Leg Lymphoedema After Inguinal and Ilio-Inguinal Lymphadenectomy for Melanoma: Results from a Prospective, Randomised Trial.

BACKGROUND: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema. METHODS: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex®) > 10 or change of L-Dex® > 10 from baseline. RESULTS: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection. CONCLUSIONS: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study's small sample did not have the statistical evidence to support an overall difference between the surgical groups.

Advances in the Direct Study of Carbon Burning in Massive Stars.

The ^{12}C+^{12}C fusion reaction plays a critical role in the evolution of massive stars and also strongly impacts various explosive astrophysical scenarios. The presence of resonances in this reaction at energies around and below the Coulomb barrier makes it impossible to carry out a simple extrapolation down to the Gamow window-the energy regime relevant to carbon burning in massive stars. The ^{12}C+^{12}C system forms a unique laboratory for challenging the contemporary picture of deep sub-barrier fusion (possible sub-barrier hindrance) and its interplay with nuclear structure (sub-barrier resonances). Here, we show that direct measurements of the ^{12}C+^{12}C fusion cross section may be made into the Gamow window using an advanced particle-gamma coincidence technique. The sensitivity of this technique effectively removes ambiguities in existing measurements made with gamma ray or charged-particle detection alone. The present cross-section data span over 8 orders of magnitude and support the fusion-hindrance model at deep sub-barrier energies.

Inguinal and Ilio-inguinal Lymphadenectomy in Management of Palpable Melanoma Lymph Node Metastasis: A Long-Term Prospective Evaluation of Morbidity and Quality of Life.

PURPOSE: Prospective data are lacking on long-term morbidity of inguinal lymphadenectomy including the influence of extent of surgery, use of radiotherapy, and patient factors. The aim of this study is to evaluate the effects of these factors on patient outcome, quality of life (QOL), regional symptoms, and limb volumes after inguinal or ilio-inguinal lymphadenectomy for melanoma. METHODS: Analysis of the subgroup of patients with inguinal lymph node field relapse of melanoma, treated by inguinal or ilio-inguinal lymphadenectomy in the ANZMTG/TROG randomized trial of adjuvant radiotherapy versus observation. RESULTS: Sixty-nine patients, 46 having undergone inguinal and 23 ilio-inguinal lymphadenectomy, with median follow-up of 73 months were analyzed. Mean limb volume increased rapidly after surgery (7% by 3 months) and continued to increase for at least another 18 months. Patients with body mass index (BMI) ≥ 25 kg/m2 had greater limb volume increase than normal-weight patients (13.3% versus 6.9%, P = 0.030). QOL improved over the first 18 months, but despite initial improvement, regional symptoms persisted long term. Type of surgery (inguinal or ilio-inguinal lymphadenectomy) had no demonstrably significant effect on limb volume (9.9% versus 13.4%, P = 0.35), QOL (P = 0.68), or regional symptoms (P = 0.65). There was no difference in overall survival between inguinal and ilio-inguinal lymphadenectomy [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.40-1.40, P = 0.43]. CONCLUSIONS: Inguinal lymphadenectomy for melanoma is a potentially morbid procedure with significant increases in limb volume. Patients report reasonable QOL but may have ongoing regional symptoms. Overweight/obesity is associated with poorer QOL, increased limb volume, and regional symptoms.

Disposition and metabolism in 1-(2-chloroethyl)-3-(2',3',4'-tri-o-acetyl, ribopyranosyl)-1-nitrosourea in rats.

The antineoplastic activity in animals of 1-(2-chloroethyl)-3-(2',3',4'-tri-O-acetyl, ribopyranosyl)-1-nitrosourea (RPCNU) has been widely demonstrated. The present study deals with the disposition and the metabolism of three 14C-labeled species of RPCNU. The chemical plasma half-life of the drug was less than 5 min. Within the first min after injections, most of the radioactivity derived from ethyl-14C groups were recovered as volatile products. Among these, 2-chloroethanol was identified as a main component. Analysis of labeled species in urine after administration of [ethyl-14C]RPCNU showed that thiodiacetic acid and its sulfoxide were major metabolites of RPCNU (62% of the urinary radioactivity). Traces of N-acetylcarboxymethyl- and N-acetylhydroxyethylcysteine) were also detected. The only labeled species concentrating in particular tissues was that carrying the chloroethyl moiety. Uptake to high levels of [ethyl-14C]RPCNU did occur in liver, kidney, pancreas, thymus, and Harder's gland.

