Second primary cancers (SPCs) are diagnosed in over 5% of patients after a first primary cancer (FPC). We explore here the impact of immune checkpoint inhibitors (ICIs) given for an FPC on the risk ...of SPC in different age groups, cancer types and treatments.
The files of the 46 829 patients diagnosed with an FPC in the Centre Léon Bérard from 2013 to 2018 were analyzed. Structured data were extracted and electronic patient records were screened using a natural language processing tool, with validation using manual screening of 2818 files of patients. Univariate and multivariate analyses of the incidence of SPC according to patient characteristics and treatment were conducted.
Among the 46 829 patients, 1830 (3.9%) had a diagnosis of SPC with a median interval of 11.1 months (range 0-78 months); 18 128 (38.7%) received cytotoxic chemotherapy (CC) and 1163 (2.5%) received ICIs for the treatment of the FPC in this period. SPCs were observed in 7/1163 (0.6%) patients who had received ICIs for their FPC versus 437/16 997 (2.6%) patients receiving CC and no ICIs for the FPC versus 1386/28 669 (4.8%) for patients receiving neither CC nor ICIs for the FPC. This reduction was observed at all ages and for all histotypes analyzed. Treatment with ICIs and/or CC for the FPC are associated with a reduced risk of SPC in multivariate analysis.
Immunotherapy with ICIs alone and in combination with CC was found to be associated with a reduced incidence of SPC for all ages and cancer types.
•From 2013 to 2018, 3.9% of the 46 829 patients diagnosed with a first cancer presented with an SPC.•Treatment of the first cancer with ICIs was associated with a major reduction of SPC.•CC given for an FPC was also associated with a lower magnitude of reduction of SPC.•There were no SPC in cancer patients treated with ICIs in the localized phase of their first cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lung vessel muscularization during hypoxic pulmonary hypertension is associated with local renin-angiotensin system activation. The expression of angiotensin II (Ang II) AT1 and AT2 receptors in this ...setting is not well known and has never been investigated during normoxia recovery. We determined both chronic hypoxia and normoxia recovery patterns of AT1 and AT2 expression and distal muscularization in the same lungs using in situ binding, reverse transcriptase/polymerase chain reaction, and histology. We also used an isolated perfused lung system to evaluate the vasotonic effects of AT1 and AT2 during chronic exposure to hypoxia with and without subsequent normoxia recovery. Hypoxia produced right ventricular hypertrophy of about 100% after 3 wk, which reversed with normoxia recovery. Hypoxia for 2 wk was associated with simultaneous increases (P<0.05) in AT1 and AT2 binding (16-fold and 18-fold, respectively) and in muscularized vessels in alveolar ducts (2. 8-fold) and walls (3.7-fold). An increase in AT2 messenger RNA (mRNA) (P<0.05) was also observed, whereas AT1 mRNA remained unchanged. After 3 wk of hypoxia, muscularization was at its peak, whereas all receptors and transcripts showed decreases (P<0.05 versus hypoxia 2 wk for AT1 mRNA), which became significant after 1 wk of normoxia recovery (P<0.05 versus hypoxia 2 wk). Significant reversal of muscularization (P<0.01) was found only after 3 wk of normoxia recovery in alveolar wall vessels. Finally, the AT1 antagonist losartan completely inhibited the vasopressor effect of Ang II in hypoxic and normoxia-restored lungs, whereas the AT2 agonist CGP42112A had no effect. Our data indicate that in lungs, chronic hypoxia-induced distal muscularization is associated with early and transient increases in AT2 and AT1 receptors probably owing to hypoxia- dependent transcriptional and post-transcriptional regulatory mechanisms, respectively. They also indicate that the vasotonic response to Ang II is mainly due to the AT1 subtype.
Ether anaesthesia has been used in rodents for routine blood sampling in toxicological studies for many years. Because of the highly flammable nature of ether and the inability to control the depth ...of anaesthesia, more suitable alternatives are needed. This study was conducted to compare data obtained using ether or isoflurane. Groups of male and female Sprague-Dawley rats, 5 weeks of age, were maintained on a normal diet for up to 25 weeks. Body weights were recorded during the study. Blood was sampled from the retro-orbital sinus under the different anaesthetics from the animals at 8, 12, 21 and from females only at 25 weeks of age for the analysis of standard haematology and biochemical parameters. These animals were killed at 25 weeks of age for histological examination. Body weights were unaffected. The major biochemical and haematological parameters were similar at the various time points with both types of anaesthetic. Minor variations, such as an increase in potassium and a reduction in glucose with isoflurane were seen, but there was no consistent trend. Examination of the liver, kidneys, heart and lungs did not reveal any changes that were considered to be associated with either anaesthetic. Blood was taken for prolactin analysis from a subgroup of animals at 12 weeks of age anaesthetised with ether or isoflurane, and from tail-bled animals without anaesthesia, these animals being killed at 17 weeks of age for histological examination. The level of prolactin at 12 weeks of age was reduced in the isoflurane group particularly in the males. This is considered to indicate that there was less stress. Based on these results, isoflurane is proposed as a suitable alternative to ether.PUBLICATION ABSTRACT
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
65.
Tumefaction of the back of the hand Augey, F; Daumont, A; Chassagne-Clement, C
Annales de dermatologie et de vénéréologie
129, Issue:
5 Pt 1
Journal Article
Abstract only
8562
Background: Diffuse large B-cell lymphoma (DLBCL) usually relapses early following treatment but some relapses happen 5 years or later. Few data exist regarding clinical ...characteristics and outcome of these patients (pts). Methods: We performed a retrospective analysis of all pts from two centers in Lyon/France between 1980–2003 who presented a biopsy proven relapse 5 years or later following diagnosis of DLBCL. All available biopsies were revised and immunohistochemistry (IHC) completed. Results: Among 1492 pts with DLBCL, 54 were eligible. Clinical characteristics at diagnosis were: median age 57 y; stage I-II 63% (34/54); IPI low/low intermediate 84% (41/49) and extranodal involvement (EN) 66% (35/53). IHC at diagnosis: CD20 100% (46/46), CD10 28% (10/36), bcl-6 53% (9/17), MUM1 48% (11/23), bcl-2 68% (19/28), germinal-center phenotype (GC) 57% (12/21) and non-GC 43% (9/21). 47/53 received CHOP/ACVBP-like regimens, 1 autologous transplantation (ASCT) and 1 rituximab. Median time from diagnosis to relapse was 7.4 years (5–20.5 years). 44 pts (81%) had DLBCL histology at time of relapse and 10 pts (19%) indolent histology. MUM1 expression at diagnosis was associated with DLBCL histology at relapse (p=0.037). Clinical characteristics at relapse were: median age 66 y; stage I-II 48% (26/54); 73% (31/43) with DLBCL at relapse had EN. 54% (15/28) with DLBCL at relapse had a GC phenotype and 46% (13/28) a non-GC phenotype. Treatment at relapse included rituximab in 21/54 and ASCT in 15/54 with 7 pts receiving both. Estimated 5-year event-free survival (EFS) and overall survival (OS) after relapse were 25% and 35% for all pts. Pts with DLBCL histology at relapse had an estimated 5-year EFS and OS of 18% and 28%. Pts with indolent histology had an estimated 5-year EFS and OS of 55% and 67%. Conclusions: Patients with DLBCL who present a late relapse usually had localized stage, favorable IPI and extranodal involvement at diagnosis. However, even if initial characteristics at time of first treatment were favorable, outcome of pts with DLBCL at time of relapse remains poor and aggressive treatment, such as ASCT, should be pursue whenever possible. Some patients relapsed with indolent histology and have a better outcome.
No significant financial relationships to disclose.
1 Institut National de la Santé et de la
Recherche Médicale (INSERM) U127/572, Institut
Fédératif de Recherche Circulation Paris VII, Hôpital
Lariboisière, Université Denis Diderot, Paris; and
2 ... INSERM U492, Institut de Médecine
Moléculaire, Hôpital Henri-Mondor, Créteil,
France
Right ventricular myocardial hypertrophy
during hypoxic pulmonary hypertension is associated with local
renin-angiotensin system activation. The expression of angiotensin II
type 1 (AT 1 ) and type 2 (AT 2 ) receptors in this
setting has never been investigated. We have therefore examined the
chronic hypoxia pattern of AT 1 and AT 2
expression in the right and left cardiac ventricles, using in situ
binding and RT-PCR assays. Hypoxia produced right, but not left,
ventricular hypertrophy after 7, 14, and 21 days, respectively. Hypoxia
for 2 days was associated in each ventricle with a simultaneous and
transient increase ( P < 0.05) in AT 1 binding
and AT 1 mRNA levels in the absence of any significant
change in AT 2 expression level. Only after 14 days of
hypoxia, AT 2 binding increased ( P < 0.05) in
the two ventricles, concomitantly with a right ventricular decrease
( P < 0.05) in AT 2 mRNA. Along these data,
AT 1 and AT 2 binding remained unchanged in both
the left and hypertrophied right ventricles from rats treated with
monocrotaline for 30 days. These results indicate that chronic hypoxia
induces modulations of AT 1 and AT 2 receptors in
both cardiac ventricles probably through direct and indirect
mechanisms, respectively, which modulations may participate in myogenic
(at the level of smooth or striated myocytes) rather than in the growth
response of the heart to hypoxia.
chronic hypoxia; heart ventricles; angiotensin II; AT 1
and AT 2 receptor subtypes
Accumulating evidence suggests that angiotensin II type II (AT(2)) receptor subtype negatively regulates cell proliferation in pathophysiological conditions associated with tissue remodeling. ...However, the mechanisms through which AT(2) receptor achieves this effect remain poorly understood. In this study, we demonstrate that expression of AT(2) receptor inhibits the proliferation of rat fibroblasts in a ligand-independent manner. The antiproliferative action of AT(2) is dependent on the density of surface receptors. We show that AT(2) receptor expression negatively regulates G1 phase progression in both cycling cells and G0-arrested cells stimulated to re-enter the cell cycle, but has no detectable effect on apoptosis. The delay in cell-cycle progression of AT(2)-expressing cells is associated with downregulation of cyclin E expression, decreased assembly of cyclin E-Cdk2 complexes, and the resulting attenuation of Cdk2 activation. The induction of Cdk4 expression and activity is also markedly attenuated, which likely contributes to the inhibition of cyclin E expression. Ectopic expression of Cdk4 alleviates the proliferation defect of AT(2)-expressing cells. These findings suggest that the growth-inhibitory effects of the AT(2) receptor are attributable in part to its spontaneous inhibitory action on the cell cycle machinery.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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