Prognostic impact of incomplete surgical clearance of radioiodine sensitive local lymph node metastases diagnosed by post-operative <Superscript>124</Superscript>I-NaI-PET/CT in patients with papillary thyroid cancer

Purpose

Nodal involvement is an independent risk factor of recurrence in papillary thyroid cancer (PTC). Neither the international guidelines nor the recently introduced ongoing risk adaptation concept consider the extent of initial surgical clearance of radioiodine sensitive lymph node metastases in their stratification systems. We investigated the prognostic relevance of incomplete initial surgical clearance in patients with purely lymphogeneous metastatic PTC (pN1 M0) despite successful radioiodine therapy. Accurate assessment of pre-ablative nodal status was attempted using PET/CT studies with both ¹²⁴I-NaI and ¹⁸F-FDG along with high-resolution cervical ultrasound.

Methods

Sixty-five patients with histologically diagnosed lymph node metastases (pN1 M0) were retrospectively analyzed. Patients with iodine-negative lymph node metastases diagnosed by ¹⁸F-FDG PET/CT or distant metastases were excluded from the analysis. The association of disease recurrence with the pre-ablative nodal status, as well as other baseline characteristics, were examined applying nonparametric tests for independent samples and multiple regression analysis. Patients with persistent lymph node metastases in ¹²⁴I-NaI PET/CT were further divided according to the additional presence or absence of FDG-uptake in ¹⁸F-FDG PET/CT. Survival analyses were performed using Kaplan–Meier curves and the Cox proportional hazards model for uni- and multivariate analyses to assess the influence of prognostic factors on progression free survival (PFS).

Results

Incomplete metastatic lymph node resection captured by ¹²⁴I-NaI PET/CT (n?=?33) was an independent risk factor for recurrence (61 % vs 25 %, p?=?0.006) and shorter PFS (46 months vs not reached, HR 4.0 [95 %-CI, 1.7–9.2], p?=?0.001). Ultrasound could detect lymph node metastases only in 19/33 patients (58 %). Among patients with positive nodal status, FDG-avidity of metastatic iodine positive lymph nodes worsened the outcome (16 vs 69 months, p?=?0.047). From all other investigated factors including age, N-stage (N1a vs N1b), and T-Stage (T4 vs T1-3), only large tumor size (pT4) had a significant impact on PFS (HR 2.9 [95 %-CI, 1.3–6.4], p?=?0.007).

Conclusions

Incomplete initial surgical clearance of lymph node metastases even after successful radioiodine therapy may increase the chances of recurrence and is an independent risk factor for impaired survival of patients with PTC. Pre-ablative (dual tracer PET/CT) imaging with ¹²⁴I-Na and ¹⁸F provides a prognostic tool for these patients and may considerably complement the current risk stratification systems.

     

Absorption des médicaments lors de syndrome du grêle court

Short bowel syndrome (SBS) occurs when a patient is left with less than 200 cm of functional small intestine. Drug absorption is mostly a passive process and can be affected by the surface area of the remaining gastrointestinal tract. Oral medication absorption is often impaired and larger doses, or other administration routes may be required. Although patients with SBS do need pharmacotherapy for symptoms associated with their pathology or for other comorbidities, there are few published case reports on drug absorption, and few studies have been conducted in small patients’ samples. Moreover, due to the highly heterogeneous nature of this patient population, it is difficult to directly apply the findings of the published literature to specific patients. Drug dosages should be guided by the monitoring of clinical endpoints and/or of biomarkers.     

A prospective study to assess the outcomes of revision anterior cruciate ligament reconstruction

Purpose

Continuously increasing numbers of primary anterior cruciate ligament (ACL) reconstructions invites a parallel increase in graft failures and need for revision ACL reconstruction surgery. High failure rates has previously stigmatised the revision surgery. We performed this study using multiple outcome measures together with clinical examination to offer a full assessment of the outcomes of this procedure.

Methods

Twenty patients, with mean age of 29.4 years (17–50 years), were included in this study prior to their revision ACL reconstruction surgery. All patients were followed prospectively collecting the Knee injury and Osteoarthritis Outcome (KOOS), International Knee Documentation Committee (IKDC) and Tegner-Lysholm scores pre- and post-operatively together with clinical assessment of the antero-posterior knee laxity.

