Resonant micro-opto-mechanical modulators fabricated by femtosecond laser micromachining

Integrated modulators of optical phase or intensity are essential elements to reconfigure dynamically the operation of a complex waveguide circuit, or to achieve convenient optical switching within a fiber network. Thermo-optic effects are commonly exploited to achieve dynamic phase modulation in glass-based devices, since nonlinear optical effects are weak in such substrates. Thermo-optic modulators rely on electric resistive heaters patterned on top of the waveguides: they are reliable and easy to fabricate, but they suffer from slow response, dictated by the thermal diffusion dynamics. On the other hand, optically-coupled microstructures in glass, driven at their mechanical resonances, may provide interesting possibilities to achieve modulation of the optical signals in the kilohertz range and higher. In this work, we demonstrate integrated-optics intensity modulators based on micro-cantilevers with resonant oscillation frequencies in the tens-of-kilohertz range. The mechanical structures are realized in alumino-borosilicate glass substrate by water-assisted femtosecond-laser ablation. With the same femtosecond laser an optical waveguide is inscribed within the oscillating beam; a waveguide also continues in the substrate beyond the cantilever's tip. Since the entire device, with all its optical and mechanical parts, is realized in a single fabrication process, relative alignment is guaranteed. If the cantilever is at rest, light propagating in the internal waveguide yields maximum coupling to the remaining part of the waveguide. When the device is excited at resonance by means of a piezo-electric actuator, the cantilever oscillation produces periodical variations of the coupling efficiency, with an observed contrast higher than 10 dB

Three-dimensional and dual-color fluorescence microscopy on a chip

In this work we present two microscopes on chip based on Light Sheet Fluorescence Microscopy, capable to automatically perform 3D and dual-color imaging of specimens diluted in a liquid suspension. A microfluidic channel is used for automatic sample delivery, while integrated optical components such as optical waveguides and lenses are used to illuminate the sample flowing in the channel. The devices are fabricated by femtosecond laser micromachining in a glass substrate. Benefiting from the versatility of the fabrication technique we present two prototypes that have been optimized for different samples such as single cells and Drosophila embryos

Hyperthermic intraperitoneal chemotherapy and colorectal cancer: From physiology to surgery

The pursuit of this paper is to collect principal reviews and systematic reviews about hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) used in colorectal cancer (CRC). We focus on principal biological aspects of CRC, hyperthermia effects, and surgical procedures. We searched PubMed/MEDLINE for the principal reviews and systematic reviews published from 2010 to 2021 regarding the bimodal treatment (CRS + HIPEC) against local and advanced CRC. In the literature, from several studies, it seems that the efficacy of bimodal treatment with an accurate CRS can extend overall survival. Despite these studies, there are not still any straight guidelines more detailed and scheduled about the use of combined treatment in patients with CRC. Even if the concept is still not very clear and shared, after a careful evaluation of the published data, and after some technical and pathophysiological descriptions, we concluded that it is possible to improve the overall survival and quality of life and to reduce the tumor relapse in patients affected by locally advanced (pT4) CRC with peritoneal metastases

Lactate dehydrogenase in hepatocellular carcinoma: something old, something new

Hepatocellular carcinoma (HCC) is the most common primary liver tumour (80-90%) and represents more than 5.7% of all cancers. Although in recent years the therapeutic options for these patients have increased, clinical results are yet unsatisfactory and the prognosis remains dismal. Clinical or molecular criteria allowing a more accurate selection of patients are in fact largely lacking. Lactic dehydrogenase (LDH) is a glycolytic key enzyme in the conversion of pyruvate to lactate under anaerobic conditions. In preclinical models, upregulation of LDH has been suggested to ensure both an efficient anaerobic/glycolytic metabolism and a reduced dependence on oxygen under hypoxic conditions in tumour cells. Data from several analyses on different tumour types seem to suggest that LDH levels may be a significant prognostic factor. The role of LDH in HCC has been investigated by different authors in heterogeneous populations of patients. It has been tested as a potential biomarker in retrospective, small, and nonfocused studies in patients undergoing surgery, transarterial chemoembolization (TACE), and systemic therapy. In the major part of these studies, high LDH serum levels seem to predict a poorer outcome. We have reviewed literature in this setting trying to resume basis for future studies validating the role of LDH in this diseas

Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies

The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug resistance, and the major neuronal isoform of RAF, BRAF and MEK pathways play a critical and central role in HCC escape from TKIs activity. Advanced HCC patients with a BRAF mutation display a multifocal and/or more aggressive behavior with resistance to TKI. Moreover, also long non-coding RNA (lnc-RNA) have been studied in epigenetic studies for BRAF aggressiveness in HCC. So far, lnc-RNA of BRAF could be another mechanism of cancer proliferation and TKI escape in HCC and the inhibition could become a possible strategy treatment for HCC. Moreover, recent preclinical studies and clinical trials evidence that combined treatments, involving alternative pathways, have an important role of therapy for HCC and they could bypass resistance to the following TKIs: MEK, ERKs/ribosomal protein S6 kinase 2 (RSK2), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). These initial data must be confirmed in clinical studies, which are currently ongoing. Translational research discoveries could create new strategies of targeted therapy combinations, including BRAF pathway, and they could eventually bring light in new treatment of HCC

Systematic review of irreversible electroporation role in management of locally advanced pancreatic cancer

Background: Ablative techniques provide in patients with locally advanced pancreatic cancer (LAPC) symptomatic relief, survival benefit and potential downsizing. Irreversible Electroporation (IRE) represents potentially an ideal solution as no thermal tissue damage occurs. The purpose of this review is to present an overview on safety, feasibility, oncological results, survival and quality of life improvement obtained by IRE. Methods: A systematic search was performed in PubMed, regarding the use of IRE on PC in humans for studies published in English up to March 2019. Results: 15 original studies embodying 691 patients with unresectable LAPC who underwent IRE were included. As emerged, IRE works better on tumour sizes between 3–4 cm. Oncological results are promising: median OS from diagnosis or treatment up to 27 months. Two groups investigated borderline resectable tumours treated with IRE before resection with margin attenuation, whereas IRE has proved to be effective in pain control. Conclusions: Electroporation is bringing new hopes in LAPC management. The first aim of IRE is to offer a palliative treatment. Further efforts are needed for patient selection, as well as the use of IRE for ‘margin accentuation’ during surgical resection. Even if promising, IRE needs to be validated in large, randomized, prospective series

Laparoscopic vs. open mesorectal excision for rectal cancer: Are these approaches still comparable? A systematic review and metaanalysis

Background To analyze pathologic and perioperative outcomes of laparoscopic vs. open resections for rectal cancer performed over the last 10 years. Methods A systematic literature search of the following databases was conducted: Cochrane Central Register of Controlled Trials, MEDLINE (through PubMed), EMBASE, and Scopus. Only articles published in English from January 1, 2008 to December 31, 2018 (i.e. the last 10 years), which met inclusion criteria were considered. The review only included articles which compared Laparoscopic rectal resection (LRR) and Open Rectal Resection (ORR) for rectal cancer and reported at least one of the outcomes of interest. The analyses followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement checklist. Only prospective randomized studies were considered. The body of evidence emerging from this study was evaluated using the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. Outcome measures (mean and median values, standard deviations, and interquartile ranges) were extracted for each surgical treatment. Pooled estimates of the mean differences were calculated using random effects models to consider potential inter-study heterogeneity and to adopt a more conservative approach. The pooled effect was considered significant if p <0.05. Results Five clinical trials were found eligible for the analyses. A positive involvement of CRM was found in 49 LRRs (8.5%) out of 574 patients and in 30 ORRs out of 557 patients (5.4%) RR was 1.55 (95% CI, 0.99–2.41; p = 0.05) with no heterogeneity (I2 = 0%). Incorrect mesorectal excision was observed in 56 out of 507 (11%) patients who underwent LRR and in 41 (8.4%) out of 484 patients who underwent ORR; RR was 1.30 (95% CI, 0.89–1.91; p = 0.18) with no heterogeneity (I2 = 0%). Regarding other pathologic outcomes, no significant difference between LRR and ORR was observed in the number of lymph nodes harvested or concerning the distance to the distal margin. As expected, a significant difference was found in the operating time for ORR with a mean difference of 41.99 (95% CI, 24.18, 59.81; p <0.00001; heterogeneity: I2 = 25%). However, no difference was found for blood loss. Additionally, no significant differences were found in postoperative outcomes such as postoperative hospital stay and postoperative complications. The overall quality of the evidence was rated as high. Conclusion Despite the spread of laparoscopy with dedicated surgeons and the development of even more precise surgical tools and technologies, the pathological results of laparoscopic surgery are still comparable to those of open ones. Additionally, concerning the pathological data (and particularly CRM), open surgery guarantees better results as compared to laparoscopic surgery. These results must be a starting point for future evaluations which consider the association between ‘‘successful resection” and long-term oncologic outcomes. The introduction of other minimally invasive techniques for rectal cancer surgery, such as robotic resection or transanal TME (taTME), has revealed new scenarios and made open and even laparoscopic surgery obsolete

