Tandem Ring Research Articles

PO0115: Validation of Scintillator-Based In Vivo Dosimetry for Pulsed Dose Rate Brachytherapy with Tandem Ring Applicators for Cervical Cancer

PO0115: Validation of Scintillator-Based In Vivo Dosimetry for Pulsed Dose Rate Brachytherapy with Tandem Ring Applicators for Cervical Cancer

Palladium-catalyzed double activation of Si-C(sp3) bond of benzosilacyclobutenes synergized with unexpected olefin migration and ring-opening hydrolysis

A regioselective silicon-carbon bond activation of silacycles has emerged as a powerful strategy to access organosilicon compounds with functional groups. In contrast, progress in the development of new reaction systems for the tandem and double Si-C bond activation of silacycles has lagged. In this regard, there have been no reports of Si-C(sp3) bond activation of benzosilacyclobutenes and its tandem transformations. Herein, we address this challenging, disclosing the first example of palladium-catalyzed double Si-C bond activation of benzosilacyclobutenes and its tandem ring expansion and ring-opening transformations, in which various functionalized silanols that have ester groups are synthesized in this reaction. The main feature of this novel transformation is the highly selective activation of the Si-C(sp3) bond of benzosilacyles to achieve [4 + 2] cycloaddition with ester-activated alkynes and subsequent ring-opening and σ-bond metathesis with H2O. Moreover, the DFT studies realized the origin of Si-C(sp3) bond activation, olefin migration, and ring-opening hydrolysis in the unprecedent reaction process.

Non-reciprocity in a silicon photonic ring resonator with time-modulated regions.

Non-reciprocity and breaking of the time-reversal symmetry is conventionally achieved using magneto-optic materials. However, the integration of these materials with complementary metal-oxide semiconductor (CMOS)-compatible platforms is challenging. Temporal modulation is a well-suited approach for achieving non-reciprocity in integrated photonics. However, existing experimental implementations based on this method in silicon uses traveling-wave modulation in the whole structure or tandem ring or waveguide modulators, and they lead to high insertion loss and large footprint. In this work we achieve, to the best of our knowledge, the first experimental demonstration of non-reciprocity in a compact single silicon photonic ring resonator with time-modulated regions, fabricated with a CMOS-compatible commercial foundry. We demonstrate symmetry breaking of counter-rotating modes in an active silicon photonic ring resonator by applying phase-shifted RF signals to only two small p-i-n junctions on the ring, without employing traveling-wave modulation in the whole structure. The non-reciprocity is caused by the cross-coupling between the counter-rotating modes of the ring, which breaks their degeneracy. By reversing the polarity of the RF phase difference (e.g. (45°,-45°) asymmetric phases) opposite resonance wavelengths are obtained, with a 16-dB contrast between the transmissions of the asymmetric phases and a low insertion loss of 0.6 dB under 27 dBm RF power. We achieve the highest ratio of the asymmetric transmission to the insertion loss, among the state-of-the-art silicon non-reciprocal integrated optical structures based on time varying modulation. The non-reciprocal ring can be used as a magnetic-free, low-loss, compact, and CMOS-compatible integrated optical isolator.

A Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid.

Sutezolid is an in-development thiomorpholine derivative of the FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic routes for preparing sutezolid start with thiomorpholine as a key structural building block; unfortunately, this material was identified as a major cost driver for the API, which will limit the potential uptake of this treatment in lower income regions. In this work, an alternative, lower-cost synthetic strategy to a known p-phenylenediamine intermediate to sutezolid has been demonstrated. The key step in this process is the construction of the thiomorpholine ring by a nucleophilic sulfide ring closure on an activated bis(2-hydroxyethyl)-functionalized aniline, which was in turn made by reaction of 3,4-difluoronitrobenzene and diethanolamine. This sulfide treatment has the added benefit of affecting a Zinin reduction of the nitro functional group, which alleviates the need for the transition metal reduction used in previous routes. After optimization, this key reaction was able to provide the desired aniline intermediate in yields between 65 and 80% and, after a standard charcoal treatment, purity of >94%. Initial demonstrations of the full 3-step strategy were successfully conducted on scales up to 100 g with overall yields of 53-68%. This preliminary work will serve as the foundation for a broader low-cost redesign of the sutezolid synthetic process.

