PREDICT-GTN 1: Can we improve the FIGO scoring system in gestational trophoblastic neoplasia?

Gestational trophoblastic neoplasia (GTN) patients are treated according to the eight-variable International Federation of Gynaecology and Obstetrics (FIGO) scoring system, that aims to predict first-line single-agent chemotherapy resistance. FIGO is imperfect with one-third of low-risk patients developing disease resistance to first-line single-agent chemotherapy. We aimed to generate simplified models that improve upon FIGO. Logistic regression (LR) and multilayer perceptron (MLP) modelling (n = 4191) generated six models (M1-6). M1, all eight FIGO variables (scored data); M2, all eight FIGO variables (scored and raw data); M3, nonimaging variables (scored data); M4, nonimaging variables (scored and raw data); M5, imaging variables (scored data); and M6, pretreatment hCG (raw data) + imaging variables (scored data). Performance was compared to FIGO using true and false positive rates, positive and negative predictive values, diagnostic odds ratio, receiver operating characteristic (ROC) curves, Bland-Altman calibration plots, decision curve analysis and contingency tables. M1-6 were calibrated and outperformed FIGO on true positive rate and positive predictive value. Using LR and MLP, M1, M2 and M4 generated small improvements to the ROC curve and decision curve analysis. M3, M5 and M6 matched FIGO or performed less well. Compared to FIGO, most (excluding LR M4 and MLP M5) had significant discordance in patient classification (McNemar's test P < .05); 55-112 undertreated, 46-206 overtreated. Statistical modelling yielded only small gains over FIGO performance, arising through recategorisation of treatment-resistant patients, with a significant proportion of under/overtreatment as the available data have been used a priori to allocate primary chemotherapy. Streamlining FIGO should now be the focus.     

Subacute cutaneous lupus erythematosus leukoderma treated with melanocyte‐keratinocyte transplantation procedure

Depigmented lesions may occur as postinflammatory sequelae of subacute cutaneous lupus erythematosus (SCLE), leading to great psychosocial impact. A 53‐year‐old male patient presented with post‐SCLE depigmented facial lesions after five years of disease stability. We proposed surgical treatment with melanocyte‐keratinocyte transplantation procedure (MKTP), and after five months the patient achieved 90% repigmentation, without Koebner phenomenon (KP). In theory, KP is a possible complication of MKTP procedure since the preparation of the receptor area involves the use of dermabrasion. In an attempt to avoid it, we suggest to maintain the treatment of the underlying disease and wait for a minimum period of disease stability before the procedure.     

Reading the unique DNA methylation landscape of the brain: Non-CpG methylation,hydroxymethylation, and MeCP2

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.     

Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

Age-related variations in gene expression patterns of renal cell carcinoma

Background

Clear cell renal cell carcinoma (ccRCC) is known to occur across the adult lifetime traversing the spectrum of age-related organismal changes. Little is known as to how the aging process may affect the course of renal cell carcinoma (RCC) and the repertoire of genes involved.

Hypofractionation vs. conventional radiotherapy fractionation in the conservative treatment of T1 glottic cancer: a prospective cohort study

Definitive radiotherapy is an effective single-modality in T1 glottic cancer. Hypofractionated schemes could offer excellent results in a shorter treatment period. We aimed to evaluate the clinical outcomes and toxicity comparing conventional vs. hypofractionated radiotherapy treatment in T1N0M0-glottic cancer. Between Jan-1st, 2005 and August-1st, 2017, in a prospective cohort study, with 10-year follow-up, 138 patients were treated with conventional schedule 2 Gy/day, total dose 70 Gy/7 weeks (N = 71) or hypofractionated schedule 2, 2–2, 25 Gy/day, total dose 63, 8–63 Gy/5, 5 weeks (N = 67). Endpoints were clinical-response rate, local relapse-free survival (LRFS), laryngectomy-free survival (LFS), toxicity rates, relapse-free survival (RFS), metastasis-free survival (MFS), second tumour-free survival (2TFS), and overall survival (OS). All patients showed a complete clinical response. No differences were found for LRFS (p = 0.869), LFS (p = 0.975), RFS (p = 0.767), MFS (p = 0.601), 2TFS (p = 0.293), or OS (p = 0.685). Acute toxicity for skin and mucosae was similar (p = 0.550 and p = 0.698). Acute laryngeal toxicity was higher in the hypofractionation group (p = 0.004), due to an increase in slight moderate grade. No differences in late laryngeal edema were found (p = 0.989). Radiotherapy offers high rate survival, local control, and larynx preservation after 5–10-year follow-up. A hypofractionation could be preferable, since it offers the same results as conventional with fewer treatment sessions.     