Results

After a mean follow up interval of 30 months (16–60 months) significant post-operative improvement of IKDC, Tegner-Lysholm scores and knee antero-posterior laxity together with the Symptoms, Activities of Daily Living (ADL) and Quality of Life (QOL) components of the KOOS score was noticed (P < 0.05). However, there was no similar improvement in pain and sports components of the KOOS score (P > 0.05). There was no difference in the outcomes of different graft types.

Conclusion

Good outcomes of revision ACL reconstruction surgery are achievable. The use of different graft types did not affect the outcome of the procedure. Most of the patients opted to less aggressive sports participation after the revision procedure.     

Double-chimaerism after transplantation of two human leucocyte antigen mismatched,unrelated cord blood units

The small number of progenitor cells is the major limitation to the use of umbilical cord blood (UCB) for the transplantation of adults. We tested the hypothesis that two units transplanted simultaneously could each contribute to haematopoietic reconstitution. A patient with advanced acute lymphocytic leukaemia received a mismatched, unrelated UCB transplant using units from two donors after conditioning. The recipient achieved a complete remission without graft-versus-host disease. Double chimaerism was documented in several leucocyte subpopulations; both units contributed to haematopoiesis until relapse. Triple chimaerism was present from relapse until death due to leukaemia. This approach may potentially improve UCB transplantation outcome for adults lacking a histocompatible donor.     

Vitamin D Receptor (VDR) Gene Polymorphisms (<Emphasis Type="Italic">Fok</Emphasis>I, <Emphasis Type="Italic">Bsm</Emphasis>I) and their Relation to Vitamin D Status in Pediatrics βeta Thalassemia Major

Vitamin D is critical for calcium, phosphate homeostasis and for mineralization of the skeleton, especially during periods of rapid growth. Vitamin D Deficiency leads to rickets (in children) and osteomalacia (in adults). Expression and activation of the vitamin D receptor (VDR) are necessary for the effects of vitamin D, in which several single nucleotide polymorphisms have been identified especially (FokI, BsmI). In this study serum 25 (OH) vitamin D3 levels were estimated by Enzyme Linked Immunosorbent Assay [ELISA], VDR (FokI, BsmI) gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism assay [PCR–RFLP].Serum levels of calcium, phosphorus, alkaline phosphatase and ferritin were determined in 50 Pediatrics beta thalassemia major patients and 60 controls. Patients had significantly lower serum calcium (p < 0.001) lower serum vitamin D3 (p < 0.001) with elevated levels of phosphorus (p < 0.001) and alkaline phosphatase than controls (p = 0.04). Of the patients studied, 60 % had vitamin D deficiency (<20 ng/ml), 20 % had vitamin D insufficiency (21–30 ng/ml) and 20 % had sufficient vitamin D status (>30 ng/ml). Patients harboring mutant (Ff,ff) and wild (BB) genotypes were associated with lower serum calcium (p = 0.08, 0.02) respectively, lower vitamin D3 levels (p < 0.001, 0.01) respectively. They were also suffering from more bony complications although the difference was not statistically significant (p > 0.05). In conclusion, these results suggest that the VDR (FokI, BsmI) gene polymorphisms influence vitamin D status, (Ff,ff), BB genotypes had lower vitamin D levels, so they might influence risk of development of bone diseases in beta thalassemia major.     

Pulse wave analysis of the aortic pressure waveform in patients with vasovagal syncope