Visible-light-induced tandem ring opening/1,6-conjugate addition of cyclobutanols with p-quinone methides under metal- and additive-free conditions

A visible-light-mediated tandem ring opening/1,6-conjugate addition of cyclobutanols with p-quinone methides was developed. This protocol allowed the formation of δ,δ-diaryl ketones in the presence of a readily available organic photocatalyst.

Effect of External Beam Radiation Therapy (EBRT) and Brachytherapy (BT) on Circulating MDSC Populations in Patients Treated Definitively for Cervical Cancer

The immunosuppressive function of myeloid derived suppressor cells (MDSCs) has been implicated in the regulation of immune responses against cancer. MDSCs have been associated with progression and poor response to therapy in various types of cancer, including cervical cancer. Radiation treatment (RT) alters immune cell populations within the tumor and is thought to augment antitumor responses. However, whether RT also recruits immunosuppressive MDSC populations is not well understood. Here, we investigate how circulating MDSC populations change in response to RT and if changes in MDSC frequency or subsets is predictive of RT responses in cervical cancer patients. Newly diagnosed, treatment-naïve pts with locally advanced carcinoma of the cervix will be enrolled from July 2022 to July 2023. EBRT to the pelvis was delivered at a dose of 45 Gy in 25 fractions with a simultaneous integrated boost of 52-55 Gy to involved regional lymph nodes and parametria and concurrent weekly cisplatin. Gross tumor was boosted via interstitial or tandem ring BT (22.5-27.5 Gy) after completion of EBRT. Serial blood samples were collected prior to initiating therapy (T0), post-EBRT and pre-BT (T1), and one-month post-BT (T2). Treatment response was determined based on pre-treatment MRI compared to MRI post-EBRT. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood using density gradient centrifugation and stained for analysis via flow cytometry. MDSC populations were identified by Live/Dead-CD11b+CD33+HLA-DR- staining. MDSC subsets were further subdivided into granulocytic (G-, CD15+CD14-), monocytic (M-, CD15-CD14+), or early-MDSCs (e-, CD15-CD14-). Blood samples were collected at indicated time points for four patients (FIGO stage IIA-IIB). Three had partial responses to chemoradiotherapy (CRT), while one had a complete response. All three patients with partial response had an increase in total frequency of circulating MDSCs in response to EBRT/BT (mean %fx MDSC 16.6 at T0 to 35.9 at T2), and an increase in total MDSCs in two of these patients occurred with EBRT alone. Interestingly, the patient that had a complete response had fewer MDSCs at T2 relative to T0 (35.8% at T0 to 27% at T2). Proportion of MDSC subsets varied considerably among the patients, and all had altered distribution of subsets in response to RT. G-MDSCs expanded the most to RT while M-MDSCs and e-MDSCs were less affected (mean fold change from T0 to T2 G-MDSC 4.75, M-MDSC 1.27, e-MDSC 0.942). In this cohort of patients, an increase in MDSC frequency occurred after RT and altered subset distribution. Only the patient with a complete response had fewer total MDSCs following completion of CRT, suggesting further studies are needed to determine if circulating MDSCs could be a biomarker for treatment response to RT in cervical cancer.

Synthesis of Curved Polycyclic Arenes Embedded with Oxepine and Thiepine Using Ring Expansion Strategy.

A tandem oxidative ring expansion of a six- to seven-membered ring was developed to construct a new class of negatively curved polycyclic arenes embedded with oxepine and thiepine, namely, dibenzo[b,f]phenanthro[9,10-d]oxepine (DBPO) and dibenzo[b,f]phenanthro[9,10-d]thiepine (DBPT), respectively. Mechanistic studies disclosed that an unexpected [4 + 2] cycloadduct formed between the alkene moiety of o-biphenyl-linked methylenexanthenes and o-chloranil serves as a radical cation or a dication equivalent that facilitates the FeCl3-mediated tandem ring expansion process.

