From the identification of actionable molecular targets to the generation of faithful neuroblastoma patient-derived preclinical models.

BACKGROUND: Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent. METHODS: Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models. RESULTS: Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as "very high priority", that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient's tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors. CONCLUSIONS: PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.

Dissipative coupling in a Bragg-grating-coupled single resonator with Fano resonance for anti-PT-symmetric gyroscopes.

Anti-parity-time-symmetric Hamiltonians show an enhanced sensitivity to external perturbations that can be used for high-performance angular velocity sensing. Dissipative coupling is a valuable way for realizing anti-PT-symmetric Hamiltonians with optical resonators and is usually obtained by means of auxiliary waveguides. Here, we model and experimentally show the dissipative coupling between two counterpropagating modes of a single resonator, by means of a Bragg-grating placed in the feeding bus. The proposed solution enables the possibility of accurately designing the dissipative coupling strength in integrated non-Hermitian gyroscopes, thus providing high flexibility in the design of the proposed sensor. Moreover, we theoretically and experimentally demonstrate that the dissipative coupling between two counterpropagating modes of the same resonant cavity can give rise to an asymmetric Fano resonance.

A Novel NUTM1-NSMCE2 Fusion Gene in a Pediatric Chest NUT Carcinoma.

Nuclear protein of the testis carcinoma is an exceedingly rare and poorly differentiated carcinoma characterized by BDR4::NUTM1 gene translocation. Typically, the tumor affects young adults, and no standardized recommendations for therapeutic management have been available since 2022; the clinical course remains mostly dismal. We report the successful multimodal treatment of a 13-year-old boy affected by a primary chest NUT-carcinoma with a novel NUTM1 rearrangement that remains in complete continuous remission at 30 months from diagnosis.

Real-world experience with filgotinib for rheumatoid arthritis in Germany : A retrospective chart review.

BACKGROUND: Real-world data for filgotinib, a Janus kinase (JAK)1 inhibitor, are limited in patients with rheumatoid arthritis (RA). OBJECTIVES: To explore real-world filgotinib use in patients with RA in Germany. MATERIALS AND METHODS: This retrospective chart review included patients aged ≥ 18 years with confirmed moderate to severe RA who initiated filgotinib before December 1, 2021, with ≥ 6 months of medical records available prior to filgotinib initiation or after initial diagnosis. Patient characteristics, prior treatments, reasons for initiating/discontinuing filgotinib, disease activity, dose adjustments and concomitant treatments were recorded. RESULTS: In total, 301 patients from 20 German rheumatology outpatient units were included. One-third were aged ≥ 65 years and almost half had ≥ 1 cardiovascular (CV) risk factor. Most patients initiated filgotinib as monotherapy (83.7%; 12.7% of whom with glucocorticoids) and at the 200 mg dose (84.7%); higher proportions of those initiating the 100 versus 200 mg dose were aged ≥ 65 years and had renal impairment or ≥ 1 CV risk factor. Oral administration (78.4%), fast onset of action (66.8%) and administration as monotherapy (65.4%) were the most common reasons for initiating filgotinib. At 12 months, 41 (18.4%) patients had discontinued filgotinib, most commonly due to lack of effectiveness. After 6­months of follow-up, 36.8% of patients had achieved Clinical Disease Activity Index (CDAI) remission and 45.6% had achieved CDAI low disease activity. CONCLUSIONS: In clinical practice in Germany, reasons for initiating filgotinib in patients with RA were related to dosing flexibility and general JAK inhibitor attributes. Filgotinib was used predominantly as monotherapy and was effective and generally well tolerated; however, longer-term data in larger, prospective cohorts are needed.

High-Performance Pockels Effect Modulation and Switching in Silicon-Based GaP/Si, AlP/Si, ZnS/Si, AlN/3C-SiC, GaAs/Ge, ZnSe/GaAs, and ZnSe/Ge Superlattice-On-Insulator Integrated Circuits.

