The CMG Helicase Bypasses DNA-Protein Cross-Links to Facilitate Their Repair.

Covalent DNA-protein cross-links (DPCs) impede replication fork progression and threaten genome integrity. Using Xenopus egg extracts, we previously showed that replication fork collision with DPCs causes their proteolysis, followed by translesion DNA synthesis. We show here that when DPC proteolysis is blocked, the replicative DNA helicase CMG (CDC45, MCM2-7, GINS), which travels on the leading strand template, bypasses an intact leading strand DPC. Single-molecule imaging reveals that GINS does not dissociate from CMG during bypass and that CMG slows dramatically after bypass, likely due to uncoupling from the stalled leading strand. The DNA helicase RTEL1 facilitates bypass, apparently by generating single-stranded DNA beyond the DPC. The absence of RTEL1 impairs DPC proteolysis, suggesting that CMG must bypass the DPC to enable proteolysis. Our results suggest a mechanism that prevents inadvertent CMG destruction by DPC proteases, and they reveal CMG's remarkable capacity to overcome obstacles on its translocation strand.

To incise or not and where: SET-domain methyltransferases know.

The concept of the histone code posits that histone modifications regulate gene functions once interpreted by epigenetic readers. A well-studied case is trimethylation of lysine 4 of histone H3 (H3K4me3), which is enriched at gene promoters. However, H3K4me3 marks are not needed for the expression of most genes, suggesting extra roles, such as influencing the 3D genome architecture. Here, we highlight an intriguing analogy between the H3K4me3-dependent induction of double-strand breaks in several recombination events and the impact of this same mark on DNA incisions for the repair of bulky lesions. We propose that Su(var)3-9, Enhancer-of-zeste and Trithorax (SET)-domain methyltransferases generate H3K4me3 to guide nucleases into chromatin spaces, the favorable accessibility of which ensures that DNA break intermediates are readily processed, thereby safeguarding genome stability.

Synthesis of Superbulky Amide Ligands by Addition of Polar Reagents to Sila-Imine.

The chemistry of extremely bulky amide ligands is troubled by difficulties in deprotonation of the parent amine. As an alternative route to superbulky amide reagents, the addition of polar reagents to a sila-imine has been investigated. Attempts to synthesize the superbulky amide anion (tBu3Si)2N- by addition of tBuLi to tBu2Si=N(SitBu3) failed and gave tBu3Si(tBu2HSi)NLi and isobutene. Reaction of the sila-imine with KOtBu successfully led to tBu3Si[tBu2(tBuO)Si]NK which crystallized as a separated ion-pair. Reaction with the slightly bulkier KOAd (Ad=1-adamantyl) led in presence of THF to ether ring-opening. Reaction with tBuOH gave tBu3Si[tBu2(tBuO)Si]NH but this amine cannot be easily deprotonated. Reaction with (BDI*)MgnBu in presence of THF gave (BDI*)Mg+ ⋅ (THF)2 and the non-coordinating anion tBu3Si[tBu2(nBu)Si]N-; BDI*=ß-diketiminate ligand HC[C(tBu)N-DIPP]2, DIPP=2,6-diisopropylphenyl. Reaction of Mg(nBu)2 with tBu2Si=N(SitBu3) led to a Mg complex with one amide ligand: tBu3Si[tBu2(nBu)Si]N-. The other superbulky amide anion isomerized by internal deprotonation of a tBu-substituent to give a primary carbanion that is also coordinated to Mg. Although the amide-to-carbanion isomerization is highly contrathermodynamic, it allows for coordination of both anions to a single Mg center. The new bulky amides are rare cases of halogen-free weakly coordinating anions.

Texture analysis of 18F-FDG PET/CT and CECT: Prediction of refractoriness of Hodgkin lymphoma with mediastinal bulk involvement.

