Soluble PD-L1 and Circulating CD8+PD-1+ and NK Cells Enclose a Prognostic and Predictive Immune Effector Score in Immunotherapy Treated NSCLC patients.

INTRODUCTION: Upfront criteria to foresee immune checkpoint inhibitors (ICIs) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to non-invasively define predictive immune profiles in ICI-treated advanced non-small cell lung cancer (NSCLC). METHODS: Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICIs as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD-1+ and NK (FACS) cells were assessed and interlaced to generate an Immune effector Score (IeffS). Lung Immune Prognostic Index (LIPI) was computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and treatment response. RESULTS: High sPD-L1 and low CD8+PD-1+ and NK number had negative impact on PFS (P < 0.001), OS (P < 0.01) and ICI-response (P < 0.05). Thus, sPD-L1high, CD8+PD-1+low and NKlow were considered as risk factors encompassing IeffS, whose prognostic power outperformed that of individual features and slightly exceeded that of LIPI. Accordingly, the absence of these risk factors portrayed a favorable IeffS characterizing patients with significantly (P < 0.001) prolonged PFS (median NR vs 2.3 months) and OS (median NR vs 4.1) and greater benefit from ICIs (P < 0.01). We then combined each risk parameter composing IeffS and LIPI (LDHhigh, dNLRhigh), thus defining three distinct prognostic classes. A remarkable impact of IeffS-LIPI integration was documented on survival outcome (PFS, HR = 4.61; 95%CI = 2.32-9.18; P < 0.001; OS, HR=4.03; 95%CI=1.91-8.67; P < 0.001) and ICI-response (AUC=0.90, 95%CI=0.81-0.97, P < 0.001). CONCLUSION: Composite risk models based on blood parameters featuring the tumor-host interaction might provide accurate prognostic scores able to predict ICI benefit in NSCLC patients.

Robotic versus laparoscopic surgery for rectal cancer: a comparative cost-effectiveness study.

BACKGROUND: The differences between the costs of robotic rectal resection and of the laparoscopic approach are still not well known. The aim of this study was to evaluate the cost-effectiveness of robotic versus laparoscopic surgery. METHODS: We conducted an observational, comparative, prospective, non-randomized study on patients having laparoscopic and robotic rectal resection between February 2014 and March 2018 at the Sanchinarro University Hospital, Madrid. Outcome parameters included surgical and post-operative costs, quality adjusted life years (QALY) and incremental cost per QALY gained or the incremental cost effectiveness ratio (ICER). The primary endpoint was to compare cost effectiveness in the robotic and laparoscopic surgery groups. A willingness-to-pay of 20,000€ and 30,000€ per QALY was used as a threshold to determine the most cost-effective treatment. RESULTS: A total of 81 RRR and 104 LRR were included. The mean operative costs were higher for RRR (4307.09€ versus 3834.58€; p = 0.04), although mean overall costs were similar (7272.03€ for RRR and 6968.63€ for the LLR; p = 0.44). Mean QALYs at 1 year for the RRR group (0.8482) was higher than that associated with LRR (0.6532) (p = 0.018). At a willingness-to-pay threshold of 20,000€ and 30,000€ there was a 95.54% and 97.18% probability, respectively, that RRR was more cost-effective than LRR. CONCLUSIONS: Our data regarding the cost-effectiveness of RRR versus LRR shows a benefit for RRR.

Robotic-assisted gastrectomy compared with open resection: a comparative study of clinical outcomes and cost-effectiveness analysis.

In the last decade, there have clearly been important changes in the surgical approach of gastric cancer treatment due to an increased interest in the minimally invasive surgical approach (MIS). The higher cost of robotic surgery procedures remains an important issue of debate. The objective of the study is to compare the main operative and clinical outcomes and to assess the incremental cost-effectiveness ratios (ICERs) of the two techniques. This is a prospective cost-effectiveness and clinical study when comparing the robotic gastrectomy (RG) technique with open gastrectomy (OG) in gastric cancer. Outcome parameters included surgical and post-operative costs, quality-adjusted life years (QALY) and incremental cost per QALY gained or the incremental cost-effectiveness ratio (ICER). The incremental utility was 0.038 QALYs and the estimated ICER for patients was dominated by robotic approach. The probability that the robotic approach was cost effective was 94.04% and 94.20%, respectively, at a WTP threshold of 20,000€ and 30,000€ per QALY gained. RG for gastric cancer represents a cost-effective procedure compared with the standard OG.

First case of complete full robotic surgical resection of leiomyosarcoma of the right renal vein.

