Novel approaches facilitating neuraxial anesthesia placement in pregnant women with morbid obesity: case descriptions.

Clinical management of pregnant women with morbid obesity poses challenges in performing neuraxial anesthesia as well as positioning for cesarean delivery. Occupational injuries are also known to occur while caring for patients with morbid obesity. We describe two novel approaches to assist neuraxial anesthesia administration and positioning for cesarean delivery. With the assistance of the Institution's Safe Patient Handling and Mobility Team, a universal high-back sling can be placed to lift the patient into a sitting position before neuraxial anesthesia procedure. After placement of combined spinal epidural anesthesia, the ceiling lift is used to lift the patient into a seated position and then rotate to the appropriate location on the operating room table to facilitate supine positioning. The lifting system reduces shearing of the patient's posterior and compromising the epidural site. Team members also report reduced effort required when positioning patients from seated to supine on the operating room table. The second approach is the application of TraxiTM abdominal pannus retractor to retract fat folds encroaching on the epidural placement site in pregnant women with morbid obesity. This is particularly useful when the traditional taping of fat folds away from the site is inadequate. The pannus retractor results in a flatter surface facilitating epidural placement. We have introduced these two approaches into our clinical practice for pregnant women with morbid obesity requiring cesarean delivery under neuraxial anesthesia.

Impact of endometrial preparation on early pregnancy loss and live birth rate after frozen embryo transfer: a large multicenter cohort study (14 421 frozen cycles).

STUDY QUESTION: Does the endometrial preparation protocol (artificial cycle (AC) vs natural cycle (NC) vs stimulated cycle (SC)) impact the risk of early pregnancy loss and live birth rate after frozen/thawed embryo transfer (FET)? SUMMARY ANSWER: In FET, ACs were significantly associated with a higher pregnancy loss rate and a lower live birth rate compared with SC or NC. WHAT IS KNOWN ALREADY: To date, there is no consensus on the optimal endometrial preparation in terms of outcomes. Although some studies have reported a higher pregnancy loss rate using AC compared with NC or SC, no significant difference was found concerning the pregnancy rate or live birth rate. Furthermore, no study has compared the three protocols in a large population. STUDY DESIGN SIZE DURATION: A multicenter retrospective cohort study was conducted in nine reproductive health units in France using the same software to record medical files between 1 January 2012 and 31 December 2016. FET using endometrial preparation by AC, modified NC or SC were included. The primary outcome was the pregnancy loss rate at 10 weeks of gestation. The sample size required was calculated to detect an increase of 5% in the pregnancy loss rate (21-26%), with an alpha risk of 0.5 and a power of 0.8. We calculated that 1126 pregnancies were needed in each group, i.e. 3378 in total. PARTICIPANTS/MATERIALS SETTING METHODS: Data were collected by automatic extraction using the same protocol. All consecutive autologous FET cycles were included: 14 421 cycles (AC: n = 8139; NC: n = 3126; SC: n = 3156) corresponding to 3844 pregnancies (hCG > 100 IU/l) (AC: n = 2214; NC: n = 812; SC: n = 818). Each center completed an online questionnaire describing its routine practice for FET, particularly the reason for choosing one protocol over another. MAIN RESULTS AND THE ROLE OF CHANCE: AC represented 56.5% of FET cycles. Mean age of women was 33.5 (SD ± 4.3) years. The mean number of embryos transferred was 1.5 (±0.5). Groups were comparable, except for history of ovulation disorders (P = 0.01) and prior delivery (P = 0.03), which were significantly higher with AC. Overall, the early pregnancy loss rate was 31.5% (AC: 36.5%; NC: 25.6%; SC: 23.6%). Univariable analysis showed a significant association between early pregnancy loss rate and age >38 years, history of early pregnancy loss, ovulation disorders and duration of cryopreservation >6 months. After adjustment (multivariable regression), the early pregnancy loss rate remained significantly higher in AC vs NC (odds ratio (OR) 1.63 (95% CI) [1.35-1.97]; P < 0.0001) and in AC vs SC (OR 1.87 [1.55-2.26]; P < 0.0001). The biochemical pregnancy rate (hCG > 10 and lower than 100 IU/l) was comparable between the three protocols: 10.7% per transfer. LIMITATIONS REASONS FOR CAUTION: This study is limited by its retrospective design that generates missing data. Routine practice within centers was heterogeneous. However, luteal phase support and timing of embryo transfer were similar in AC. Univariable analysis showed no difference between centers. Moreover, a large number of parameters were included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: Our study shows a significant increase in early pregnancy loss when using AC for endometrial preparation before FET. These results suggest either a larger use of NC or SC, or an improvement of AC by individualizing hormone replacement therapy for patients in order to avoid an excess of pregnancy losses. STUDY FUNDING/COMPETING INTERESTS: The authors declare no conflicts of interest in relation to this work. G.P.-B. declares consulting fees from Ferring, Gedeon-Richter, Merck KGaA, Theramex, Teva; Speaker's fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter, Theramex, Teva. N.C. declares consulting fees from Ferring, Merck KGaA, Theramex, Teva; Speaker's fees or equivalent from Merck KGaA, Ferring. C.R. declares a research grant from Ferring, Gedeon-Richter; consulting fees from Gedeon-Richter, Merck KGaA; Speaker's fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter; E.M.d'A. declares Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Theramex, Teva. I.C-D. declares Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, IBSA. N.M. declares a research grant from Merck KGaA, MSD, IBSA; consulting fees from MSD, Ferring, Gedeon-Richter, Merck KGaA; Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Teva, Goodlife, General Electrics. TRIAL REGISTRATION NUMBER: N/A.