To recognize patients at high risk of refractory disease, the identification of novel prognostic parameters improving stratification of newly diagnosed Hodgkin Lymphoma (HL) is still needed. This study investigates the potential value of metabolic and texture features, extracted from baseline 18F-FDG Positron Emission Tomography/Computed Tomography (PET) and Contrast-Enhanced Computed Tomography scan (CECT), together with clinical data, in predicting first-line therapy refractoriness (R) of classical HL (cHL) with mediastinal bulk involvement. We reviewed 69 cHL patients who underwent staging PET and CECT. Lesion segmentation and texture parameter extraction were performed using the freeware software LIFEx 6.3. The prognostic significance of clinical and imaging features was evaluated in relation to the development of refractory disease. Receiver operating characteristic curve, Cox proportional hazard regression and Kaplan-Meier analyses were performed to examine the potential independent predictors and to evaluate their prognostic value. Among clinical characteristics, only stage according to the German Hodgkin Group (GHSG) classification system significantly differed between R and not-R. Among CECT variables, only parameters derived from second order matrices (gray-level co-occurrence matrix (GLCM) and gray-level run length matrix (GLRLM) demonstrated significant prognostic power. Among PET variables, SUVmean, several variables derived from first (histograms, shape), and second order analyses (GLCM, GLRLM, NGLDM) exhibited significant predictive power. Such variables obtained accuracies greater than 70% at receiver operating characteristic analysis and their PFS curves resulted statistically significant in predicting refractoriness. At multivariate analysis, only HISTO_EntropyPET extracted from PET (HISTO_EntropyPET ) and GHSG stage resulted as significant independent predictors. Their combination identified 4 patient groups with significantly different PFS curves, with worst prognosis in patients with higher HISTO_EntropyPET values, regardless of the stage. Imaging radiomics may provide a reference for prognostic evaluation of patients with mediastinal bulky cHL. The best prognostic value in the prediction of R versus not-R disease was reached by combining HISTO_EntropyPET with GHSG stage.

Short-term outcomes of preoperative chemotherapy with docetaxel, oxaliplatin, and S-1 for gastric cancer with extensive lymph node metastasis (JCOG1704).

BACKGROUND: The prognosis for marginally resectable gastric cancer with extensive lymph node metastasis (ELM) remains unfavorable, even after R0 resection. To assess the safety and efficacy of preoperative docetaxel, oxaliplatin, and S-1 (DOS), we conducted a multicenter phase II trial. METHODS: Eligibility criteria included histologically proven HER2-negative gastric adenocarcinoma with bulky nodal (bulky N) involvement around major branched arteries or para-aortic node (PAN) metastases. Patients received three cycles of docetaxel (40 mg/m2, day 1), oxaliplatin (100 mg/m2, day 1), and S-1 (80-120 mg/body, days 1-14), followed by gastrectomy with D2 plus PAN dissection. Subsequently, patients underwent postoperative chemotherapy with S-1 for 1 year. The primary endpoint was major (grade ≥ 2a) pathological response rate (pRR) according to the Japanese Classification of Gastric Carcinoma criteria. RESULTS: Between October 2018 and March 2022, 47 patients (bulky N, 20; PAN, 17; both, 10) were enrolled in the trial. One patient was ineligible. Another declined any protocol treatments before initiation. Among the 45 eligible patients who initiated DOS chemotherapy, 44 (98%) completed 3 cycles and 42 (93%) underwent R0 resection. Major pRR and pathological complete response rates among the 46 eligible patients, including the patient who declined treatment, were 57% (26/46) and 24% (11/46), respectively. Common grade 3 or 4 toxicities were neutropenia (24%), anorexia (16%), febrile neutropenia (9%), and diarrhea (9%). No treatment-related deaths occurred. CONCLUSIONS: Preoperative chemotherapy with DOS yielded favorable pathological responses with an acceptable toxicity profile. This multimodal approach is highly promising for treating gastric cancer with ELM.

Enhancing stereotactic ablative boost radiotherapy dose prediction for bulky lung cancer: A multi-scale dilated network approach with scale-balanced structure loss.