Use of an in vitro model of tissue-engineered human skin to study keratinocyte attachment and migration in the process of reepithelialization

To produce a stable epidermis, keratinocytes need to be firmly attached to the basement membrane. However, following wounding, keratinocytes are required to develop a migratory phenotype in order to reepithelialize the wound. To investigate some of the issues underlying reepithelialization, we have developed a three-dimensional in vitro model of tissue-engineered skin, comprising sterilized human dermis seeded with human keratinocytes and dermal fibroblasts. Using this model, we have shown that the inclusion of fibroblasts within the model increases the stability of keratinocyte attachment. We have also demonstrated that keratinocyte migration occurs most effectively in the absence of a basement membrane and following the inclusion of fibroblasts in the model. In addition, subjecting the keratinocyte layer to mechanical trauma induces a migratory phenotype. We conclude that this three-dimensional in vitro wound model can be used to increase our understanding of the factors that enhance keratinocyte migration and hence wound healing in vivo.     

Death due to anaesthesia at Groote Schuur Hospital, Cape Town--1956-1987. Part II. Causes and changes in aetiological pattern of anaesthetic-contributory death

A general analysis of the clinical failures that were responsible for deaths attributable to anaesthesia over a 30-year period, 1956-1987, is presented. Four particular general failures in clinical management were responsible for 80% of anaesthetic-contributory deaths (ACD). These were in descending order of frequency: (i) failures in airway management, of which the majority were associated with the complications of endotracheal intubation (27% of ACD); (ii) failures in pulmonary ventilation management (20% of ACD); (iii) failures in blood volume control (19% of ACD); and (iv) failures in arrhythmia control (17% of ACD). Computation of these groups of causes by the decade reveals a distinct and progressive change in the aetiological pattern of these deaths with time. While the incidence of ACD over the period decreased 6-fold from 0.43 to 0.07/1,000 anaesthetics, that proportion due to failures in airway management, in general, and complications of intubation, in particular, has progressively increased. This has been accompanied by a reciprocal decrease in deaths due to circulatory factors. It is postulated that this change arises from the fact that the physical skills, manual dexterity and clinical judgement demanded by the former have not changed with time, whereas the latter depend on intellectual responses to information derived from ever-improving vital function monitoring.     

Experience with the 'skew flap' below-knee amputation

A review of 353 lower limb amputations over the last 7 years has been performed to assess the results of the skew flap myoplastic below-knee amputation which was introduced in April 1983 because of reported advantages in terms of wound healing and earlier ambulation. Comparing the first 3 1/2 year period with the second, the total number of amputations decreased by 31 per cent. The number of above-knee amputations remained similar in the two periods (82,62), whilst the number of Gritti-Stokes amputations fell from 79 to 21 (0.001 greater than P greater than 0.01). The proportion of below-knee (BK) amputations increased from 50 (23.7 per cent) to 59 (41.5 per cent) (0.01 greater than P greater than 0.025). The groups were comparable in terms of previous vascular surgery and co-existing medical conditions. The time to full stump healing was significantly shorter in the skew flap group compared with the earlier Burgess type BK amputation (P = 0.001), and there was a trend to fewer stump failures in the skew flap group. We therefore feel that the skew flap amputation gives superior results to the Burgess BK amputation in terms of healing and a lower complication rate, allowing a higher proportion of BK amputations to be performed. A prospective randomized trial of the two techniques is in hand to determine the accuracy of this hypothesis.