Vascular reflex mechanisms contribute to vasovagal syncope. However, the alterations in central haemodynamics in patients with vasovagal syncope are unknown. 30 consecutive patients (36.5 ± 15 years, 14 females) with recurrent vasovagal syncope (VVS) and a positive tilt table test were compared to 39 age- and sex-matched controls (36.9 ± 16 years, 15 females) with a negative tilt table result and no history of syncope. Central aortic pressure parameters including augmentation index and central pulse pressure as markers of aortic stiffness were generated non-invasively by applanation tonometry of the radial artery and use of a validated mathematical transfer function. No difference in aortic augmentation index was observed between groups. (VVS 9 ± 2.6 vs. Control 11 ± 2.4, p = 0.8). However, in patients with vasovagal syncope the aortic pressure waveform significantly differed from healthy controls. A prolonged time to the peak of aortic pressure wave (aortic T2) was observed in patients with vasovagal syncope (226 ± 24 vs. 208 ± 21 ms, p = 0.001). Furthermore time to the first shoulder of the aortic pressure wave (aortic T1) was slightly shorter compared to healthy controls, but did not reach statistical significance (106 ± 22 vs. 110 ± 12 ms, p = 0.33). Patients with vasovagal syncope have an altered aortic pressure waveform at rest, but no signs of elevated aortic stiffness. The underlying mechanisms for these findings may potentially result from a complex imbalance of the autonomic nervous system with a continuous deregulation of the sympathetic and parasympathetic reflex arcs.     

Comparison of the isomerization mechanisms of human melanopsin and invertebrate and vertebrate rhodopsins