HFO‐1234yf as a CF3 Building Block: Synthesis of Trifluoromethyl Quinoline and Chromene Derivatives from Trifluoromethyl‐ynones

AbstractTrifluoromethyl ynones derived from the refrigerant gas HFO‐1234yf (2,3,3,3‐tetrafluoropropene) react with nucleophiles via a Michael‐type addition process and the allenolate intermediate formed reacts intramolecularly with a carbonyl group to form heterocyclic derivatives. Thus, reaction of 2‐amino and 2‐hydroxyl benzaldehyde or ketone substrates with trifluoromethyl ynone derivatives gives trifluoromethyl quinoline and chromene products by a one‐pot tandem ring closing sequence, forming pharmaceutically relevant structures from an inexpensive starting material without the need for transition metals or column chromatography. The 2‐trifluoromethylquinoline products also show unusual fluxional behaviour, which was explored through 2‐D NMR and X‐ray crystallographic studies.

Organocatalytic Cloke–Wilson Rearrangement: Carbocation-Initiated Tandem Ring Opening/Cyclization of Cyclopropanes under Neutral Conditions

We report a metal-, acid-, and base-free 2-(bromomethyl)naphthalene (2-BMN)-promoted organocatalytic Cloke-Wilson rearrangement of chain doubly activated cyclopropanes for the construction of 2,3-dihydrofurans via a carbocation-initiated tandem intramolecular ring-opening/recyclization process. The strategy is especially suitable for the construction of furan units in complex molecules, providing a solution to the problem of heavy-metal residues in dihydrofuran-containing drugs synthesized by traditional metal-based protocols. Thus, it is of potential interest in synthetic and medicinal chemistry.

Polymeric α-diimine palladium catalysts for olefin (co)polymerization

In this contribution, a series of α-diimine palladium complexes with two vinyl units were designed and synthesized. Tandem ring opening metathesis polymerization/cross metathesis of cycloolefins in the presence of these complexes as chain-transfer agents resulted in a series of well-defined polymeric α-diimine Pd catalysts with improved catalytic performances. These polymeric Pd complexes can catalyze polymerization of ethylene and result in increased molecular weight of polyethylene products compared with their molecular analogues. In the polymerization of 1-hexene, the polymeric catalysts led to less isomerization, resulting in increased conversions of 1-hexene and higher molecular weights. Moreover, polymeric palladium catalysts show improved tolerance to polar comonomers, leading to higher activities as well as higher molecular weights in ethylene–methyl acrylate copolymerization. Most importantly, tuning of catalyst performance can be achieved by varying the structure or amount of cyclic monomer used in the preparation of these well-defined polymeric catalysts starting from the simple homogeneous platform.

Reagent‐Controlled Chemodivergent Approach to Thiazolines and Thiazines from α‐N‐Hydroxyimino Dithioesters

AbstractA chemoselective route to thiazolines and thiazines has been devised by heterocyclization of viable α‐N‐hydroxyimino‐β‐oxodithioesters with 2‐chloroethylamine hydrochloride/3‐chloropropylamine hydrochloride, which does not require metals or additives and proceeds at 0–60 °C. The overall transformation involves base mediated intramolecular cyclization of α‐N‐hydroxyimino‐β‐oxodithioesters to 4‐membered oxazete‐4‐thione intermediates followed by coupling with chloroalkyl amines via tandem ring cleavage and C−N/C−S bonds formation enabling the construction of thiazolines/thiazines in one‐pot. This strategy allows broadening the arsenal of synthetic methods to obtain N,S‐heterocycles utilizing substrates prepared according to reported procedures.magnified image

Nickel‐Catalyzed Tandem Ring Contraction of TEMPO and C−N Bond Transamination of Enaminones toward Amino Diversity of Enaminones

AbstractThe reactions of N,N‐substituted enaminones with TEMPO leading to the synthesis of 2,2‐dimethyl pyrrolidine functionalized new enaminones have been established by Ni(II) catalysis. The interesting ring contraction on TEMPO as well as the enaminone C−N bond amination bring new tool for generating molecular diversity of enaminones in the amino group fragment.

Intracavitary brachytherapy with additional Heyman capsules in the treatment of cervical cancer

PurposeBrachytherapy is a mandatory component of primary radiochemotherapy in cervical cancer. The dose can be applied with a traditional intracavitary approach (IC alone) or with multiple catheter brachytherapy to optimize dose distribution in an individual concept. We therefore evaluated whether the utilization of a tandem–ring applicator plus additional intracavitary applicators (add IC) provides an advantage over the traditional IC alone approach, as this method is less time consuming and less invasive compared to a combined intracavitary/interstitial brachytherapy.MethodsTwenty three procedures of intracavitary brachytherapy for cervical cancer with additional intracavitary applicators performed in seven patients treated between 2016 and 2018 in our institution were included in this study. Plans were optimized for D90 HR-CTV with and without the utilization of the additional applicators and compared by statistical analysis.ResultsD90 for HR-CTV was 5.71 Gy (±1.17 Gy) for fractions optimized with add IC approach and 5.29 Gy (±1.24 Gy) for fractions without additional applicators (p < 0.01). This translates to a calculated mean EQD2 HR-CTV D90 of 80.72 Gy (±8.34 Gy) compared to 77.84 Gy (±8.49 Gy) after external beam therapy and four fractions of brachytherapy for add IC and IC alone, respectively (p < 0.01). The predictive value of improved coverage of HR-CTV in the first fraction was high.ConclusionIn a subgroup of cases, the addition of intracavitary Heyman capsules can be an alternative to interstitial brachytherapy to improve the plan quality compared to standard IC alone brachytherapy. The benefit from the addition of applicators in the first fraction is predictive for the following fractions.

Comparison of Vaginal Dosimetry Between Tandem Ovoid (TO) and Tandem Ring (TR) Applicator in CT-Based High Dose Rate Intracavitary Brachytherapy of Cervix

Comparison of Vaginal Dosimetry Between Tandem Ovoid (TO) and Tandem Ring (TR) Applicator in CT-Based High Dose Rate Intracavitary Brachytherapy of Cervix

Dose to pelvic lymph nodes in locally advanced cervical cancer during high-dose-rate brachytherapy with tandem-ring applicators.

PurposeThe present study aimed to assess the correlation between dose to pelvic lymph nodes and to point B with tandem-ring (TR) applicators for intra-cavitary brachytherapy treatment of locally advanced cervical cancer.Material and methodsCervical cancer patients treated at brachytherapy department of Lucien Neuwirth Cancer Center, from 2015 to 2018, were included. Target delineation was performed in compliance with GEC-ESTRO guidelines. Revised American Brachytherapy Society (ABS) point A was determined (ARN (right) and ALN (left)) as well as Manchester point B. Prescription dose was 25-35 Gy in 5 fractions. Pelvic lymph nodes were delineated, then dose to points A and B, and dose-volume histogram (DVH) parameters of delineated lymph nodes were extracted. Significant relationships or correlations between lymph nodes reference points, dosage to points B, and their DVH parameters were investigated.ResultsThe mean dose and mean percentage of the prescription dose to the left and right points B were 4.6 ±0.18 Gy and 82.08 ±0.72%, respectively. Pearson correlation coefficient R = 0.81 (p-value = 0.00) between dose to ARN and ALN points and prescription dose was obtained. Negative correlation between CTVHR volume and difference between French and ABS prescription points was found.ConclusionsDose to point B can be a moderate surrogate for maximum, minimum, and median dose to the internal iliac and presacral lymph node, but cannot be for maximum dose to the obturator lymph node. Points B cannot be a reliable substitute for common and external iliac chains.