New cysteamine (2-chloroethyl)nitrosoureas. Synthesis and preliminary antitumor results.

Three chemical pathways were used for the synthesis of four new N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]- and N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N- or N'-nitrosoureas. These compounds are plasma metabolites of CNCC, a promising antineoplastic (2-chloroethyl)nitrosourea. Preliminary antitumor evaluation was performed against L1210 leukemia implanted intraperitoneally in mice. Among these compounds, two of them exhibited a greater antitumor activity compared to that of the parent mixture.

[Treatment of inguinal hernias. Is the Bassani's technique current yet? A prospective, randomized trial comparing three operative techniques: Bassini, Shouldice and McVay]. / Tratamento das hérnias inguinais: bassani ainda atual? Estudo randomizado, prospectivo e comparativo entre três técnicas operatórias: Bassini, Shouldice, McVay.

OBJECTIVE: To compare late results (recurrence) of three different techniques for treatment of inguinal hernias in the adult: Bassini, Shouldice and McVay. PATIENTS AND METHODS: The operative late results of three surgical techniques: Bassini, Shouldice and McVay in 119 adult patients with inguinal hernias (some with bilateral pathology, totalizing 136 hernias) were analyzed. The majority of patients were males (93.3%). The analysis was prospective, randomized, with uniform distribution of all three types of inguinal hernia (direct, indirect and combined) among the three groups of operative techniques. The number of recurrences was submitted to an actuarial analysis for a period of 4 years. The results underwent statistical analysis by the Kaplan-Mayer test with actuarial survival curves. RESULTS: Eight hernia operations by the Bassini technique recurred in this time span, 3 in the Shouldice group and 2 in McVay. Among the Bassini recurrences, the worst results were observed with direct hernias (29% recurrence) when compared with indirect ones (16% recurrence). Overall recurrence rates plotted in an actuarial survival curve for 4 years, revealed statistically significant differences between Bassini and Shouldice: 35.7% versus 23.7%; the same happened when comparing Bassini to McVay: 35.7% versus 8.5%. The differences between Shouldice and McVay were not significant. CONCLUSION: A recurrence rate of 35.7% for inguinal herniorraphy with the Bassini technique in a General Surgery University Clinic was surprising and obliged us to interrupt the trial. Our observations point to a prohibitive high failure rate when dealing with the Bassini technique, which was, over a century, the most popular treatment of inguinal hernia all over the world. Shouldice and McVay techniques, even though more complex, should be preferred whenever one makes the choice for "conventional" hernia treatment.

Extreme deuterium excesses in ultracarbonaceous micrometeorites from central Antarctic snow.

Primitive interplanetary dust is expected to contain the earliest solar system components, including minerals and organic matter. We have recovered, from central Antarctic snow, ultracarbonaceous micrometeorites whose organic matter contains extreme deuterium (D) excesses (10 to 30 times terrestrial values), extending over hundreds of square micrometers. We identified crystalline minerals embedded in the micrometeorite organic matter, which suggests that this organic matter reservoir could have formed within the solar system itself rather than having direct interstellar heritage. The high D/H ratios, the high organic matter content, and the associated minerals favor an origin from the cold regions of the protoplanetary disk. The masses of the particles range from a few tenths of a microgram to a few micrograms, exceeding by more than an order of magnitude those of the dust fragments from comet 81P/Wild 2 returned by the Stardust mission.

Twelve-month short-term safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration.