We propose new a Si-based waveguided Superlattice-on-Insulator (SLOI) platforms for high-performance electro-optical (EO) 2 × 2 and N × M switching and 1 × 1 modulation, including broad spectrum and resonant. We present a theoretical investigation based on the tight-binding Hamiltonian of the Pockels EO effect in the lattice-matched undoped (GaP)N/(Si2)M, (AlP)N/(Si2)M, (ZnS)N/(Si2)M, (AlN)N/(3C-SiC)M, (GaAs)N/(Ge2)M, (ZnSe)N/(GaAs)M, and (ZnSe)N/(Ge2)M wafer-scale short-period superlattices that are etched into waveguided networks of small-footprint Mach-Zehnder interferometers and micro-ring resonators to yield opto-electronic chips. The spectra of the Pockels r33 coefficient have been simulated as a function of the number of the atomic monolayers for "non-relaxed" heterointerfaces. The large obtained r33 values enable the SLOI circuit platforms to offer a very favorable combination of monolithic construction, cost-effective manufacturability, high modulation/switching speed, high information bandwidth, tiny footprint, low energy per bit, low switching voltage, near-IR-and-telecom wavelength coverage, and push-pull operation. By optimizing waveguide, clad, and electrode dimensions, we obtained very desirable values of the VπL performance metric, in the range of 0.062 to 0.275 V·cm, portending a bright future for a variety of applications, such as sensor networks or Internet of Things (IoT).

Non-Hermitian Sensing in Photonics and Electronics: A Review.

Recently, non-Hermitian Hamiltonians have gained a lot of interest, especially in optics and electronics. In particular, the existence of real eigenvalues of non-Hermitian systems has opened a wide set of possibilities, especially, but not only, for sensing applications, exploiting the physics of exceptional points. In particular, the square root dependence of the eigenvalue splitting on different design parameters, exhibited by 2 × 2 non-Hermitian Hamiltonian matrices at the exceptional point, paved the way to the integration of high-performance sensors. The square root dependence of the eigenfrequencies on the design parameters is the reason for a theoretically infinite sensitivity in the proximity of the exceptional point. Recently, higher-order exceptional points have demonstrated the possibility of achieving the nth root dependence of the eigenfrequency splitting on perturbations. However, the exceptional sensitivity to external parameters is, at the same time, the major drawback of non-Hermitian configurations, leading to the high influence of noise. In this review, the basic principles of PT-symmetric and anti-PT-symmetric Hamiltonians will be shown, both in photonics and in electronics. The influence of noise on non-Hermitian configurations will be investigated and the newest solutions to overcome these problems will be illustrated. Finally, an overview of the newest outstanding results in sensing applications of non-Hermitian photonics and electronics will be provided.

A novel BRD4-LEUTX fusion in a pediatric sarcoma with epithelioid morphology and diffuse S100 expression.

Malignant epithelioid soft tissue tumors encompass a wide spectrum of lesions. Among them, Epithelioid Malignant Peripheral Nerve Sheath Tumors (MPNST) constitute a distinct subgroup, accounting for <5% of all MPNST. Epithelioid MPNST are infrequently associated with neurofibromatosis type 1, occasionally arise in a schwannoma and show diffuse S100 and CD34 expression, often combined with INI-1 loss. However, the molecular mechanisms underlying the tumorigenesis of epithelioid MPNST remain largely unknown. We describe a case of a 10-year-old girl with an epithelioid malignancy of the orbit. The tumor proved positive for S100, CD34 and SOX10, and, although INI-1 expression was maintained, the overall features suggested the possibility of an epithelioid MPNST, arising in an unusual location. NGS analysis revealed a novel in-frame BRD4-LEUTX fusion gene. LEUTX plays an important role in embryonal genome activation and its expression is mostly suppressed postnatally. We were able to detect increased levels of LEUTX transcript in the tumor, indicating that BRD4-LEUTX fusion leads to LEUTX re-activation. To our knowledge, this fusion has never been reported previously. Whether the current case represents an example of epithelioid MPNST or a distinct tumor entity remains to be determined.

Compact resonant 2 × 2 crossbar switch using three coupled waveguides with a central nanobeam.

This theoretical simulation paper presents designs and projected performance of ∼1550-nm silicon-on-insulator (SOI) and ∼2000-nm Ge-on-Si-on-nitride and Ge-on-nitride 2×2 optical crossbar switches based upon a three-waveguide coupler in which the central waveguide is a nanobeam actuated by the thermo-optical (TO) effect. A TO heater stripe is located atop the central nanobeam. To implement accurate and realistic designs, the 3D finite difference time domain approach was employed. The metrics of crossbar switching, insertion loss (IL) and crosstalk (CT) were evaluated for choices of 3-waveguide structure parameters and TO-induced index changes. The predicted ILs and CTs were excellent, enabling the designed devices to be considered as fundamental building blocks in wavelength-division-multiplexed cross-connect (WXC) applications. Proposed here are compact, nonblocking space-and-wavelength routing switches to be constructed in a monolithic, industry-standard SOI chip (and in Ge-on-SON and GON chips). Specifics are given for realizing 16 × 16 × Mλ WXCs as well as reconfigurable, multi-resonant, programmable hexagonal and diamond meshes.