Automatic contouring using deformable image registration for tandem-ring or tandem-ovoid brachytherapy.

PurposeTo investigate the effectiveness of deformable image registration (DIR)-based automatic contouring for tandem-ring (T-R) or tandem-ovoid (T-O) 3-dimensional computed tomography (CT)-based image-guided brachytherapy (IGBT).Material and methodsCT images of 28 patients with intact cervical cancer were retrospectively analyzed. Selected group had T-R or T-O insertion for IGBT. Hybrid DIR was performed between first fraction CT and subsequent CTs for IGBT. First IGBT CT images were reference images. All DIRs were performed based on these first IGBT CT scans. Contour similarities between manual and automated segmentations were evaluated with dice similarity coefficient (DSC) score. Mean volumes of the structures were delineated manually and automatically compared. Finally, dosimetric comparisons were performed in order to obtain how contour differences affect the doses to target and organs at risk (OARs).ResultsIn general, mean volumes of the automatic contours were larger than manual contours for both T-R and T-O insertions. However, the difference in volume was statistically significant for the small bowel only (p < 0.05 and p < 0.01 for T-R and T-O, respectively). The DSC scores were small for the small bowel and the sigmoid in both applicator sets. When the two different applicator sets were compared, the performance of DIR-based contour propagation for the rectum was worse in T-O compared to T-R application. Dosimetric comparisons showed that volume differences between the manual and propagated contours did not affect dose-volume parameters. The treatment plans based on manually contoured targets also well-covered DIR contours. The average time for DIR was 2.0 ±0.1 minutes per fraction compared to 14.0 ±0.4 minutes in manual contouring (p < 0.001).ConclusionsDIR-based automatic contouring of the structures seems successful for both the T-R and T-O applications in cervical IGBT. DIR significantly decreased the time for contouring. Our results indicate that automatic contouring in IGBT is safe and time-saving.

Development of New Synthetic Methods for Carbazole Compounds Aimed at Drug Discovery and Exploratory Research on Pharmaceutical Materials

We are developing the synthesis of biologically interesting carbazole compounds, including natural products by tandem cyclic reactions. In this report, we describe the new synthesis of carbazole-1,4-quinones as follows; 1) the synthesis of carbazole-1,4-quinones using a tandem ring closing metathesis (RCM) -dehydrogenation reaction, 2) a novel one-pot synthesis of carbazole-1,4-quinone by consecutive Pd-catalyzed cyclocarbonylation, desilylation, and oxidation reactions. Two new synthetic strategies were applied to the synthesis of carbazole-1,4-quinone alkaloids and ellipticine quinones, and then the antiproliferative activity against HCT-116 and HL-60 cells of the synthesized compounds were evaluated.

Comparative dosimetry of brachytherapy treatment planning between a volume-based plan by CT and a point-based plan by TAUS in CT datasets for brachytherapy

Abstract Aim: To evaluate comparative dosimetry of brachytherapy treatment planning between a volume-based plan by computed tomography (CT) and a point-based plan by transabdominal ultrasound (TAUS) in CT datasets for brachytherapy. Materials and methods: From 2019 to 2021, 59 different datasets of CT images were collected from 38 patients treated by intracavitary brachytherapy with tandem ovoid or tandem ring applicators. At that time, TAUS was performed to prevent uterine perforation and to evaluate topography of the cervix during application. In volume-based planning by CT, the target dose was used to keep the dose at 90% of high-risk clinical target volume (HR-CTV), to give a dose of at least 7Gy, while in the point-based plan by TAUS, the target dose was used to keep the minimum dose to eight cervix reference points (measured by TAUS), to give a dose of at least 7Gy. The doses to targets and organs at risk were evaluated and compared between volume-based planning by CT and the point-based plan by TAUS. Results: Of 59 fractions, a tandem ovoid applicator was used in 48 fractions (81·3%). In the volume-based plan by CT, the mean doses to HR-CTV(D90), intermediate-risk clinical target volume (IR-CTV)(D90), bladder(D2cc), rectum(D2cc) and sigmoid colon(D2cc) were 7·0, 3·9, 4·9, 2·9 and 3·3 Gy, respectively, while in the point-based plan by TAUS, the mean doses to HR-CTV(D90), IR-CTV(D90), bladder(D2cc), rectum(D2cc) and sigmoid colon(D2cc) were 8·2, 4·6, 5·9, 3·4 and 3·9 Gy, respectively. The percentages of mean dose differences between TAUS and CT of HR-CTV(D90), IR-CTV(D90), bladder(D2cc), rectum(D2cc) and sigmoid colon(D2cc) were 17·7, 19·5, 20·5, 19·5, 21·3 and 19·8%, respectively. With the target dose to the point-based plan by TAUS (7 Gy to the cervix reference points), this was close to D98 of HR-CTV with a mean percentage of difference of 0·6%. Findings: The point-based plan by TAUS showed higher values to targets and organs at risk than the volume-based plan by CT. With the point-based plan by TAUS, it was close to D98 of HR-CTV.

Automatic Contouring Using Deformable Image Registration for Tandem-Ring or Tandem-Ovoid Brachytherapy

To investigate the effectiveness of deformable image registration (DIR)-based automatic contouring for tandem-ring (T-R) or tandem-ovoid (T-O) 3-dimensional computed tomography (CT)-based image-guided brachytherapy (IGBT).CT images of 28 patients with intact cervical cancer were retrospectively analyzed. The selected group had T-R or T-O insertion for IGBT. The hybrid DIR was performed between the first fraction CT and the subsequent CTs of the IGBT. The first IGBT CT images were the reference images. All DIRs were performed based on these 1st IGBT CT scans. The contour similarities between the manual and automated segmentations were evaluated with Dice Similarity Coefficient (DSC) score. Mean volumes of the structures delineated manually and automatically were compared. Finally, dosimetric comparisons were performed in order to obtain how contour differences affect the target and organs at risk (OARs) doses.In general, mean volumes of the automatic contours were larger than manual contours for both T-R and T-O insertions. However, the difference in the volume was statistically significant for the small bowel only (P < 0.05 and P < 0.01 for T-R and T-O, respectively). The DSC scores were small for small bowel and sigmoid in both applicator sets. When the two different applicator sets were compared, the performance of DIR-based contour propagation for the rectum was worse in the T-O than the T-R application. Dosimetric comparisons showed that the volume differences between the manual and propagated contours did not affect the dose distributions. The plans based on manually contoured targets also covered the DIR contours well. The average time for DIR was 2 ± 0.1 minutes per fraction compared to 14 ± 0.in manual contouring (P < 0.001).DIR-based automatic contouring of the structures seems successful for both the T-R and T-O applications in cervical IGBT. DIR significantly decreased the time for contouring. Our results indicate that automatic contouring in IGBT is safe and time-saving.

Efficient one-pot tandem synthesis and cytotoxicity evaluation of 2,3-disubstituted quinazolin-4(3H)-one derivatives

Twenty 2,3-disubstituted quinazolin-4(3H)-one derivatives 1–20 were successfully synthesized in moderate to good yields (25–82%). Their syntheses were based on a one pot tandem ring opening procedure followed by iodine-catalyzed oxidative cyclization of isatoic anhydride with aldehydes, using water as the only solvent under both classical and microwave irradiation conditions. Cytotoxicity assays of the prepared compounds against three human cancer cell lines (HeLa, MCF-7, and A549) indicated that 2, 3, and 20 possessed moderate activities against MCF-7 cells (IC50 = 47.2 μM, 43.9 μM, and 44.9 μM, respectively). Good cytotoxic activities against A549 cells were observed for 3 and 8 with IC50 values of 30.7 μM and 29.8 μM, respectively, which were comparable to the positive control, 5-fluorouracil (5-FU, IC50 = 27.9 μM). Furthermore, compound 4 exhibited slightly stronger activity (IC50 = 23.6 μM) than the positive control 5-FU against the A549 cell line.