Comparative modeling and ab initio multiconfigurational quantum chemistry are combined to investigate the reactivity of the human nonvisual photoreceptor melanopsin. It is found that both the thermal and photochemical isomerization of the melanopsin 11-cis retinal chromophore occur via a space-saving mechanism involving the unidirectional, counterclockwise twisting of the =C11H-C12H= moiety with respect to its Lys340-linked frame as proposed by Warshel for visual pigments [Warshel A (1976) Nature 260(5553):679–683]. A comparison with the mechanisms documented for vertebrate (bovine) and invertebrate (squid) visual photoreceptors shows that such a mechanism is not affected by the diversity of the three chromophore cavities. Despite such invariance, trajectory computations indicate that although all receptors display less than 100 fs excited state dynamics, human melanopsin decays from the excited state ∼40 fs earlier than bovine rhodopsin. Some diversity is also found in the energy barriers controlling thermal isomerization. Human melanopsin features the highest computed barrier which appears to be ∼2.5 kcal mol⁻¹ higher than that of bovine rhodopsin. When assuming the validity of both the reaction speed/quantum yield correlation discussed by Warshel, Mathies and coworkers [Weiss RM, Warshel A (1979) J Am Chem Soc 101:6131–6133; Schoenlein RW, Peteanu LA, Mathies RA, Shank CV (1991) Science 254(5030):412–415] and of a relationship between thermal isomerization rate and thermal activation of the photocycle, melanopsin turns out to be a highly sensitive pigment consistent with the low number of melanopsin-containing cells found in the retina and with the extraretina location of melanopsin in nonmammalian vertebrates.For a long time it was assumed that the human retina contains only two types of photoreceptor cells: the rods and cones responsible for dim-light and daylight vision, respectively. However, recent studies have revealed the existence of a small number of intrinsically photosensitive retinal ganglion cells (ipRGCs) that regulate nonvisual photoresponses (1). ipRGCs express an atypical opsin-like protein named melanopsin (2, 3) which plays a role in the regulation of unconscious visual reflexes and in the synchronization of endogenous physiological responses to the dawn/dusk cycle (circadian rhythms) (4, 5).Melanopsins are unique among vertebrate photoreceptors because their amino acid sequence shares greater similarity to invertebrate than vertebrate rhodopsin (i.e., the photoreceptor of rods) (6, 7). Like rhodopsins, melanopsins feature an up–down bundle architecture of seven transmembrane α-helices incorporating the 11-cis isomer of retinal as a covalently bound protonated Schiff base (PSB11 in Fig. 1A). Light-induced (i.e., photochemical) isomerization of PSB11 to its all-trans isomer (PSBAT) triggers an opsin conformational change that, ultimately, activates the receptor and signaling cascade (8, 9). However, similar to invertebrate and in contrast to vertebrate rhodopsins, melanopsins are bistable (10). Indeed, although vertebrate rhodopsins need a retinoid cycle (11) to regenerate PSB11, melanopsins have an intrinsic light-driven chromophore regeneration function via PSBAT back-isomerization. Furthermore, past studies have shown that melanopsins use an invertebrate-like signal transduction cascade (12).Open in a separate windowFig. 1.PSB11 chromophore reactivity. (A) Chromophore structure and isomerization to PSBAT. (B) Schematic representation of the photochemical (full arrows) and thermal (dashed arrows) isomerization paths. The CI is located energetically above the TS, features a different geometrical structure, and drives a far-from-equilibrium process. ΔE_S1-S0, τ_cis→trans, and Ea^T (in red) are the fundamental quantities computed in the present work.Melanopsins are held responsible for photoentrainment, using the changes of irradiance and spectral composition to adjust the circadian rhythm (13). The different studies carried out so far on melanopsin light sensitivity do not lead to consistent results. Although Do et al. (14) argue that ipRGCs work at extremely low irradiation intensities showing a single-photon response larger than rods, Ferrer et al. (15) conclude that the melanopsin has a reduced sensitivity relative to visual pigments. On the other hand, these photoreceptors would be expected to display high light sensitivity (14). In the vertebrate retina their density is 10⁴ times lower than that of rhodopsins. Moreover, the receptor is not confined in a dedicated cellular domain such as the outer segment of rods and cones, resulting in a ipRGCs photon capture more than 10⁶-fold lower than that of rods and cones per unit of retina illumination. A high sensitivity of melanopsins would also be consistent with their presence in extraretina locations such as in pineal complex, deep brain, and derma of nonmammalian vertebrates (e.g., amphibian) (16–18). The amount of light that can penetrate into such regions is limited and enriched in the red component due to light scattering by the surrounding tissues (14).The molecular-level understanding of the primary light response of melanopsin is a prerequisite for the comprehension of more complex properties such as its activation and sensitivity. Despite numerous studies carried out since its discovery (16), there is presently little information on the molecular mechanism of melanopsin activation. The common PSB11 chromophore of melanopsins and rhodopsins does not guarantee that the same mechanism operates in both photoreceptors. This not only concerns light-induced activation but also thermal activation: a process whose rate limits the photoreceptor light sensitivity and that is currently associated with thermal, rather than photochemical, PSB11 isomerization (19–24).The mechanism of light-induced PSB11 isomerization in vertebrate rhodopsins has been extensively investigated. Spectroscopic studies have shown that in bovine rhodopsin (Rh) the isomerization occurs on a subpicosecond timescale (25–27). Moreover, the observation of ground state (S₀) vibrational coherence (28) is consistent with a direct transfer of the excited state (S₁) population to the photoproduct (Fig. 1B) passing through a conical intersection (CI). Such a path has been located along the S₁ potential energy surface by constructing a multiconfigurational quantum chemistry (MCQC) based computer model of the photoreceptor (29–31) and spectroscopically supported by probing in the infrared (31). More recently (32), the same computer model has been used to map the Rh thermal isomerization path (Fig. 1B) providing information on the transition states controlling the reaction.Here we present a computational study focusing on the mechanism of photochemical and thermal isomerization of human melanopsin (hMeOp). This would require the construction of a computer model of hMeOp starting from the receptor crystal structure. However, the lack of hMeOp crystallographic data does not allow the use of the protocol previously applied in Rh studies. The significant sequence similarity between squid rhodopsin (sqRh), whose crystal structure is available (PDB code: 2Z73) (33), and hMeOp (40%, SI Appendix, Fig. S1) provides the fundamentals for constructing a structural model of hMeOp at a significant atomic resolution. Building on a study by Batista and coworkers (34) on murine melanopsin, we combine comparative modeling of hMeOp with MCQC to construct a quantum mechanics/molecular mechanics (QM/MM) computer model capable of simulating the photochemical and thermal isomerization reactions of hMeOp. The results are then compared with those found using Rh and sqRh models constructed using the same protocol. Such a comparison is expected to provide information on the differences in spectral and functional properties of these evolutionary distant pigments. As we will show below, the models indicate that hMeOp has a faster photochemical isomerization dynamics and a higher thermal isomerization barrier than both Rh and sqRh.     

Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3-mutated (FLT3m) AML is a challenging leukemia to manage, particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment-naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN-HMA was 60% (94% in treatment-naïve AML and 42% in r/r AML). Early (60-days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00-0.60, P = .03). Cytogenetics-molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia-free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi (P = .01), while ASXL1 or TET2 mutations showed a non-significant association toward higher CR/CRi (P = .07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN-HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients.