The impact of treatment for childhood classical Hodgkin lymphoma according to the EuroNet-PHL-C2 protocol on serum anti-Müllerian Hormone.

STUDY QUESTION: What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)? SUMMARY ANSWER: Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL. WHAT IS KNOWN ALREADY: Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol. STUDY DESIGN, SIZE, DURATION: This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years. LIMITATIONS, REASONS FOR CAUTION: The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol. STUDY FUNDING/COMPETING INTEREST(S): The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Extended Reichardt's Dye-Synthesis and Solvatochromic Properties.

Three new pyridinium-phenolate dyes based on the benchmark solvatochromic dye Betaine 30 were synthesised. The dyes contained phenylene spacers between the donor and acceptor groups. Their UV-Vis absorption spectra were measured, with the dyes showing strong negative solvatochromic behaviour comparable to that of Betaine 30. These results stood in contrast to the behaviour of the π-extended dye Betaine 21, originally reported in 1963. This dye was synthesised and found to be significantly more solvatochromic than previously reported but prone to degrade. All π-extended dyes synthesised were found to be unstable in certain solvents. Although the increased distance between donor and acceptor did not enhance solvatochromism to the extent predicted, it was still determined that the reduced planarity caused by a phenylene spacer is not as detrimental as believed.

Alveolar type I cells can give rise to KRAS-induced lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

Harvesting Triplet Excitons in High Mobility Emissive Organic Semiconductor for Efficiency Enhancement of Light-Emitting Transistors.

Organic light-emitting transistors (OLETs), a kind of highly integrated and minimized optoelectronic device, demonstrate great potential applications in various fields. The construction of high-performance OLETs requires the integration of high charge carrier mobility, strong emission, and high triplet exciton utilization efficiency in the active layer. However, it remains a significant long-term challenge, especially for single component active layer OLETs. Herein, the successful harvesting of triplet excitons in a high mobility emissive molecule, 2,6-diphenylanthracene (DPA), through the triplet-triplet annihilation process is demonstrated. By incorporating a highly emissive guest into the DPA host system, an obvious increase in photoluminescence efficiency along with exciton utilization efficiency results in an obvious enhancement of external quantum efficiency of 7.2 times for OLETs compared to the non-doped devices. Moreover, well-tunable multi-color electroluminescence, especially white emission with Commission Internationale del'Eclairage  of (0.31, 0.35), from OLETs is also achieved by modulating the doping concentration with a controlled energy transfer process. This work opens a new avenue for integrating strong emission and efficient exciton utilization in high-mobility organic semiconductors for high-performance OLETs and advancing their related functional device applications.

Protection of Boronic Acids Using a Tridentate Aminophenol ONO Ligand for Selective Suzuki-Miyaura Coupling.

Boronic acid protecting group chemistry powerfully enhances the versatility of Suzuki-Miyaura cross-coupling. Prominent examples include trifluoroborate salts, N-methyliminodiacetic acid (MIDA) boronates, and 1,8-diaminonaphthalene boronamides. In this work, we present a bis(2-hydroxybenzyl)methylamine (BOMA) ligand that forms tridentate complexes with boronic acids much like the MIDA ligand but the deprotection is facilitated by organic acids. The BOMA boronates showed considerable stability in both aqueous base and acid, and a variety of chemoselective reactions were performed on these boronates, including selective Suzuki-Miyaura coupling, palladium-catalyzed borylation, ester hydrolysis, alkylation, lithiation-borylation, and oxidative hydroxydeboronation.

Thoracoscopic Resection of a Rare Congenital Lung Lesion With a Tracheal Bronchus.

A tracheal bronchus is a rare anatomic variant characterized by a bronchus originating from the trachea rather than the carina. These are most commonly asymptomatic and found incidentally but can cause recurrent pneumonias in children. Here, we present a case of a thoracoscopic resection of an azygous lobe with a tracheal bronchus in a 9-year-old female.

A predictive model of the effect of therapeutic radiation on the human ovary.