Role of centers with different patient volumes in the management of rhabdomyosarcoma. An analysis by the Italian Pediatric Soft Tissue Sarcoma Committee.

PROCEDURE: The survival of children with rhabdomyosarcoma (RMS) has gradually improved as a result of the adoption of multidisciplinary treatments. Dedicated skills and facilities are indispensable and more readily available at reference centers. In this study, we examined the role of centers' experience (based on the number of patients treated) in their management of patients with RMS. METHODS: We analyzed 342 patients with localized RMS enrolled in the European RMS 2005 protocol from October 2005 to December 2016 at 31 Italian centers that are part of the Soft Tissue Sarcoma Committee (STSC). We grouped the centers by the number of patients each one enrolled (Group 1: >40; Group 2: <40 and >10; and Group 3: <10), and compared a number of indicators to assess the appropriateness of patients' diagnostic workup and treatment and their survival. RESULTS: Overall, 74.6% of patients were treated at 10 centers, and only three of them classifiable as high-volume centers. Only minor differences emerged between the three patient groups in terms of diagnostic investigations and treatment modalities. Survival was similar in the three groups. Approximately, one in four children treated at the centers in Groups 2 and 3 traveled to another center for surgery or radiotherapy. CONCLUSION: Patients treated at STSC centers with different amounts of experience had similar results in terms of survival. This is attributable to all centers in the network adhering to protocol recommendations and receiving the STSC's support on diagnostics and multidisciplinary treatments for RMS.

Ultrafast electro-optical disk modulators for logic, communications, optical repeaters, and wavelength converters.

We propose a U-shaped pn junction in a silicon-on-insulator microdisk resonator to effectively double the junction-mode overlap in the state-of-the-art, vertical pn junction microdisk electro-optical (EO) modulators. The U-shaped pn junction promotes the maximum overlap between the junction depletion zone and the whispering gallery optical mode in the microdisk. By fully depleting the p region of the npn-sequenced U-junction, the capacitance is reduced below 3 fF, which significantly improves the speed and power performance. In this work, we implement the high-efficiency, depleted U-junction design to maximize the operating bandwidth of EO modulators, EO logic elements, EO 2 × 2 switches for wavelength-division cross-connects, 2 × 2 reconfigurable optical add-drop multiplexers, optical-to-electrical-to-optical (OEO) repeaters-with-gain, OEO wavelength converters, and 2 × 2 optical-optical logic gates. These devices all operate in the 7.6-to-50 GHz bandwidth range with ultralow energy consumption between 0.4 and 9.8 fJ/bit. By using CMOS-compatible materials and fabrication-feasible design dimensions, our proposed high-performance devices offer a promising potential in next-generation, high-volume electro-optical communications and computing circuits.

Isavuconazole Treatment of Cerebral and Pulmonary Aspergillosis in a Pediatric Patient With Acute Lymphoblastic Leukemia: Case Report and Review of Literature.

Invasive aspergillosis in hematologic pediatric patients is an opportunistic infection that is difficult to treat, with a high mortality rate when localized in the central nervous system. We are describing a 3-year-old girl who was affected by acute lymphoblastic leukemia who developed cerebral and pulmonary aspergillosis during induction chemotherapy. The patient failed first-line voriconazole treatment because of being a CYP2C19 ultrarapid metabolizer and received effective isavuconazole therapy with no notable side effects.

On-Chip Group-IV Heisenberg-Limited Sagnac Interferometric Gyroscope at Room Temperature.

A room-temperature strip-guided "manufacturable" Silicon-on-Insulator (SOI)/GeSn integrated-photonics quantum-gyroscope chip operating at 1550 nm is proposed and analysed. We demonstrate how the entangled photons generated in Si Spontaneous Four Wave Mixing (SFWM) can be used to improve the resolution of a Sagnac interferometric gyroscope. We propose different integrated architectures based on degenerate and non-degenerate SFWM. The chip comprises several beam splitters, two SFWM entangled photon sources, a pump filter, integrated Mach-Zehnder interferometric gyro, and an array of waveguide coupled GeSn/Ge/Si single-photon avalanche detectors. The laser pumped SWFM sources generate the signal-idler pairs, which, in turn, are used to measure the two-photon, four-photon, and higher order coincidences, resulting in an increasing of the gyro resolution by a factor of two and four, with respect to the classical approach.

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers.

Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.

High-sensitivity real-splitting anti-PT-symmetric microscale optical gyroscope.

