologic score and serum amylase activity and also to alleviate alveolar edema and acute respiratory distress syndrome; however, no studies are available in clinical human acute pancreatitis. Another substance, such as interleukin 10, was efficacious in decreasing the severity and mortality of lethal pancreatitis in rats, but seems to have no effect on human severe acute pancreatitis. Thus, the main problem in acute pancreatitis, especially in the severe form of the disease, is the difficulty of planning clinical studies capable of giving reliable statistically significant answers regarding the benefits of the various proposed therapeutic agents previously tested in experimental settings. According to the pathophysiology of acute pancreatitis, the efficacy of the drugs already available, such as gabexate mesilate, lexipafant and somatostatin should be re-evaluated and should be probably administered in a different manner. Of course, also in this case, we need adequate studies to test this hypothesis.

We report the imaging of a patient in whom the diagnosis of acute pancreatitis and the assessment of disease severity was carried out using echo-enhanced ultrasonography. Contrast-enhanced computed tomography confirmed the echo-enhanced ultrasonography picture. Echo-enhanced ultrasonography may become the imaging technique of choice in assessing the severity of acute pancreatitis since it is easy to perform, safe and lends itself to emergency situations. Most importantly, this technique should be also useful for following-up patients and it may be also an alternative to MRI in those patients in whom contrast-enhanced computed tomography cannot be carried out.

In an era such as the present one in which there is a high demand for health services with the associated pressure of controlling spending, health care organizations are concerned about the cost-effectiveness of quality improvement interventions. On the other hand, the impact of the disease and the treatment on the patient's overall well-being and functioning has become a topic of growing interest not only in clinical research but also in practice. The clinical evaluation of the benefits of specific treatments for chronic, debilitating and incurable diseases should increasingly include formal assessment of patient activity and well-being. Thus, health-related quality of life as subjectively perceived by the patient, is becoming a major issue in the evaluation of any therapeutic intervention, mainly in patients with chronic or difficult diseases where the aim of the intervention is to keep patients either symptom-free and capable of living in the community for a long time or to reduce the discomfort caused by the disease. In this paper, we review the current knowledge on the quality of life assessment in chronic pancreatitis patients.