PURPOSE: Partial stereotactic ablative boost radiotherapy (P-SABR) effectively treats bulky lung cancer; however, the planning process for P-SABR requires repeated dose calculations. To improve planning efficiency, we proposed a novel deep learning method that utilizes limited data to accurately predict the three-dimensional (3D) dose distribution of the P-SABR plan for bulky lung cancer. METHODS: We utilized data on 74 patients diagnosed with bulky lung cancer who received P-SABR treatment. The patient dataset was randomly divided into a training set (51 plans) with augmentation, validation set (7 plans), and testing set (16 plans). We devised a 3D multi-scale dilated network (MD-Net) and integrated a scale-balanced structure loss into the loss function. A comparative analysis with a classical network and other advanced networks with multi-scale analysis capabilities and other loss functions was conducted based on the dose distributions in terms of the axial view, average dose scores (ADSs), and average absolute differences of dosimetric indices (AADDIs). Finally, we analyzed the predicted dosimetric indices against the ground-truth values and compared the predicted dose-volume histogram (DVH) with the ground-truth DVH. RESULTS: Our proposed dose prediction method for P-SABR plans for bulky lung cancer demonstrated strong performance, exhibiting a significant improvement in predicting multiple indicators of regions of interest (ROIs), particularly the gross target volume (GTV). Our network demonstrated increased accuracy in most dosimetric indices and dose scores in different ROIs. The proposed loss function significantly enhanced the predictive performance of the dosimetric indices. The predicted dosimetric indices and DVHs were equivalent to the ground-truth values. CONCLUSION: Our study presents an effective model based on limited datasets, and it exhibits high accuracy in the dose prediction of P-SABR plans for bulky lung cancer. This method has potential as an automated tool for P-SABR planning and can help optimize treatments and improve planning efficiency.

Dosimetric impact of intrafraction patient motion on MLC-based 3D-conformal spatially fractionated radiation therapy treatment of large and bulky tumors.

PURPOSE: To evaluate the dosimetric impact on spatially fractionated radiation therapy (SFRT) plan quality due to intrafraction patient motion via multi-field MLC-based method for treating large and bulky (≥8 cm) unresectable tumors. METHODS: For large tumors, a cone beam CT-guided 3D conformal MLC-based SFRT method was utilized with 15 Gy prescription. An MLC GTV-fitting algorithm provided 1 cm diameter apertures with a 2 cm center-to-center distance at the isocenter. This generated a highly heterogeneous sieve-like dose distribution within an hour, enabling same-day SFRT treatment. Fifteen previously treated SFRT patients were analyzed (5 head & neck [H&N], 5 chest and lungs, and 5 abdominal and pelvis masses). For each plan, intrafraction motion errors were simulated by incrementally shifting original isocenters of each field in different x-, y-, and z-directions from 1 to 5 mm. The dosimetric metrics analyzed were: peak-to-valley-dose-ratio (PVDR), percentage of GTV receiving 7.5 Gy, GTV mean dose, and maximum dose to organs-at-risk (OARs). RESULTS: For ±1, ±2, ±3, ±4, and ±5 mm isocenter shifts: PVDR dropped by 3.9%, 3.8%, 4.0%, 4.1%, and 5.5% on average respectively. The GTV(V7.5) remained within 0.2%, and the GTV mean dose remained within 3.3% on average, compared to the original plans. The average PVDR drop for 5 mm shifts was 4.2% for H&N cases, 10% for chest and lung, and 2.2% for abdominal and pelvis cases. OAR doses also increased. The maximum dose to the spinal cord increased by up to 17 cGy in H&N plans, mean lung dose (MLD) changed was small for chest/lung, but the bowel dose varied up to 100 cGy for abdominal and pelvis cases. CONCLUSION: Due to tumor size, location, and characteristics of MLC-based SFRT, isocenter shifts of up to ±5 mm in different directions had moderate effects on PVDR for H&N and pelvic tumors and a larger effect on chest tumors. The dosimetric impact on OAR doses depended on the treatment site. Site-specific patient masks, Vac-Lok bags, and proper immobilization devices similar to SBRT/SRT setups should be used to minimize these effects.

Reactivity and Steric Parameters from 2D to 3D Bulky Pyridines: Increasing Steric Demand at Nitrogen with Chiral Azatriptycenes.

Sterically hindered pyridines embedded in a three-dimensional triptycene framework have been synthesized, and their resolution by chiral HPLC enabled access to unprecedented enantiopure pyridines exceeding the known steric limits. The design principles for new axially chiral pyridine derivatives are then described. To rationalize their associations with Lewis acids and transition metals, a comprehensive determination of the steric and electronic parameters for this new class of pyridines was performed. This led to the general parameterization of the steric parameters (percent buried volume %VBur, Tolman cone angle θ, and He8_steric descriptor) for a large set of two- and three-dimensional pyridine derivatives. These parameters are shown to describe quantitatively their interactions with carbon- and boron-centered Lewis acids and were used to predict the ΔG° of association with the prototypical B(C6F5)3 Lewis acid widely used in frustrated Lewis pair catalysis. This first parameterization of pyridine sterics is a fundamental basis for the future development of predictive reactivity models and for guiding new applications of bulky and chiral pyridines in organocatalysis, frustrated Lewis pairs, and transition-metal catalysis.