BACKGROUND: Leiomyosarcomas present high postoperative morbidity and poor prognosis [1]. In the literature, only few cases of localized small leiomyosarcoma have been described [2, 3]. These cases might benefit from a minimally invasive approach. Robotic surgery has been claimed to have several advantages over laparoscopy such as enhanced vision and instruments movements which might make more feasible the execution of this type of surgery where partial renal resection is required. METHODS: A 53-year-old female with a medical history of myeloid leukemia and with chronic renal failure (creatinine: 2.6) was referred to our hospital for an incidental finding of right perirenal tumor of almost 3 cm compatible with leiomyosarcoma arising from the right renal vein. RESULTS: The operation was performed using a Da Vinci Robotic Surgical System model Si (Intuitive Surgical, Sunnyvale, CA, USA).Robotic ports were placed in a standard configuration for minimally invasive right nephrectomy. The dissection started with the partial mobilization of the right liver and Kocher maneuver. After the identification of the inferior vena cava the tumor was finally localized and dissected. Resection ended with a partial right vein resection and suture. Pathological final exam confirmed the diagnosis with margins free from tumor. CONCLUSIONS: In selected cases, robotic resection of leiomyosarcoma might be a safe and feasible procedure in experienced hands.

Robotic versus laparoscopic surgery for rectal cancer: a comparative study of clinical outcomes and costs.

PURPOSE: The costs involved in performing robotic surgery present a critical issue which has not been well addressed yet. The aims of this study are to compare the clinical outcomes and cost differences of robotic versus laparoscopic surgery in the treatment of rectal cancer and to conduct a literature review of the cost analysis. METHODS: This is an observational, comparative study whereby data were abstracted from a retrospective database of patients who underwent laparoscopic and robotic rectal resection from October 2010 to March 2017, at Sanchinarro University Hospital, Madrid. An independent company performed the financial analysis, and fixed costs were excluded. RESULTS: A total of 86 robotic and 112 laparoscopic rectal resections were included. The mean operative time was significantly lower in the laparoscopic approach (336 versus 283 min; p = 0.001). The main pre-operative data, overall morbidity, hospital stay and oncological outcomes were similar in both groups, except for the readmission rate (robotic: 5.8%, laparoscopic: 11.6%; p = 0.001). The mean operative costs were higher for robotic surgery (4285.16 versus 3506.11€; p = 0.04); however, the mean overall costs were similar (7279.31€ for robotic and 6879.8€ for the laparoscopic approach; p = 0.44). We found four studies reporting costs, three comparing robotic versus laparoscopy costs, with all of them reporting a higher overall cost for the robotic rectal resection. CONCLUSION: Robotic rectal resection has similar clinical outcomes to that of the conventional laparoscopic approach. Despite the higher operative costs of robotic rectal resection, overall mean costs were similar in our series.

Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo.

Galectin-1 (Gal-1) is involved in tumoral angiogenesis, hypoxia and metastases. Actually the Gal-1 expression profile in multiple myeloma (MM) patients and its pathophysiological role in MM-induced angiogenesis and tumoral growth are unknown. In this study, we found that Gal-1 expression by MM cells was upregulated in hypoxic conditions and that stable knockdown of hypoxia inducible factor-1α significantly downregulated its expression. Therefore, we performed Gal-1 inhibition using lentivirus transfection of shRNA anti-Gal-1 in human myeloma cell lines (HMCLs), and showed that its suppression modified transcriptional profiles in both hypoxic and normoxic conditions. Interestingly, Gal-1 inhibition in MM cells downregulated proangiogenic genes, including MMP9 and CCL2, and upregulated the antiangiogenic ones SEMA3A and CXCL10. Consistently, Gal-1 suppression in MM cells significantly decreased their proangiogenic properties in vitro. This was confirmed in vivo, in two different mouse models injected with HMCLs transfected with anti-Gal-1 shRNA or the control vector. Gal-1 suppression in both models significantly reduced tumor burden and microvascular density as compared with the control mice. Moreover, Gal-1 suppression induced smaller lytic lesions on X-ray in the intratibial model. Overall, our data indicate that Gal-1 is a new potential therapeutic target in MM blocking angiogenesis.

Preoperative treatment with gemcitabine plus nab-paclitaxel is a safe and effective chemotherapy for pancreatic adenocarcinoma.