Optical gyroscopes measure the angular velocity using the Sagnac effect. However, the resonance splitting due to the Sagnac effect is directly proportional to the linear dimensions of the device. Consequently, integrated optical gyroscopes are still the subject of research. We propose the idea and the design of an anti-parity-time (APT)-symmetric optical gyroscope exhibiting a resonance splitting independent from the dimensions of the device. With a 80 µm×40 µm footprint integrated device, we demonstrated that it is possible to achieve a resonance splitting 106 times higher than the one obtained through the classical Sagnac effect. With respect to the previously proposed parity-time (PT)-symmetric gyroscope, our solution exhibits a real frequency splitting, directly measurable at the output power spectrum. Moreover, it can be kept at its exceptional point more accurately than the PT-symmetric counterpart. Finally, the anti-PT-symmetric gyroscope presented here can detect the sign of the angular velocity differently from the PT-symmetric one.

HCV resistance compartmentalization within tumoral and non-tumoral liver in transplanted patients with hepatocellular carcinoma.

BACKGROUND & AIMS: We investigated the HCV-RNA amount, variability and prevalence of resistance-associated substitutions (RASs), in plasma, hepatic tumoral and non-tumoral tissue samples in patients undergoing liver-transplant/hepatic-resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis. METHODS: Eighteen HCV-infected patients undergoing LT/HR, 94.0% naïve to direct-acting antivirals (DAAs), were analysed. HCV-RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non-tumoral tissues were analysed using Sanger and Ultra-deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic-variability and phylogenetic analysis were evaluated. RESULTS: At the time of LT/HR, HCV-RNA was quantifiable in all compartments of DAA-naïve patients and was generally lower in tumoral than in non-tumoral tissues (median [IQR] = 4.0 [1.2-4.3] vs 4.3[3.1-4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV-RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non-tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected-patients, and by UDPS in other two patients. HCV-compartmentalization resulted to be associated with HBcAb-positivity (P = 0.013). UDPS showed approximately higher genetic-variability in NS3/NS5A sequences in all compartments. Phylogenetic-analysis showed defined and intermixed HCV-clusters among/within all compartments, and were strongly evident in the only non-cirrhotic patient, with plasma and non-tumoral sequences generally more closely related. CONCLUSIONS: Hepatic compartments showed differences in HCV-RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV-strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs.

Human Fibrinogen Concentrate and Fresh Frozen Plasma in the Management of Severe Acquired Hypofibrinogenemia in Children With Acute Lymphoblastic Leukemia: Results of a Retrospective Survey.

OBJECTIVE OF THE STUDY: In this study we aimed to retrospectively evaluate how centers, belonging to the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP), manage severe acquired hypofibrinogenemia in children with acute lymphoblastic leukemia, particularly evaluating the therapeutic role of human fibrinogen concentrate (HFC) and fresh frozen plasma (FFP). METHODS: We conducted a survey among AIEOP centers; thereafter, we collected and analyzed data with regard to the treatment of episodes of severe acquired hypofibrinogenemia occurring during the induction and reinduction phases of the AIEOP-BFM ALL 2009 protocol. RESULTS: In total, 15 of the 37 AIEOP centers invited to join the survey agreed to collect the data, with 10 and 5 centers declaring to react to severe acquired hypofibrinogenemia (<70 mg/dL) by administering HFC or FFP, respectively. Of the 150 episodes of severe hypofibrinogenemia occurring in 101 patients, 47.3% were treated with HFC and 52.7% with FFP, with a normalization of fibrinogen levels achieved in greater proportion and in a shorter amount of time in the HFC group as compared with the FFP group. None of the patients presented with bleeding or thrombosis during the observation period. CONCLUSIONS: Even with the limitations of the retrospective nature of this study, HFC seems to be a safe and effective alternative to FFP for replacement therapy in case of severe hypofibrinogenemia in children with acute lymphoblastic leukemia.

Invasive mucormycosis in children with cancer: A retrospective study from the Infection Working Group of Italian Pediatric Hematology Oncology Association.