Immunotherapeutic approaches for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate due to the fact that the diagnosis usually occurs at anadvanced stage. Even in case of curative surgical treatment, recurrence is common. Sorafenib and regorafenib are the only therapeutic agents that have been demonstrated to be effective in advanced HCC, thus novel curative approaches are urgently needed. Recent studies focus on the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a real challenge for conventional immunotherapy in these patients. Spontaneous immune responses against tumor antigens have been detected, and new immune therapies are under investigation: dendritic cell vaccination, immune-modulator strategy, and immune checkpoint inhibition. In recent years different clinical trials examining the use of immunotherapy to treat HCC have been conducted with initial promising results. This review article will summarize the literature data concerning the potential immunotherapeutic approaches in HCC patient

The VIMOS VLT Deep Survey :Evolution of the major merger rate since z~1 from spectroscopicaly confirmed galaxy pairs

From the VIMOS VLT Deep Survey we use a sample of 6447 galaxies with I_{AB} < 24 to identify 251 pairs of galaxies, each member with a secure spectroscopic redshift, which are close in both projected separation and in velocity. We find that at z ~ 0.9, 10.9 +/- 3.2 % of galaxies with M_B(z) < -18-Qz are in pairs with separations dr < 20 kpc/h, dv < 500 km/s, and with dM_B < 1.5, significantly larger than 3.76 +/- 1.71 % at z ~ 0.5; we find that the pair fraction evolves as (1+z)^m with m = 2.49 +/- 0.56. For brighter galaxies with M_B(z=0) < -18.77, the pair fraction is higher and its evolution with redshift is somewhat flatter with m=1.88 \pm 0.40, a property also observed for galaxies with increasing stellar masses. Early type, dry mergers, pairs increase their relative fraction from 3 % at z ~ 0.9 to 12 % at z ~ 0.5. We find that the merger rate evolves as N_{mg}=(9.05 +/- 3.76) * 10^{-4}) * (1+z)^{2.43 +/- 0.76}. We find that the merger rate of galaxies with M_B(z) < -18-Qz has significantly evolved since z ~ 1. The merger rate is increasing more rapidly with redshift for galaxies with decreasing luminosities, indicating that the flat evolution found for bright samples is not universal. The merger rate is also strongly dependent on the spectral type of galaxies involved, late type mergers being more frequent in the past, while early type mergers are more frequent today, contributing to the rise in the local density of early type galaxies. About 20 % of the stellar mass in present day galaxies with log(M/M_{sun}) > 9.5 has been accreted through major merging events since z ~ 1, indicating that major mergers have contributed significantly to the growth in stellar mass density of bright galaxies over the last half of the life of the Universe.Comment: 22 pages, 19 figures, accepted in A&