A Gold(I)-Acetylene Complex Synthesised using Single-Crystal Reactivity.

Using single-crystal to single-crystal solid/gas reactivity the gold(I) acetylene complex [Au(L1)(η2-HC≡CH)][BArF 4] is cleanly synthesized by addition of acetylene gas to single crystals of [Au(L1)(CO)][BArF 4] [L1=tris-2-(4,4'-di-tert-butylbiphenyl)phosphine, ArF=3,5-(CF3)2C6H3]. This simplest gold-alkyne complex has been characterized by single crystal X-ray diffraction, solution and solid-state NMR spectroscopy and periodic DFT. Bonding of HC≡CH with [Au(L1)]+ comprises both σ-donation and π-backdonation with additional dispersion interactions within the cavity-shaped phosphine.

The tumor core boost study: A feasibility study of radical dose escalation to the central part of large tumors with an integrated boost in the palliative treatment setting.

PURPOSE: For patients with large tumors palliative radiotherapy often is the only local treatment option. To prevent toxicity the administered doses are low. Dose escalation to the tumor could be an option to better smyptom control and prolong local control rates. In this prospective study we used a very pragmatic approach with a simultaneously integrated boost (SIB) to an almost geometrically defined tumor core to achieve this. The primary endpoint was to demonstrate feasibility. METHOD: Patients with solid tumors > 4 cm in diameter of different histologies were eligible in this single arm, prospective, multi-institutional clinical feasibility trial with two treatment concepts: 5â€¯× 5 Gy with an integrated boost to the tumor core of 5â€¯× 10 Gy or 10â€¯× 3 Gy with a boost of 10â€¯× 6 Gy. The objective of dose escalation in this study was to deliver a minimum dose of 150% of the prescribed dose to the gross tumor volume (GTV) tumor core and to reach a maximum of at least 200% in the tumor core. RESULTS: In all, 21 patients at three study sites were recruited between January 2019 and November 2020 and were almost evenly spread (9 to 12) between the two concepts. The treated planning target volumes (PTV) averaged 389.42 cm3 (range 49.4-1179.6 cm3). The corresponding core volumes were 72.85 cm3 on average (range 4.21-338.3 cm3). Dose escalation to the tumor core with mean doses of 167.7-207.7% related to the nonboost prescribed isodose led to PTV mean doses of 120.5-163.3%. Treatment delivery and short-term follow-up was successful in all patients. CONCLUSIONS: Palliative radiotherapy with SIB to the tumor core seems to be a feasible and well-tolerated treatment concept for large tumors. The applied high doses of up to 50 Gy in 5 fractions (or 60 Gy in 10 fractions) did not cause unexpected side effects in the 42 day follow-up period. Further research is needed for more information on efficacy and long-term toxicity.

Synthesis of Sterically Encumbered Alkaline-Earth Metal Amides Applying the In Situ Grignard Reagent Formation.

Magnesium and calcium are too inert to deprotonate amines directly. For the synthesis of bulky amides alternative strategies are required and in the past, N-bound trialkylsilyl groups have been used to ease metalation reactions. The in situ Grignard reagent formation in stirred suspensions of magnesium or calcium with hydryl halide and imine in THF allows the synthesis of a plethora of amides with bulky silyl-free substituents. Ball milling protocols partially favor competitive side reactions such as aza-pinacol coupling reactions. Calcium is the advantageous choice for the in situ Grignard reagent formation and subsequent addition onto the imines yielding bulky calcium bis(amides) whereas the stronger reducing heavier alkaline-earth metals strontium and barium are less selective and hence, the aza-pinacol coupling reaction becomes competitive. Exemplary, the solid-state molecular structures of [(Et2 O)Mg(N(Ph)(CHPh2 )2 ] and [(Et2 O)2 Ca(N(Ph)(CHPh2 )2 ] have been determined.

[IPr#-PEPPSI]: A Well-Defined, Highly Hindered and Broadly Applicable Pd(II)-NHC (NHC = N-Heterocyclic Carbene) Precatalyst for Cross-Coupling Reactions.

In this Special Issue, "Featured Papers in Organometallic Chemistry", we report on the synthesis and characterization of [IPr#-PEPPSI], a new, well-defined, highly hindered Pd(II)-NHC precatalyst for cross-coupling reactions. This catalyst was commercialized in collaboration with MilliporeSigma, Burlington, ON, Canada (no. 925489) to provide academic and industrial researchers with broad access to reaction screening and optimization. The broad activity of [IPr#-PEPPSI] in cross-coupling reactions in a range of bond activations with C-N, C-O, C-Cl, C-Br, C-S and C-H cleavage is presented. A comprehensive evaluation of the steric and electronic properties is provided. Easy access to the [IPr#-PEPPSI] class of precatalysts based on modular pyridine ligands, together with the steric impact of the IPr# peralkylation framework, will facilitate the implementation of well-defined, air- and moisture-stable Pd(II)-NHC precatalysts in chemistry research.

Nascent myoma as a cause of urinary retention.

We present the case of a 47-year-old woman with a bulky, nascent necrotic myoma, which at first glance appeared to be a malignant process in the cervix. It caused significant retention of urine due to compression of the bladder and ureters, hydronephrosis and deterioration of renal function. A fully developed picture of the "bulge syndrome" dominated - lymphedema of the lower limbs and lower abdomen, pain in the lower abdomen, constipation, secondary secondary urinary infection, and paradoxical ischuria. During a gynecological examination in a specula, a strong-smelling, necrotic tumour was visualized reaching half of the vagina, which was causing a bloody discharge, which brought the patient to the examination. A biopsy was taken from the tumour. A permanent urinary catheter was inserted into the urinary bladder with gradual adjustment of renal functions. Due to the difficulties and the benign histological findings from the biopsy, a simple abdominal hysterectomy with bilateral salpingectomy from a lower midline incision was indicated. The operation was complicated by an extensive adhesive process and blood loss of 1,200 mL, with a decrease in hemoglobin in the blood count from 128 g/L to 79 g/L and the need for three blood transfusions. In the postoperative period, there is a prompt recovery of spontaneous micturition with normalization of bladder function, subsidence of lymphedema and subjective complaints of the patient.

Remarkable enantioselectivity enhancement of the extractors with nonaxial chirality in liquid-liquid extraction of underivatized amino acids by introducing t-butyl group.

A class of carbonyl extractors, (R)-3, (R)-4, and (R)-5, with nonaxial chirality containing asymmetric carbons has been synthesized and studied for their efficiencies in enantioselective liquid-liquid extraction for underivatized amino acids. The bulky t-butyl ketone extractors, (R)-4 and (R)-5, showed the stereoselectivities ranging 5.4-9.4 of l/d ratio much better than those of the aldehyde extractor, (R)-3, ranging 2.4-5.2. The imine formation rates and yields of the t-butyl ketones were not significantly affected by their bulkiness and even in the absence of resonance-assisted hydrogen bond. This work confirms that a bulky t-butyl ketone can be a good choice in the development of an extractor not only with axial chirality but also with nonaxial chirality for the enantioselective extraction of unprotected amino acids.

Laparoscopic Ultra-radical Lymph Node Debulking Using Yasargil Clamps for Gynecological Malignancies: Results from a Large, Multicenter, Retrospective Analysis.

STUDY OBJECTIVE: Resection of bulky lymph nodes in gynecologic oncology is a challenging procedure. Considering the risk of intraoperative vascular injury, a technique to avoid severe complications is mandatory. In this study, we aimed to analyze the feasibility of laparoscopic ultraradical lymph node debulking using Yasargil clamps in patients with gynecologic cancer with bulky lymph node metastases. DESIGN: Multicenter retrospective case series (ClinicalTrialg.gov ID: NCT05318170), between September 2010 and April 2020. SETTING: Units of Gynecologic Oncology. PATIENTS: Patients with gynecologic cancer with bulky lymph node metastases. INTERVENTIONS: Laparoscopic ultraradical lymph node debulking using Yasargil clamps. MEASUREMENTS AND MAIN RESULTS: Forty-three patients with gynecologic cancer with bulky pelvic and/or aortic lymph nodes metastases undergoing laparoscopic lymph node debulking surgery using Yasargil clamps were included. Median surgical time was 300 minutes (range, 120-550 minutes); median estimated blood loss was 170 mL (range, 0-700 mL). Median size of lymph nodes was 50 mm (range, 25-100). R0 resection was achieved in all cases. Four intraoperative complications (9.3%) occurred. No conversion to open surgery was required. There were 8 postoperative complications, classified grade 2 or worse. There were no cases with intra- or postoperative mortality. CONCLUSION: In our experience, in carefully selected patients with gynecologic cancer with bulky lymph nodes, laparoscopic lymph node debulking using Yasargil clamps could be considered a valid option to avoid potential severe vascular intraoperative complications.

Dynamic tracing using ultra-bright labeling and multi-photon microscopy identifies endothelial uptake of poloxamer 188 coated poly(lactic-co-glycolic acid) nano-carriers in vivo.

The potential of poly(lactic-co-glycolic acid) (PLGA) to design nanoparticles (NPs) and target the central nervous system remains to be exploited. In the current study we designed fluorescent 70-nm PLGA NPs, loaded with bulky fluorophores, thereby making them significantly brighter than quantum dots in single-particle fluorescence measurements. The high brightness of NPs enabled their visualization by intravital real-time 2-photon microscopy. Subsequently, we found that PLGA NPs coated with pluronic F-68 circulated in the blood substantially longer than uncoated NPs and were taken up by cerebro-vascular endothelial cells. Additionally, confocal microscopy revealed that coated PLGA NPs were present in late endothelial endosomes of cerebral vessels within 1 h after systemic injection and were more readily taken up by endothelial cells in peripheral organs. The combination of ultra-bright NPs and in vivo imaging may thus represent a promising approach to reduce the gap between development and clinical application of nanoparticle-based drug carriers.

Conebeam CT-guided 3D MLC-based spatially fractionated radiation therapy for bulky masses.

For fast, safe, and effective management of large and bulky (≥8 cm) non-resectable tumors, we have developed a conebeam CT-guided three-dimensional (3D)-conformal MLC-based spatially fractionated radiation therapy (SFRT) treatment. Using an in-house MLC-fitting algorithm, Millennium 120 leaves were fitted to the gross tumor volume (GTV) generating 1-cm diameter holes at 2-cm center-to-center distance at isocenter. SFRT plans of 15 Gy were generated using four to six coplanar crossfire gantry angles 60° apart with a 90° collimator, differentially weighted with 6- or 10-MV beams. A dose was calculated using AcurosXB algorithm, generating sieve-like dose channels without post-processing the physician-drawn GTV contour within an hour of CT simulation allowing for the same day treatment. In total, 50 extracranial patients have been planned and treated using this method, comprising multiple treatment sites. This novel MLC-fitting algorithm provided excellent dose parameters with mean GTV (V7.5 Gy) and mean GTV doses of 53.2% and 7.9 Gy, respectively, for 15 Gy plans. Average peak-to-valley dose ratio was 3.2. Mean beam-on time was 3.32 min, and treatment time, including patient setup and CBCT to beam-off, was within 15 min. Average 3D couch correction from original skin-markers was <1.0 cm. 3D MLC-based SFRT plans enhanced target dose for bulky masses, including deep-seated large tumors while protecting skin and adjacent critical organs. Additionally, it provides the same day, safe, effective, and convenient treatment by eliminating the risk to therapists and patients from heavy gantry-mounted physical GRID-block-we recommend other centers to use this simple and clinically useful method. This rapid SFRT planning technique is easily adoptable in any radiation oncology clinic by eliminating the need for plan optimization and patient-specific quality assurance times while providing dosimetry information in the treatment planning system. This potentially allows for dose-escalation to deep-seated masses to debulk unresectable large tumors providing an option for neoadjuvant treatment. An outcome study of clinical trial is underway.

Retrospective single-center experience with OEPA/COPDAC and PET-CT based strategy for pediatric Hodgkin lymphoma in a LMIC setting.