INTRODUCTION: Recently, novel chemotherapeutic agents like nab-paclitaxel and gemcitabine demonstrated a survival benefit over gemcitabine alone in metastatic pancreatic cancer. However, there are limited clinical results using this chemotherapy in potentially resectable pancreatic adenocarcinoma. Our aim is to report the oncological results of patients affected by potentially resectable pancreatic adenocarcinoma that underwent surgery after a combination of gemcitabine and nab-paclitaxel. METHODS: A total of 25 patients have been included. We evaluated: (1) Drug toxicity; (2) tumoral response (tumoral size at CT scan, SUV of FDG PET-CT scan and CA 19.9; (3) resection rate; (4) R0 resection rate and histopathological response and (5) survival and disease free survival. RESULTS: Overall treatment was well tolerated. Treatment resulted in a statistical decrease of CA19-9 (p = 0.019) tumoral size (p = 0.04) and SUV (p = 0.004). The resection rate was 68% (17/25 patients). All specimens were R0 and 13 of 17 specimens had major pathological regressions (complete and important response). Median survival and medial disease free survival of patients that underwent surgery was 21 months and 19 months, respectively at a mean follow up of 38.5 months. CONCLUSIONS: This data suggests that nab-paclitaxel and gemcitabine is a safe and effective neoadjuvant treatment for potentially resectable pancreatic adenocarcinoma. This promising data should be confirmed in larger, randomized studies.

Quantitative comparison between the commercial software STRATOS(®) by Philips and a homemade software for voxel-dosimetry in radiopeptide therapy.

BACKGROUND: Targeted radionuclide therapy is a rapidly growing modality. A few commercial treatment planning systems are entering the market. However, some in-house systems are currently developed for a more flexible and customized dosimetry calculation at voxel-level. For this purpose, we developed a novel software, VoxelMed, and performed a comparison with the software STRATOS. METHODS: The validation of both of them was undertaken using radioactive phantoms with different volume inserts. A cohort of 10 patients was also studied after a therapeutic administration of (177)Lu-labelled radiopeptides. The activity, number of disintegrations, absorbed dose and dose-volume histogram (DVH) were calculated for the phantoms and the kidneys in patients, which were the main critical organs at risk in this study. RESULTS: In phantoms the absorbed doses computed with VoxelMed and STRATOS agree within 5%. In patients at the voxel-level the absorbed dose to kidneys (VoxelMed: mean 0.66 Gy/GBq) showed a limited difference of 5%, but with a remarkable range (-40%, +60%) between the two software packages. Voxel-dosimetry allows to estimate the dose non-homogeneities in volumes, which may be evaluated through DVHs. CONCLUSION: This study demonstrates that a fully 3D voxel-dosimetry with multiple SPECT images is feasible by using home-made or commercial software package and absorbed dose results obtained are similar. The main difference between the studied tools was observed in the activity integration method (effective vs physical half-time to time activity curve tail). We believe that an effective half-time integration method produces a more accurate approximation of clinical uptake and resultant dosimetry.

An organizational model to improve the robotic system among general surgeons.

INTRODUCTION: Robotic surgery has gained wide acceptance in recent years. However its development is slower and the lack of high level experience with this technique is an important limitation. This manuscript discusses some of the reasons of it and aims to describe the organizational system we have progressively established in our center in order to improve the development of Robotic program in our surgical area. METHODS: Some points may be required to improve the robotic program development in a general surgical department, including: a broad availability of robotic system in a surgical area; an ideal setting area with mainly oncological and hepato-biliary-pancreatic disease; the need of a mainly young team; a broad application of the robotic system in more general surgical fields; a high motivation on robotic use; a departmental and institutional economical effort. We have tried to achieve these goals before starting the robotic program in our department at October 2010. RESULTS: From October 2010 until November 2013 a total of 170 procedures have been performed, 92% of them for malignant diseases. Conversion rate and overall morbidity was 5% and 19%, respectively. CONCLUSIONS: The organizational model defined in our center is facilitating the constant and progressive development of the robotic program. A broad and flexible availability of the robotic system, a progressive increase of young surgeons joining this technology as well as the institutional and departmental economical effort are the points with which the robotic system may increase its development in a surgical department.

Validation of an original questionnaire for patients with psoriatic arthritis: the Psoriatic Arthritis Impact Profile (PAIP).

BACKGROUND AND AIMS: There is a wide evidence that Psoriatic Arthritis (PsA) as well as Psoriasis (Ps) lead to significant health problems and interfere with the patient quality of life (QoL). Even though a validated questionnaire for Ps is available, no questionnaire for PsA is currently present in literature. The aim of our work has been to confirm the efficacy of our original questionnaire as well as to validate it, through the comparison with other existing recognised and accepted questionnaires, such as MOF-SF36, HAQ, McGill Pain Questionnaire, and Zeung Self-Rating Depression and Anxiety Scales. MATERIALS AND METHODS: We have realized a questionnaire for PsA (Psoriatic Arthritis Impact Questionnaire, PAIP), in terms of psychological and rheumatological evaluation, QoL, social and economic assets. RESULTS: The statistical comparisons between PAIP and the accepted questionnaires (see above) confirm that PAIP is widely validated and represents a useful tool suitable for clinical evaluation and management of patients with PsA. CONCLUSIONS: The indexes of the correlation among the different parts of PAIP and the other questionnaires have shown positive correlations. Moreover, PAIP presents a dedicated unit for the economical and therapeutic parameters, The short time for compilation (15 minutes), the easy of comprehension of the questions, and - above all - the validation of PAIP, make our questionnaire a useful tool, suitable for the clinical management of the patients with PsA.