BACKGROUND: Invasive mucormycosis is a rare but frequently fatal fungal disease. The acute and rapidly progressive evolution causes unfavourable outcome in 22%-59% of patients and its treatment represents a clinical challenge, especially in immunocompromised patients. Current data in paediatric oncological patients are limited. OBJECTIVES: The infection Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) analysed the episodes of invasive mucormycosis occurred between 2009 and 2016. PATIENTS: Fifteen cases of proven mucormycosis (male/female 8/7; median age 14.1 years, range 7.7-18.6) were reported after chemotherapy for acute leukaemia and lymphoma (12) and allogeneic stem cell transplantation (3). The aetiology was Rhizopus oryzae 4, Lichtheimia corymbifera 3 and Mucor spp. 8. RESULTS: Paranasal sinus was the primary site of infection in 14/15 patients combined with orbital involvement (9), central nervous system (8), lung (4), thyroid gland and kidney (1). All patients received liposomal Amphotericin B (L-AmB) (3-10 mg/kg), with surgical debridement in 14/15 cases. Eleven patients received maintenance treatment with posaconazole (9) or isavuconazole (2). Eight out of fifteen patients (53.3%) died, after 3-6 months. CONCLUSIONS: Mucormycosis involved mainly the sinu-orbital site and affected children >10 years. Despite aggressive treatment with high-dose L-AmB and timely surgical debridement, the mortality rate remains still high.

Methane Gas Photonic Sensor Based on Resonant Coupled Cavities.

In this paper we report methane gas photonic sensors exploiting the principle of absorption-induced redirection of light propagation in coupled resonant cavities. In particular, an example of implemented architecture consists of a Fabry-Pérot (FP) resonator coupled to a fibre ring resonator, operating in the near IR. By changing the concentration of the methane gas in the FP region, the absorption coefficient of the FP changes. In turn, the variation of the methane gas concentration allows the redirection of the light propagation in the fibre ring resonator. Then, the methane gas concentration can be evaluated by analysing the ratio between the powers of two resonant modes, counter-propagating in the fibre ring resonator. In this way, a self-referenced read-out scheme, immune to the power fluctuations of the source, has been conceived. Moreover, a sensitivity of 0.37 ± 0.04 [dB/%], defined as the ratio between resonant modes at different outputs, in a range of methane concentration included between the 0% and 5%, has been achieved. These results allow a detection limit below the lower explosive limit (LEL) to be reached with a cost-effective sensor system.

Tunable optical-microwave filters optimized for 100 MHz resolution.

New continuously tunable RF-spectrum analyzers, RF receivers, and RF signal generators are proposed and analyzed for the silicon-on-insulator integrated-photonic platform at the ~1550 nm wavelength. These RF system-on-a-chip applications are enabled by a new narrowband 2x2 Mach-Zehnder interferometer (MZI) tuned filters for reconfigurable multiplexing, demultiplexing and RF channel selection. The filter can be optimized for ~100 MHz 3-dB bandwidth (BW) by utilizing N closely coupled Bragg-grating resonators to form one effective waveguide resonator in the single-mode silicon nanowire used for each MZI arm. The number of periods M within each individual resonator is selected to engineer BW in the 0.1 to 1 GHz range. Butterworth design is employed. Continuous tuning of the 100 MHz-BW devices over 18.6 GHz has been simulated by using local micron-scale thermo-optical heater stripes on the MZI arms with a temperature rise from 0 to 48K. For the case of N = 3 and 100-nm silicon side teeth, some representative performance predictions are: insertion loss (IL) = -10.7 dB, BW = 80.5 MHz and L = 113 µm for M = 58; while IL = -0.74 dB, BW = 1210 MHz and L = 86 µm for M = 44.

Reconfigurable optical-microwave filter banks using thermo-optically tuned Bragg Mach-Zehnder devices.

A new reconfigurable, tunable on-chip optical filter bank is proposed and analyzed for the silicon-on-insulator platform at the ~1550 nm wavelength. The waveguided bank is a cascade connection of 2 x 2 Mach-Zehnder interferometer (MZI) filters. An identical standing-wave resonator is situated in each MZI "arm." Using the thermo-optic (TO) effect to perturb this waveguide's index, the TO heater stripes provide continuous tuning of the filter by shifting the resonance smoothly along the wavelength axis. To reconfigure and program the cascade array, a broadband 2 x 2 MZI-related switch is inserted between adjacent filters. The novel TO switch, described here, can provide either single or double interconnection of 2 x 2 filters. The filter resonator is a new in-guide array of N closely coupled phase-shifted Bragg-grating resonators that provide one resonant spectral profile with 5 to 100 GHz bandwidth. The length of each grating cavity in the N group is chosen according to the Butterworth filter technique, and this gives high peak transmission for the composite. The predicted spectral profiles of a three-stage cascade show two-or-three peaks, or two-or-three notches with movable wavelength-locations as well as tunable wavelength-separations between those features. A tunable notch within a wider movable passband is also feasible. Potential applications include microwave photonics, wavelength-selective systems, optical spectroscopy and optical sensing.