Radiation to the female pelvis as part of treatment for cancer predisposes young women to develop Premature Ovarian Insufficiency (POI). As the human female is born with their full complement of non-growing follicles which decline in an exponential fashion until the menopause, the age at which POI occurs is dependent on the age of the patient at treatment and the dose received by the ovary. A model that predicts the age at which POI occurs for a known dose at a known age will aid counselling patients on their fertility risk. Patients deemed to be at high risk of POI may be considered to be good candidates for established fertility preservation techniques. An updated and externally validated model of the age-related decline in human ovarian reserve was combined with the best available estimate of the median lethal dose LD50 for the human ovary. Using known age at diagnosis and posited radiotherapy treatment plan to estimate the dose to the least-affected ovary, we use an age-related model of the decline in ovarian reserve to generate a personalized age prediction of premature ovarian insufficiency. Our algorithm is available as an online calculator which graphs model outputs to inform discussions around survivor fertility. We report four example cases across different ages and diagnoses, each with two carefully designed photon and proton treatment plans. The treatment options are compared in terms of remaining fertile lifespan for the survivor. International oncology guidelines now mandate the consideration of later fertility when reviewing treatment options for children diagnosed with cancer. Our calculator (https://sites.cs.st-andrews.ac.uk/radiosensitivity), and the underlying algorithm and models, allow detailed predictions of the impact of various radiotherapy plans on fertility. These patient-specific data enhance pre-treatment discussions around post-treatment fertility and fertility preservation.

Prognostic implications of and clinical risk factors for acute lung injury and organizing pneumonia after lung transplantation: Data from a multicenter prospective cohort study.

We determined prognostic implications of acute lung injury (ALI) and organizing pneumonia (OP), including timing relative to transplantation, in a multicenter lung recipient cohort. We sought to understand clinical risks that contribute to development of ALI/OP. We analyzed prospective, histologic diagnoses of ALI and OP in 4786 lung biopsies from 803 adult lung recipients. Univariable Cox regression was used to evaluate the impact of early (≤90 days) or late (>90 days) posttransplant ALI or OP on risk for chronic lung allograft dysfunction (CLAD) or death/retransplantation. These analyses demonstrated late ALI/OP conferred a two- to threefold increase in the hazards of CLAD or death/retransplantation; there was no association between early ALI/OP and these outcomes. To determine risk factors for late ALI/OP, we used univariable Cox models considering donor/recipient characteristics and posttransplant events as candidate risks. Grade 3 primary graft dysfunction, higher degree of donor/recipient human leukocyte antigen mismatch, bacterial or viral respiratory infection, and an early ALI/OP event were significantly associated with increased late ALI/OP risk. These data from a contemporary, multicenter cohort underscore the prognostic implications of ALI/OP on lung recipient outcomes, clarify the importance of the timing of these events, and identify clinical risks to target for ALI/OP prevention.

Survival after breast cancer in women with a subsequent live birth: Influence of age at diagnosis and interval to subsequent pregnancy.

BACKGROUND: There remains a considerable concern among both patients and oncologists that having a live birth (LB) after breast cancer might adversely impact survival. METHODS: analysis of survival in a national cohort of women with breast cancer diagnosed at age 20-39 years between 1981 and 2017 (n = 5181), and subsequent LB using Scottish Cancer Registry and national maternity records. Cases had at least one subsequent LB, each was matched with up to six unexposed cases without subsequent LB, accounting for guaranteed time bias. RESULTS: In 290 women with a LB after diagnosis, overall survival was increased compared to those who did not have a subsequent LB, HR 0.65 (95%CI 0.50-0.85). Women with subsequent LB who had not had a pregnancy before breast cancer showed increased survival (HR 0.56, 0.38-0.82). There was a progressively greater interaction of subsequent LB with survival with younger age, thus for women aged 20-25 years, HR 0.30 (0.12-0.74) vs. those aged 36-39, HR 0.89 (0.42-1.87). In women with LB within five years of diagnosis, survival was also increased (HR 0.66; 0.49-0.89). Survival following LB was similar to unexposed women by ER status (both positive and negative) and in those known to have been exposed to chemotherapy. CONCLUSIONS: This analysis provides further evidence that for the growing number of women who wish to have children after breast cancer, LB does not have a negative impact on overall survival. This finding was confirmed within subgroups, including the youngest women and those not previously pregnant.

