TAMs PD-L1(+) in the reprogramming of germ cell tumors of the testis

Background: In recent years, several studies focused on the process of reprogramming of seminoma (S) cells, which regulates the transition from pure S (P-S) to S component (S-C) of mixed germ cell tumors of the testis (GCTT) and finally to embryonal carcinoma (EC) and other nonseminomatous GCTT (NS-GCTT). The accepted pathogenetic model is driven and regulated by cells (macrophages, B- and T-lymphocytes) and molecules of the tumor microenvironment (TME). Herein, we tested a series of GCTT with double staining (DS) for CD68-PD-L1 to evaluate tumor-associated macrophages (TAMs) expressing programmed death-ligand 1 (PD-L1) [TAMs PD-L1(+)] and clarify if these cells may be involved in establishing the fate of GCTT. Methods: We collected 45 GCTT (comprising a total of 62 different components of GCTT). TAMs PD-L1(+) were evaluated with three different scoring systems [TAMs PD-L1(+)/mm2, TAMs PD-L1(+)/mm2H-score, TAMs PD-L1(+) %], and compared using pertinent statistic tests (Student's t-test and Mann-Whitney U test). Results: We found that TAMs PD-L1(+) values were higher in S rather than EC (p = 0.001, p = 0.015, p = 0.022) and NS-GCTT (p < 0.001). P-S showed statistically significant differences in TAMs PD-L1(+) values compared to S-C (p < 0.001, p = 0.006, p = 0.015), but there were no differences between S-C and EC (p = 0.107, p = 0.408, p = 0.800). Finally, we found statistically significant differences also in TAMs PD-L1(+) values between EC and other NS-GCTT (p < 0.001). Conclusions: TAMs PD-L1(+) levels gradually decrease during the reprogramming of S cells {P-S [(high values of TAMs PD-L1(+)] → S-C and EC [(intermediate values of TAMs PD-L1(+)] → other NS-GCTT [(low values of TAMs PD-L1(+)], supporting a complex pathogenetic model where the interactions between tumor cells and TME components [and specifically TAMs PD-L1(+)] play a key role in determining the fate of GCTT

H&E and OCT4/CD34 for the assessment of lympho-vascular invasion in seminoma and embryonal carcinoma

Background: Lymphovascular invasion (LVI) is a relevant prognostic factor in germ cell tumors of the testis (GCTT), and it is included in the pT stage. However, its detection on hematoxylin and eosin (H&E) slides is very challenging, and previous studies reported fair to moderate inter-observer agreement among dedicated uropathologists. In the present study, we tested H&E and a recently developed in-house double staining for OCT4/CD34 to detect LVI in GCTT. Methods: Nine authors [5 non-uropathologists and 4 uropathologists] independently evaluated 34 consecutive and retrospectively enrolled cases of GCTT. We assessed the inter-observer agreement (Fleiss's Kappa) with both H&E and OCT4/CD34. Besides, we compared the consensus diagnosis on both H&E and OCT4/CD34-stained sections with the original diagnosis to evaluate the pT re-staging (McNemar test) and identify the sources of disagreement. Results: The inter-observer agreement among uropathologists plus non-uropathologists was fair with both H&E (KF=0.398; p < 0.001) and OCT4/CD34 (KF=0.312; p < 0.001). OCT4/CD34 (KF=0.290; p < 0.001) slightly reduces the inter-observer agreement compared to H&E (KF=0.321; p < 0.001) for non-uropathologists; in contrast, OCT4/CD34 (KF=0.293; p < 0.001) significantly reduces the inter-observer agreement compared to H&E (KF=0.529; p < 0.001) for uropathologists, changing it from moderate to fair. Consensus diagnosis with H&E modified the LVI status of the original diagnosis in 8/34 (23.5 %) cases (p: 0.070), with pT re-staging in 2/34 (5.9 %) cases (p: 0.500). Consensus diagnosis with OCT4/CD34 modified the LVI status of the original diagnosis in 8/34 (23.5 %) cases (p: 0.289), with pT re-staging in 3/34 (8.8 %) cases (p: 0.250). The consensus diagnosis with OCT4/CD34 modified the consensus diagnosis with H&E in 8/34 (23.5 %) cases (p: 0.727), and these findings resulted in pT-restaging in 3/34 (8.8 %) cases (p: 0.500). The sources of disagreement among uropathologists were: H&E [artefactual clefts misinterpreted as LVI in 4/6 (66.7 %) cases and true foci of LVI misinterpreted as clusters of histiocytes within the vessels in 2/6 (33.3 %) cases], OCT4/CD34 [artefactual clefts misinterpreted as LVI in 2/8 (25 %) cases, true LVI misinterpreted as artefactual clefts in 2/8 (25 %) cases or floaters in 4/8 (50 %) cases]. Conclusions: OCT4/CD34 does not improve the inter-observer agreement for the assessment of LVI in OCT4(+) GCTT. Consensus diagnosis with H&E modifies the LVI status in a significant number of cases, resulting in changes of the pT stage in a relatively small subgroup. Consensus diagnosis with OCT4/CD34 provides little additional benefit since it cannot exclude mimickers of LVI such as floaters and artefactual clefts. These results argue against the adoption of this diagnostic tool for the routine assessment of OCT4(+) GCTT

Multiple Myeloma Treatment in Real-world Clinical Practice : Results of a Prospective, Multinational, Noninterventional Study

Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: M.M. has received personal fees from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Sanofi, Novartis, and Takeda and grants from Janssen and Sanofi during the conduct of the study. E.T. has received grants from Janssen and personal fees from Janssen and Takeda during the conduct of the study, and grants from Amgen, Celgene/Genesis, personal fees from Amgen, Celgene/Genesis, Bristol-Myers Squibb, Novartis, and Glaxo-Smith Kline outside the submitted work. M.V.M. has received personal fees from Janssen, Celgene, Amgen, and Takeda outside the submitted work. M.C. reports honoraria from Janssen, outside the submitted work. M. B. reports grants from Janssen Cilag during the conduct of the study. M.D. has received honoraria for participation on advisory boards for Janssen, Celgene, Takeda, Amgen, and Novartis. H.S. has received honoraria from Janssen-Cilag, Celgene, Amgen, Bristol-Myers Squibb, Novartis, and Takeda outside the submitted work. V.P. reports personal fees from Janssen during the conduct of the study and grants, personal fees, and nonfinancial support from Amgen, grants and personal fees from Sanofi, and personal fees from Takeda outside the submitted work. W.W. has received personal fees and grants from Amgen, Celgene, Novartis, Roche, Takeda, Gilead, and Janssen and nonfinancial support from Roche outside the submitted work. J.S. reports grants and nonfinancial support from Janssen Pharmaceutical during the conduct of the study. V.L. reports funding from Janssen Global Services LLC during the conduct of the study and study support from Janssen-Cilag and Pharmion outside the submitted work. A.P. reports employment and shareholding of Janssen (Johnson & Johnson) during the conduct of the study. C.C. reports employment at Janssen-Cilag during the conduct of the study. C.F. reports employment at Janssen Research and Development during the conduct of the study. F.T.B. reports employment at Janssen-Cilag during the conduct of the study. The remaining authors have stated that they have no conflicts of interest. Publisher Copyright: © 2018 The AuthorsMultiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.publishersversionPeer reviewe

An Efficient Radio Access Control Mechanism for Wireless Network-On-Chip Architectures

Modern systems-on-chip (SoCs) today contain hundreds of cores, and this number is predicted to reach the thousands by the year 2020. As the number of communicating elements increases, there is a need for an efficient, scalable and reliable communication infrastructure. As technology geometries shrink to the deep submicron regime, however, the communication delay and power consumption of global interconnections become the major bottleneck. The network-on-chip (NoC) design paradigm, based on a modular packet-switched mechanism, can address many of the on-chip communication issues, such as the performance limitations of long interconnects and integration of large number of cores on a chip. Recently, new communication technologies based on the NoC concept have emerged with the aim of improving the scalability limitations of conventional NoC-based architectures. Among them, wireless NoCs (WiNoCs) use the radio medium for reducing the performance and energy penalties of long-range and multi-hop communications. As the radio medium can be accessed by a single transmitter at a time, a radio access control mechanism (RACM) is needed. In this paper, we present a novel RACM, which allows one to improve both the performance and energy figures of the WiNoC. Experiments, carried out on both synthetic and real traffic scenarios, have shown the effectiveness of the proposed RACM. On average, a 30% reduction in communication delay and a 25% energy savings have been observed when the proposed RACM is applied to a known WiNoC architecture

A closed loop transmitting power self-calibration scheme for energy efficient WiNoC architectures

In a wireless Network-on-Chip (WiNoC) the radio transceiver accounts for a significant fraction of the total communication energy. Recently, a configurable transceiver architecture able to regulate its transmitting power based on the location of the destination node has been proposed. Unfortunately, the use of such transceiver requires a costly, time consuming and complex characterization phase performed at design time and mainly based on the use of field solver simulators whose accuracy has not yet been proved in the context of integrated on-chip antennas. In this paper we present a closed loop transmitting power self-calibration mechanism which allows to determine on-line the optimal transmitting power for each transmitting and receiving pair in a WiNoC. The proposed mechanism is general and can be applied to any WiNoC architecture with a low overhead in terms of silicon area. Its application to three well known WiNoC architectures shows its effectiveness in drastically reducing the overall communication energy (up to 50%) with a limited impact on performance

Evolution of the subsolid pulmonary nodule: a retrospective study in patients with different neoplastic diseases in a nonscreening clinical context.

The aims of this study were to evaluate the high-resolution computed tomography (HRCT) features of subsolid pulmonary nodules (SSN) detected in cancer patients to differentiate between benign and malignant lesions, to assess their evolution during the follow-up, and to determine which neoplastic diseases are most frequently associated with the growth in size and/or density of SSN.Ninety-seven patients with a total of 146 subsolid nodules [140 pure ground-glass opacities (pGGOs) and six mixed ground-glass opacities (mGGOs)] were retrospectively recruited. Two chest radiologists independently reviewed the HRCT features of the nodules (location, shape, size, density) and the patients' clinical characteristics (sex, age, smoking and cancer history). Mean duration of follow-up was more than 2 years.During follow-up, 58\% of SSN remained stable, 10\% disappeared. An increase in size and/or density was seen in 32\% of SSN, and in particular in partly solid (mGGOs), large (≥10 mm) and irregular nodules. The majority of small-size (<5 mm) rounded SSN remained stable. SSN growth was more frequent in patients with advanced age and a history of smoking, and occurred even after a long period of stability (39\% of pGGOs "changed" over 3 years). The neoplastic diseases most frequently associated with SSN growth were cancers of lung (34\%), breast (15\%), colon (15\%) and bladder (10\%).The observation of a sample of cancer patients has shown that SSN may frequently grow in size and/or density in these patients, especially if associated powith cancers of lung, breast, colon and bladder. As the majority of SSN showed a very slow development time, a follow-up period longer than 3 years is warranted even in cancer patients