Longitudinal study of AMH variations in 122 Adolescents and Young Adults (AYA) and non-AYA lymphoma patients to evaluate the chemo-induced ovarian toxicity to further personalise fertility preservation counselling.

STUDY QUESTION: What is the influence of age and chemotherapy regimen on the longitudinal blood anti-Müllerian hormone (AMH) variations in a large series of adolescents and young adult (AYA) (15-24 years old) and non-AYA (25-35 years old) lymphoma patients? SUMMARY ANSWER: In case of alkylating regimen treatment, there was a deep and sustained follicular depletion in AYA as well as non-AYA patients; however in both groups, the ovarian toxicity was extremely low in cases of non-alkylating treatments. WHAT IS KNOWN ALREADY: AMH is now well-recognised to be a real-time indicator of ovarian follicular depletion and recovery in women treated by chemotherapy. Its longitudinal variations may discriminate between highly and minimally toxic protocols regarding ovarian function. It has been shown, in different cancer types, that age, type of chemotherapy regimen and pre-treatment AMH levels are the main predictors of ovarian recovery. Large studies on longitudinal AMH variations under chemotherapy in lymphoma patients are few but can provide the opportunity to assess the degree of follicle loss at a young age. STUDY DESIGN, SIZE, DURATION: This prospective cohort study was conducted in the Fertility Observatory of the Lille University Hospital. Data were collected between 2007 and 2016. Non-Hodgkin or Hodgkin lymphoma patients (n = 122) between 15 and 35 years old were prospectively recruited before commencing chemotherapy. Patients were treated either by a non-alkylating protocol (ABVD group; n = 67) or by an alkylating regimen (alkylating group; n = 55). PARTICIPANTS/MATERIALS, SETTING, METHODS: Serial AMH measurements were performed at baseline (AMH0), 15 days after the start of chemotherapy (AMH1), 15 days before the last chemotherapy cycle (AMH2), and at time 3, 6, 9, 12, 18 and 24 months from the end of chemotherapy. The whole study population was divided into two groups according to age: AYA (15-24; n = 65) and non-AYA (25-35; n = 57). All patients received a once monthly GnRH agonist injection during the whole treatment period. A linear mixed model was used to account for the repeated measures of single patients. MAIN RESULTS AND THE ROLE OF CHANCE: At baseline, non-AYA patients had higher BMI and lower AMH levels than AYA patients. All AYA and non-AYA patients having received ABVD protocols had regular cycles at 12 months of follow-up. In case of alkylating regimens, amenorrhoea was more frequent in non-AYA patients than in AYA patients at 12 months (37% vs 4%, P = 0.011) and at 24 months (24% vs 4%, P = 0.045). We distinguished a similar depletion phase from AMH0 to AMH2 between ABVD and alkylating groups but significantly different recovery phases from AMH2 to AMH + 24 months. AMH recovery was fast and complete in case of ABVD protocols whatever the age: AMH reached pre-treatment values as soon as the 6th month of follow-up in the AYA group (mean (95% CI) in log AMH M0 vs M6: 3.07 (2.86 to 3.27) vs 3.05 (2.78 to 3.31), P = 1.00) and in the non-AYA group (mean (95% CI) in log AMH M0 vs M6: 2.73 (2.40 to 3.05) vs 2.47 (2.21 to 2.74), P = 1.00). In contrast, no patients from the alkylating group returned to pre-treatment AMH values whatever the age of patients (AYA or non-AYA). Moreover, none of the AMH values post-chemotherapy in the non-AYA group were significantly different from AMH2. Conversely in the AYA group, AMH levels from 6 months (mean (95% CI) in log AMH: 1.79 (1.47 to 2.11), P < 0.001) to 24 months (mean (95% CI) in log AMH: 2.16 (1.80 to 2.52), P ≤ 0.001) were significantly higher than AMH2 (mean (95% CI) in log AMH: 1.13 (0.89 to 1.38)). Considering the whole study population (AYA and non-AYA), pre-treatment AMH levels influenced the pattern of the AMH variation both in alkylating and ABVD protocols (interaction P-value = 0.005 and 0.043, respectively). Likewise, age was significantly associated with the pattern of the recovery phase but only in the alkylating group (interaction P-value =0.001). BMI had no influence on the AMH recovery phase whatever the protocol (interaction P-value = 0.98 in alkylating group, 0.72 in ABVD group). LIMITATIONS, REASONS FOR CAUTION: There was a large disparity in subtypes of protocols in the alkylating group. The average duration of chemotherapy for patients treated with alkylating protocols was longer than that for patients treated with ABVD. WIDER IMPLICATIONS OF THE FINDINGS: These results make it possible to develop strategies for fertility preservation according to age and type of protocol in a large series of young lymphoma patients. In addition, it was confirmed that young age does not protect against ovarian damage caused by alkylating agents. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Agence Régionale de Santé Hauts de France and Agence Onco Hauts-de-France who provided finances for AMH dosages (n° DOS/SDES/AR/FIR/2019/282). There are no competing interests. TRIAL REGISTRATION NUMBER: DC-2008-642 and CNIL DEC2015-112.