ABVD regimen for Hodgkin lymphoma (HL) is frequently used in children and young adults in low-middle income countries (LMIC). The feasibility and safety data for 'non-ABVD' protocols from LMIC is limited. The retrospective study was conducted in a single center in India. The Euronet PHL-C1 based protocol was administered during 2010-19. A PET-CT was performed at diagnosis and following two OEPA cycles. Radiotherapy was administered for inadequate PET response. During the 10-year period, 143 patients with HL were treated. The mean age was 7.8 ± 2.5 years. Bulky disease was observed in 82 (59%). Treatment abandonment was recorded in 13 (9.1%). The median follow-up duration was 46.4 months. An inadequate PET response was observed in 41/119 (34.4%), of which 56.1% received radiotherapy. Twelve (29.3%) patients who were supposed to receive radiotherapy received 2-cycles of COPDAC instead. Sixty-nine episodes of febrile neutropenia were observed in 54 patients. Treatment-related mortality (TRM) was observed in 7 (5.3%). The majority of episodes of febrile neutropenia (61%) and TRM (86%) occurred in the first cycle of OEPA. The 4-year event-free survival (EFS) and overall survival (OS) were 86.2 ± 3.4% and 93.5 ± 2.2%, respectively. Nine (6.3%) patients relapsed. Bulky disease lacked association with inadequate PET response (p = .800) or relapse (p = 1.000). OEPA/COPDAC regimen and response assessment by PET-CT permitted therapy reduction, including radiotherapy. Febrile neutropenia and resultant TRM (5.3%) are concerning and occurred frequently in the first cycle of OEPA. The support system for managing febrile neutropenia should be optimized for administering OEPA in LMIC.

The Steric Effect in Preparations of Vanadium(II)/(III) Dinitrogen Complexes of Triamidoamine Ligands Bearing Bulky Substituents.

The reactions of newly designed lithiated triamidoamines Li3LR (R = iPr, Pen, and Cy2) with VCl3(THF)3 under N2 yielded dinitrogen-divanadium complexes with a µ-N2 between vanadium atoms [{V(LR)}2(µ-N2)] (R = iPr (1) and Pen (2)) for the former two, while not dinitrogen-divanadium complexes but a mononuclear vanadium complex with a vacant site, [V(LCy2)] (R = Cy2 (3)), were obtained for the third ligand. The V-NN2 and N-N distances were 1.7655(18) and 1.219(4) Å for 1 and 1.7935(14) and 1.226(3) Å for 2, respectively. The ν(14N-14N) stretching vibrations of 1 and 2, as measured using resonance Raman spectroscopy, were detected at 1436 and 1412 cm-1, respectively. Complex 3 reacted with potassium metal in the presence of 18-crown-6-ether under N2 to give a hetero-dinuclear vanadium complex with µ-N2 between vanadium and potassium, [VK(LCy2)(µ-N2)(18-crown-6)] (4). The N-N distance and ν(14N-14N) stretching for 4 were 1.152(3) Å and 1818 cm-1, respectively, suggesting that 4 is more activated than complexes 1 and 2. The complexes 1, 2, 3, and 4 reacted with HOTf and K[C10H8] to give NH3 and N2H4. The yields of NH3 and N2H4 (per V atom) were 47 and 11% for 1, 38 and 16% for 2, 77 and 7% for 3, and 80 and 5% for 4, respectively, and 3 and 4, which have a ligand LCy2, showed higher reactivity than 1 and 2.

Laparoscopic Radical Trachelectomy after Neoadjuvant Chemotherapy for Fertility Preservation in Early-Stage Bulky Cervical Cancer: A Case Report and Literature Review.

Management of early-stage cervical cancer (CC) in young women often faces challenges to preserve fertility, as well as to achieve an adequate oncological outcome. Although existing evidence supports a fertility-sparing treatment in the case of tumors <2 cm in diameter, the approach is less clear in bulky early-stage CC. In addition, the outcomes of radical trachelectomy performed by minimally invasive techniques are also highly debatable. Highlighting the high incidences of young women with early-stage CC, the lack of sufficient data raises considerable hindrances towards the proper counseling of this vulnerable patient group. In this report, a case of a young woman with bulky early-stage CC with a strong desire to preserve fertility is presented. A satisfactory oncological outcome was achieved after neoadjuvant chemotherapy followed by laparoscopic radical trachelectomy. Ongoing prospective trials are expected to provide stronger evidence on this topic.