BACKGROUND/AIMS: This study evaluated the short-term safety and feasibility of epiretinal strontium-90 brachytherapy delivered concomitantly with intravitreal bevacizumab for the treatment of subfoveal CNV due to AMD for 12 months. A 3-year follow-up is planned. METHODS: In this prospective, non-randomised, multicentre study, 34 treatment-naïve patients with predominantly classic, minimally classic and occult subfoveal CNV lesions received a single treatment with 24 Gy beta radiation (strontium-90) and two injections of the anti-VEGF antibody bevacizumab. Adverse events were observed. BCVA was measured using standard ETDRS vision charts. RESULTS: Twelve months after treatment, no radiation-associated adverse events were observed. In the intent-to-treat (ITT) population, 91% of patients lost <3 lines (15 ETDRS letters) of vision at 12 months, 68% improved or maintained their BCVA at 12 months, and 38% gained >/=3 lines. The mean change in BCVA observed at month 12 was a gain of 8.9 letters. CONCLUSION: The safety and efficacy of intraocular, epiretinal brachytherapy delivered concomitantly with anti-VEGF therapy for the treatment of subfoveal CNV secondary to AMD were promising in this small study population. Long-term safety will be assessed for 3 years. This regimen is being evaluated in a large, multicentre, phase III study.

Long-term response of isolated limb perfusion with hyperthermia and chemotherapy for Merkel cell carcinoma.

INTRODUCTION: Merkel cell carcinoma (MCC) is a very rare and aggressive neoplasm. Due to its rarity, therapeutic guidelines are not well established, especially for regionally advanced disease. Hyperthermic isolated limb perfusion (HILP) with Melphalan and either with or without tumor necrosis factor-alpha (TNF-alpha) is becoming more common in clinical practice, yet the long-term response is not clear. Previous reports have established indications for treatment of unresectable MCC as well as the outcome of MCC patients receiving perfusion treatment in combination with other therapies (e.g., radiation). METHOD: A review was performed of the most important articles in MEDLINE from the last 20 years related to HILP and MCC. It was possible to collect all cases of HILP from the literature. Details of one case of MCC where HILP was administered was included in the literature review. RESULTS: A total of nine cases of MCC receiving ILP were identified in the literature; of these, seven achieved a complete response, one a partial response and one no response. All five patients treated without TNF-alpha had a complete response. Of the four patients treated with TNF-alpha, two had complete, one partial and one no response. CONCLUSION: Based on the cases described, isolated limb perfusion is an acceptable option to treat regional advanced cases of MCC, and the use of TNF-alpha does not impact the overall response.

Main metabolites of 1-(2-chloroethyl)-3-[1'-(5'-p-nitrobenzoyl-2',3'-isopropylidene)-alpha, beta-D-ribofuranosyl]-1-nitrosourea and 1-(2-chloroethyl)-3-(2',3', 4'-tri-O-acetyl-alpha, beta-D-ribopyranosyl)-1-nitrosourea in rats.

The metabolism of two glycosylnitrosoureas, 1-(2-chloroethyl)-3-[1'-(5'-p-nitrobenzoyl-2',3'-isopropylidene)-alpha, beta-D-ribofuranosyl]-1-nitrosourea (RFCNU) and 1-(2-chloroethyl)-3-(2',3',4'-tri-O-acetyl-alpha, beta-D-ribopyranosyl)-1-nitrosourea (RPCNU), has been investigated in the rat. With the label on the carboxyl moiety of RFCNU, we have shown that hydrolysis of the 4-nitrobenzoyl ester occurred to a large extent in vivo; 4-nitrobenzoic acid and its glucuronide were the major urinary metabolites. Two other minor metabolites and their glucuronides were identified as 4-aminobenzoic acid and 4-acetamidobenzoic acid. With the label on the chloroethyl moieties of RFCNU and RPCNU, we have shown that chloroethanol was a major degradation product of this alkylating part of the molecule. The concentration of chloroethanol in plasma vs. time has been determined. In urine, four metabolites derived from alkylated glutathione, namely thiodiacetic acid and its sulfoxide, N-acetylcarboxymethylcysteine, and N-acetylhydroxyethylcysteine, have been identified.

The timing of the last deglaciation in North Atlantic climate records.