Robotic-assisted laparoscopic repair of a congenital rectourethral fistula with duplicated urethra.

OBJECTIVE: To describe our experience with robot-assisted laparoscopic transperitoneal repair of a congenital rectourethral fistula in a pediatric patient with a urethral duplication. METHODS: The patient is a 2-year-old male with a past medical history of Tetralogy of Fallot presenting with a febrile urinary tract infection (UTI). He was diagnosed with urethral duplication and a rectourethral fistula by voiding cystourethrogram (VCUG). The parents were counseled on various options and agreed to proceed with a robotic repair. RESULTS: Robotic-assisted transperitoneal rectourethral fistula repair was performed. The procedure time was 229 min with an estimated blood loss (EBL) of 15 mL. His postoperative course was unremarkable. At his 2-week follow-up, the urethral catheter was removed and the patient was voiding normally and having normal bowel movements. CONCLUSION: Congenital rectourethral fistula with urethral duplication is a rare anomaly with only a few reports in the literature. Pediatric robotic-assisted transperitoneal rectourethral fistula repair is a technically feasible approach in infants with minimal morbidity that allows for excellent visualization and avoids open repair.

Inconsistencies in fertility preservation for young people with cancer in the UK.

OBJECTIVE: To assess the utilisation of and funding structure for fertility preservation for children diagnosed with cancer in the UK. DESIGN: Survey of paediatric oncologists/haematologists. Questionnaires were sent electronically with reminder notifications to non-responders. SETTING: UK Paediatric Oncology Principal Treatment Centres (PTCs). PARTICIPANTS: Paediatric oncologists/haematologists with an interest in the effects of treatment on fertility representing the 20 PTCs across the UK. MAIN OUTCOME MEASURES: Referral practices, sources and length of funding for storage of gametes or gonadal tissue for children diagnosed with cancer in the preceding 12 months. RESULTS: Responses were received from 18 PTCs (90%) with responses to 98.3% of questions. All centres had referred patients for fertility preservation: ovarian tissue collection/storage 100% (n=18 centres), sperm banking 100% (n=17; one centre was excluded due to the age range of their patients), testicular tissue storage 83% (n=15), mature oocyte collection 35% (n=6; one centre was excluded due to the age range of their patients). All centres with knowledge of their funding source reported sperm cryopreservation was NHS funded. Only 60% (n=9) centres reported the same for mature oocyte storage. Of the centres aware of their funding source, half reported that ovarian and testicular tissue storage was funded by charitable sources; this increased in England compared with the rest of the UK. CONCLUSIONS: Inequality exists in provision of fertility preservation for children with cancer across the UK. There is lack of formalised government funding to support international guidelines, with resultant geographical variation in care. Centralised funding of fertility preservation for children and young adults is needed alongside establishment of a national advisory panel to support all PTCs.

Neutrophilic inflammation promotes SARS-CoV-2 infectivity and augments the inflammatory responses in airway epithelial cells.

In response to viral infection, neutrophils release inflammatory mediators as part of the innate immune response, contributing to pathogen clearance through virus internalization and killing. Pre-existing co- morbidities correlating to incidence of severe COVID-19 are associated with chronic airway neutrophilia. Furthermore, examination of COVID-19 explanted lung tissue revealed a series of epithelial pathologies associated with the infiltration and activation of neutrophils, indicating neutrophil activity in response to SARS- CoV-2 infection. To determine the impact of neutrophil-epithelial interactions on the infectivity and inflammatory responses to SARS-CoV-2 infection, we developed a co-culture model of airway neutrophilia. SARS-CoV-2 infection of the airway epithelium alone does not result in a notable pro-inflammatory response from the epithelium. The addition of neutrophils induces the release of proinflammatory cytokines and stimulates a significantly augmented pro-inflammatory response subsequent SARS-CoV-2 infection. The resulting inflammatory response is polarized with differential release from the apical and basolateral side of the epithelium. Additionally, the integrity of the epithelial barrier is impaired with notable epithelial damage and infection of basal stem cells. This study reveals a key role for neutrophil-epithelial interactions in determining inflammation and infectivity in response to SARS-CoV-2 infection.