On-the-fly dynamics simulations of transient anions.

A novel theoretical framework for describing the dynamics of transient anions is presented. An ensemble of classical trajectories is propagated on-the-fly, where resonance energies are computed with bound state techniques, and resonance widths are modeled with a combination of bound state and scattering calculations. The methodology was benchmarked against quantum dynamics results for model potential energy curves, and excellent agreement was attained. As a first application, we considered the electron induced dissociation of chloroethane. We found that electron attachment readily stretches the C-Cl bond, which stabilizes the transient anion within ∼10 fs and leads to the release of fast chloride ions. Both magnitude and shape of the computed dissociative electron attachment cross sections are very similar to the available experimental data, even though we found the results to be very sensitive on the accuracy of the underlying methods. These encouraging results place the proposed methodology as a promising approach for studies on transient anions' dynamics of medium sized molecules.

Experimental and theoretical investigations on photoabsorption and photoionization of trimethylphosphate in the vacuum-ultraviolet energy range.

In this work, we report a joint experimental-theoretical investigation on interaction of vacuum-ultraviolet radiation with trimethylphosphate (TMP) molecule (C(3)H(9)O(4)P) in gas phase. This species together with tetrahydrofuran (THF) are model compounds of deoxyribose nucleic acids (DNA)/ribose nucleic acids (RNA) backbone. Absolute photoabsorption cross sections (σ(a)) and ionization yields (η) are measured using the double-ion-chamber technique in the 11.0-21.45 eV energy range. Photoionization (σ(i)) and neutral-decay (σ(n)) cross sections in absolute scale are also derived. Moreover, theoretical photoabsorption cross sections are calculated using the time-dependent density functional theory from the excitation threshold up to 16 eV. Good agreement between the present calculated and experimental photoabsorption cross sections in the 11.0-14.5 eV range is encouraging. Also, the present measured data of σ(a) and σ(i) for TMP are about 1.3 and 1.5 times of those of THF, respectively. Thus, the experimental evidences that the majority of strand breaks being located at sugar rings in the irradiated DNA/RNA backbone moiety may be induced by a possible migration of the hole, initially created at phosphate group, to the linked sugar groups. Finally, absolute partial photoionization cross sections are derived from the experimental time-of-flight mass spectra.

The photodynamics of ethylene: a surface-hopping study on structural aspects.

Simulations of the photodynamics of ethylene were carried out by employing the semiempirical direct trajectory with surface hopping method in order to assess quantitatively the importance of different regions of the S(2)S(1) and S(1)S(0) crossing seams. The results show that during the first 50 fs after a vertical photoexcitation to the pipi(*) state, the nonadiabatic coupling between the S(1) and the S(2) states produces a recurrence pattern of oscillation of the populations in these states. Within the first 100 fs, the S(1) state population spans a limited region of the configuration space between the initial geometries and the twisted-pyramidalized minimum on the crossing seam (MXS). Depending on the way of counting, about 50% of the S(1)-->S(0) transitions occur in the pyramidalized region of the crossing seam, but not necessarily close to the MXS. The remaining 50% occurs in the H-migration and ethylidene regions. Our analysis shows that the ethylidene region becomes more important in later stages of the dynamics when the flux of trajectories that was not effectively converted to the ground state in the pyramidalized region starts to reach this part of the configuration space. The excited-state nonadiabatic dynamics could be employed to generate suitable initial phase space distributions for the hot-ethylene ground-state kinetic studies.

Photochemistry of ethylene: a multireference configuration interaction investigation of the excited-state energy surfaces.

Multireference configuration interaction with singles and doubles (MR-CISD) calculations have been performed for the optimization of conical intersections and stationary points on the ethylene excited-state energy surfaces using recently developed methods for the computation of analytic gradients and nonadiabatic coupling terms. Basis set dependence and the effect of various choices of reference spaces for the MR-CISD calculations have been investigated. The crossing seam between the S0 and S1 states has been explored in detail. This seam connects all conical intersections presently known for ethylene. Major emphasis has been laid on the hydrogen-migration path. Starting in the V state of twisted-orthogonal ethylene, a barrierless path to ethylidene was found. The feasibility of ethylidene formation will be important for the explanation of the relative yield of cis and trans H2 elimination.

Event-by-event analysis of collision-induced cluster-ion fragmentation: sequential monomer evaporation versus fission reactions.

The most abundant decay channels have been studied quantitatively for high-energy (60 keV/amu) cluster ions H (3) (+)(H (2))(m = 1-14) colliding with He atoms employing a recently developed multicoincidence technique for the simultaneous detection of the correlated fragments on an event-by-event basis. This allows us to identify decay reactions and their underlying decay mechanisms responsible for the occurrence of the U-shaped fragmentation pattern.