To determine the mechanisms governing the last deglaciation and the sequence of events that lead to deglaciation, it is important to obtain a temporal framework that applies to both continental and marine climate records. Radiocarbon dating has been widely used to derive calendar dates for marine sediments, but it rests on the assumption that the 'apparent age' of surface water (the age of surface water relative to the atmosphere) has remained constant over time. Here we present new evidence for variation in the apparent age of surface water (or reservoir age) in the North Atlantic ocean north of 40 degrees N over the past 20,000 years. In two cores we found apparent surface-water ages to be larger than those of today by 1,230 +/- 600 and 1,940 +/- 750 years at the end of the Heinrich 1 surge event (15,000 years BP) and by 820 +/- 430 to 1,010 +/- 340 years at the end of the Younger Dryas cold episode. During the warm Bølling-Allerød period, between these two periods of large reservoir ages, apparent surface-water ages were comparable to present values. Our results allow us to reconcile the chronologies from ice cores and the North Atlantic marine records over the entire deglaciation period. Moreover, the data imply that marine carbon dates from the North Atlantic north of 40 degrees N will need to be corrected for these highly variable effects.

Metabolism of 2-chloroethyl nitrosocarbamoylcystamine by rat liver subcellular fractions.

Previously we have shown that a new nitrosourea, 2-chloroethyl nitrosocarbamoylcystamine (CNCC), undergoes an extensive metabolism in the rat. Two pairs of plasma metabolites have been identified. This suggested our hypothesis that the metabolic pathway involves the reduction of the disulfur bridge followed by the methylation and the oxidation of the thiol groups. The two first intermediates, i.e. the unoxidized metabolites, could not be detected in vivo. Hence, to better understand and to confirm the proposed mechanism of biotransformation of CNCC, its in vitro metabolism has been studied. Incubation of CNCC with a rat liver homogenate or a 10,000g supernatant fraction leads to the formation of four pairs of metabolites. Among them we have identified the two first intermediates not found in vivo and the oxidized metabolites. These findings, together with the kinetics data, suggest that reduction, methylation, and oxidation are very rapid enzymatic reactions. We also show that, for completion of the reaction, the incubation mixture had to contain a cytosolic thioreductase, a microsomal and cytosolic S-methyltransferase, a microsomal oxidase, and an NADPH generating system. The sum of the amounts of metabolites found in the organic extratable material is less than the amount of CNCC metabolized. We conclude that the biotransformation of CNCC proceeds from two fast competitive mechanisms operative on both the disulfur and the nitroso groups.

Metabolic disposition of 2-chloroethyl nitrosocarbamoylcystamine in rats.

The disposition and the metabolism of 2-chloroethyl nitrosocarbamoylcystamine (CNCC), a new antitumor agent, has been studied in rats. For this purpose, three separate labeled species of CNCC have been used. The tissue distribution and the elimination of the radioactivity were determined in animals after gavage with a single dose of each labeled species of CNCC (35 mumol/kg). It was observed, after analysis of plasma taken at timed intervals after administration, that little radioactivity co-chromatographed with the parent compound. These data suggest that CNCC undergoes an important first-pass metabolism, but chromatographic analysis provided evidence for the formation of four main metabolites. These biotransformation products were isolated from pooled plasma extracts of rats treated with 200 mumol/kg of unlabeled CNCC. They were identified by the combined use of mass spectrometry and chromatographic properties. These metabolites are sulfinyl and sulfonyl derivatives arising from the bioreduction of the disulfur bridge of CNCC with subsequent methylation and oxidation. These compounds are potentially active cytostatic agents. The evaluation of their antitumor activity is currently under investigation.

(68)(28)Ni(40): Magicity versus superfluidity.

The neutron-rich (66,68)Ni have been produced at GANIL via interactions of a 65.9A MeV 70Zn beam with a 58Ni target. Their reduced transition probability B(E2;0(+)(1)-->2+) has been measured for the first time by Coulomb excitation in a (208)Pb target at intermediate energy. The B(E2) value for (68)Ni(40) is unexpectedly small. An analysis in terms of large scale shell model calculations stresses the importance of proton core excitations to reproduce the B(E2) values and indicates the erosion of the N = 40 harmonic-oscillator subshell by neutron-pair scattering.