Family size and duration of fertility in female cancer survivors: a population-based analysis.

OBJECTIVE: To assess family size and timescale for achieving pregnancy in women who remain fertile after cancer. DESIGN: Population-based analysis. SETTING: National databases. PATIENT(S): All women diagnosed with cancer before the age of 40 years in Scotland, 1981-2012 (n = 10,267) with no previous pregnancy; each was matched with 3 population controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The number and timing of pregnancy and live birth after cancer diagnosis, to 2018. RESULT(S): In 10,267 cancer survivors, the hazard ratio for a subsequent live birth was 0.56 (95% confidence interval, 0.53-0.58) overall. In women who achieved a subsequent pregnancy, age at live birth increased (mean ± SD, 31.2 ± 5.5 vs. 29.7 ± 6.1 in controls), and the family size was lower (2.0 ± 0.8 vs. 2.3 ± 1.1 live births). These findings were consistent across several diagnoses. The interval from diagnosis to last pregnancy was similar to that of controls (10.7 ± 6.4 vs. 10.9 ± 7.3 years) or significantly increased, for example, after breast cancer (6.2 ± 2.8 vs. 5.3 ± 3.3 years) and Hodgkin lymphoma (11.1 ± 5.1 vs. 10.1 ± 5.8 years). CONCLUSION(S): These data quantify the reduced chance of live birth after cancer. Women who subsequently conceived achieved a smaller family size than matched controls, but the period of time after cancer diagnosis across which pregnancies occurred was similar or, indeed, increased. Thus, we did not find evidence that women who were able to achieve a pregnancy after cancer had a shorter timescale over which they have pregnancies.

Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Unusual Alternating Crystallization-Induced Emission Enhancement Behavior in Nonconjugated ω-Phenylalkyl Tropylium Salts.

The alternating physical properties, especially melting points, of α,ω-disubstituted n-alkanes and their parent n-alkanes had been known since Baeyer's report in 1877. There is, however, no general and comprehensive explanation for such a phenomenon. Herein, we report the synthesis and examination of a series of novel ω-phenyl n-alkyl tropylium tetrafluoroborates, which also display alternation in their physicochemical characters. Despite being organic salts, the compounds with odd numbers of carbons in the alkyl bridge exist as room temperature ionic liquids. In stark contrast to this, the analogues with even numbers of carbons in the linker are crystalline solids. These solid nonconjugated molecules exhibit curious photoluminescent properties, which can be attributed to their ability to form through-space charge-transfer complexes to cause crystallization-induced emission enhancement. Most notably, the compound with the highest photoluminescent quantum yield in this series showed an unusual arrangement of carbocationic dimer in the solid state. A combination of XRD analysis and ab initio calculations revealed interesting insights into these systems.

Application of Triplet-Triplet Annihilation Upconversion in Organic Optoelectronic Devices: Advances and Perspectives.

Organic semiconductor materials have been widely used in various optoelectronic devices due to their rich optical and/or electrical properties, which are highly related to their excited states. Therefore, how to manage and utilize the excited states in organic semiconductors is essential for the realization of high-performance optoelectronic devices. Triplet-triplet annihilation (TTA) upconversion is a unique process of converting two non-emissive triplet excitons to one singlet exciton with higher energy. Efficient optical-to-electrical devices can be realized by harvesting sub-bandgap photons through TTA-based upconversion. In electrical-to-optical devices, triplets generated after the combination of electrons and holes also can be efficiently utilized via TTA, which resulted in a high internal conversion efficiency of 62.5%. Currently, many interesting explorations and significant advances have been demonstrated in these fields. In this review, a comprehensive summary of these intriguing advances on developing efficient TTA upconversion materials and their application in optoelectronic devices is systematically given along with some discussions. Finally, the key challenges and perspectives of TTA upconversion systems for further improvement for optoelectronic devices and other related research directions are provided. This review hopes to provide valuable guidelines for future related research and advancement in organic optoelectronics.