Relationships between conformational behaviour and binding affinity towards beta 1 and beta 2 adrenoceptors of some chiral phenoxypropanolamines with bulky N-substituents.

The optical isomers of a series of phenoxypropanolamine compounds with N-substituents bulkier than isopropyl have been synthesized, and their binding affinity towards beta 1 and beta 2-adrenoceptors has been determined. A computational study, including a Molecular Dynamics (MD) simulation and quenching in water and a GRID analysis provided some useful suggestions for possible interpretation patterns for the different affinity exhibited by the compounds studied.

Molecular properties of the WB4101 enantiomers and of its chiral methyl derivatives for alpha 1-adrenoceptor recognition.

The optical isomers of the well known alpha 1-antagonist WB4101 and of its derivatives with a methyl group in the oxyethyl moiety were prepared for the evaluation of their alpha-adrenoceptors binding affinity. By means of a detailed computational analysis, the present work shows that the introduction of a methyl group affects the behaviour of WB4101 in different ways. A limitation of the conformational freedom in certain regions of the torsional subspace of the potential energy function, differences in the reactivity of the protonated species towards a model proton acceptor and the quality of the superposition with the rigid template for alpha 1 antagonists, corynanthine, are examined and discussed in order to select a candidate bioactive form and possible features which act as modulators of the recognition process at the alpha 1-adrenoceptors.

Agonistic activity and charge driven interaction potentiality of PAF derivatives.

Taking into account the contribution of the C2 substituent to the interaction ability of PAF derivatives, an investigation has been undertaken on: i) the role of the presence of two unitary charges of opposite sign in the molecule; ii) the role of the spacing of the same charged moieties. For this purpose, the theoretical analysis of model compounds for newly synthesized and already known compounds has been performed by means of computer-aided modelling, molecular mechanics and semiempirical quantum chemical computational methods. The combination of the results with the available pharmacological data allows a discussion about the stereoelectronic features required for agonist interaction at the PAF receptor.

Chiral PAF agonists: synthesis, theoretical analysis of their stereoelectronic properties and structure activity relationships.

A series of chiral PAF agonists were synthesized. Modifications at the PAF structure were undertaken as far as the C2 substituents and the onium head groups are concerned. In parallel, molecular modelling studies including a MOPAC geometry optimization and the analysis of the electrostatic potential were performed on the newly synthesized and on already known PAF agonists, in order to gain a better insight into the stereoelectronic features required for interaction with the PAF receptor.

Cardiovascular and pulmonary activity of platelet-activating factor (PAF-acether) and its derivatives.

Stereoselective synthesis and biological properties of PAF-acether, its enantiomer and some analogues of both are reported. The results clearly indicate that the ONIUM SIZE and SHAPE of the various compounds tested are important in determining guinea-pig bronchoconstriction and human platelet aggregation.

QSAR in a series of muscarinic agents. Note V. New sets of rigid and flexible ligands.

A deeper insight of muscarinic receptor attachment points is obtained on studying new sets of rigid and flexible ligands. The quantitative analysis of the correspondence between biological response and structural ligand features confirms that pD2 values are strongly dependent on hydrophobic and steric parameters. Moreover, it is shown that receptor attachment points are interrelated and their simultaneous perturbations contribute to enhance the activity with comparable effectiveness.

QSAR in a series of muscarinic agents. Note IV. - New pyridine and furan derivatives.

Two new series of picolyl- and furfuryltrimethylammonium salts have been prepared and studied in order to support some hypotheses previously formulated in the study of the topology of the muscarinic receptor. The general picture of ligand interactions with receptor as seen with correlation analysis is discussed. The new quantitative structure-activity relationship is compared with those previously formulated and it is shown that biological data for new congeners are well predicted by a correlation equation published earlier.

OSAR in a series of muscarinic agents. Note III--Alkyltrimethylammonium salts, ethers and esters of choline.

In the light of the experience gained studying various sets of muscarinic ligands related to a rigid model, flexible structures such as alkyltrimethylammonium salts, ethers and esters of choline have been prepared and their affinities (pD2) have been studied. The quantitative structure-activity relationships (QSAR) show that the pD2 value is strongly dependent on hydrophobic and steric parameters of the ligand substituent. Moreover, two indicator variables are considered to take ito account extra-activities connected with ligand special structural features. The overall QSAR confirm that the electrostatic attraction, the hydrophobic bonding and the polar interaction holding the ligand on the receptor are individually weak; however, these three forces collectively permit a more complete utilization of the receptor binding site.