Mechanical ventilation and prone positioning in pregnant patients with severe COVID-19 pneumonia: experience at a quaternary referral center.

BACKGROUND: We present the care of 17 consecutive pregnant patients who required mechanical ventilation for Coronavirus Disease 2019 (COVID-19) pneumonia at a quaternary referral center in the United States. We retrospectively describe the management of these patients, maternal and fetal outcomes, as well as the feasibility of prone positioning and delivery. METHODS: Between March 2020 and June 2021, all pregnant and postpartum patients who were mechanically ventilated for COVID-19 pneumonia were identified. Details of their management including prone positioning, maternal and neonatal outcomes, and complications were noted. RESULTS: Seventeen pregnant patients required mechanical ventilation for COVID-19. Thirteen patients received prone positioning, with a total of 49 prone sessions. One patient required extracorporeal membrane oxygenation. All patients in this series survived until at least discharge. Nine patients delivered while mechanically ventilated, and all neonates survived, subsequently testing negative for SARS-CoV-2. There was one spontaneous abortion. Four emergent cesarean deliveries were prompted by refractory maternal hypoxemia or non-reassuring fetal heart rate after maternal intubation. CONCLUSIONS: Overall, maternal and neonatal survival were favorable even in the setting of severe COVID-19 pneumonia requiring mechanical ventilation. Prone positioning was well tolerated although the impact of prone positioning or fetal delivery on maternal oxygenation and ventilation are unclear.

In vivo single human sweat gland activity monitoring using coherent anti-Stokes Raman scattering and two-photon excited autofluorescence microscopy.

BACKGROUND: Eccrine sweat secretion is of central importance for control of body temperature. Although the incidence of sweat gland dysfunction might appear of minor importance, it can be a real concern for people with either hypohidrosis or hyperhidrosis. However, sweat gland function remains relatively poorly explored. OBJECTIVES: To investigate the function of single human sweat glands. METHODS: We describe a new approach for noninvasive imaging of single sweat gland activity in human palms in vivo up to a depth of 100 µm, based on nonlinear two-photon excited autofluorescence (TPEF) and coherent anti-Stokes Raman scattering (CARS). RESULTS: These techniques appear to be useful compared with approaches already described for imaging single sweat gland activity, as they allow better three-dimensional spatial resolution of sweat pore inner morphology and real-time monitoring of individual sweat events. By filling the sweat pore with oil and tuning the CARS contrast at 2845 cm(-1) , we imaged the ejection of sweat droplets from a single sweat gland when oil is pushed out by sweat flow. On average, sweat events lasted for about 30 s every 3 min under the conditions studied. On the other hand, about 20% of sweat glands were found inactive. TPEF and CARS were also used to study, at the single pore level, the antiperspirant action of aluminium chlorohydrate (ACH) and to reveal, for the first time in vivo, the formation of a plug at the pore entrance, in agreement with reported ACH antiperspirant mechanisms. CONCLUSIONS: Although data were acquired on human palms, these techniques show great promise for a better understanding of sweat secretion physiology and should be helpful to improve the efficacy of antiperspirant formulations.

Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study.

BACKGROUND: When administered in the late follicular phase to prevent an LH surge, GnRH antagonists induce a sharp decrease in serum LH levels that may be detrimental for assisted reproductive technology cycle outcome. Therefore, a prospective study was designed to assess the effects of recombinant human (r)LH supplementation during GnRH antagonist (cetrorelix) administration. METHODS: The protocol consisted of cycle programming with oral contraceptive pill, ovarian stimulation with rFSH and flexible administration of a single dose of cetrorelix (3 mg). A total of 218 patients from three IVF centres were randomized (by sealed envelopes or according to woman's birth date) to receive (n = 114) or not (n = 104) a daily injection of rLH 75 IU from GnRH antagonist initiation to hCG injection. RESULTS: The only significant difference was a higher serum peak E2 level in patients treated with rLH (1476 +/- 787 versus 1012 +/- 659 pg/ml, P < 0.001) whereas the numbers of oocytes and embryos as well as the delivery rate (25.2 versus 24%) and the implantation rate per embryo (19.1 versus 17.4%) were similar in both groups. CONCLUSIONS: These results show that in an unselected group of patients, there is no evident benefit to supplement GnRH antagonist-treated cycles with rLH.

Beneficial effects of GnRH agonist administration prior to ovarian stimulation for patients with a short follicular phase.

A short follicular phase is an early clinical feature of declining reproductive competence. The shortening of the follicular phase length is related to both advanced recruitment and selection of the dominant follicle secondary to an earlier and higher FSH rise during the luteal-follicular transition, while the late follicular growth is normal. As a short follicular phase may be detrimental for reproduction, it was postulated that increasing the duration of follicular phase could improve conception rate. For that purpose, gonadotrophin-releasing hormone agonist minidoses were administered in the mid-luteal phase to prevent the intercycle FSH rise before tailoring follicular growth by controlled exogenous FSH administration. This regimen, applied to 69 infertile ovulatory women with a short follicular phase (9.6 +/- 1.2 days) actually lengthened the follicular phase by about 3 days. It proved to be effective in 179 cycles to induce paucifollicular development (1.8 +/- 0.9 follicles) with a low cancellation rate (4%) and a moderate requirement for gonadotrophins [13.3 +/- 6.3 ampoules (75 IU)]. In those women with a high frequency (80%) of elevated basal FSH or oestradiol concentrations, the pregnancy rate reached 15.1%/cycle but the miscarriage rate remained high (44%). Thus, increasing the follicular phase length in patients with a short follicular phase may partially restore fecundity.

[Should infertile women with polycystic ovarian syndrome be treated with metformine?]. / Faut-il traiter par metformine les femmes infertiles présentant un syndrome des ovaires polykystiques ?

Polycystic ovary syndrome is a frequent endocrine disorder often associated with insulin resistance and hyperinsulinaemia which may play a role in hyperandrogenism and anovulation. The use of "insulin sensitizing" agents has been suggested to reduce insulin resistance and hyperandrogenism. In that respect, the use of metformin in polycystic ovary syndrome is reviewed. Although its mechanism of action is still unclear, metformin proved to be effective to restore cyclicity and spontaneous ovulation. The synergistic effect of clomiphene citrate and metformin was demonstrated in some studies, suggesting that metformin could be helpful for women with clomiphene citrate resistance. However, the potential effect of metformin administration for reducing hyperstimulation in women treated with exogenous FSH, or for preventing early miscarriages has to be confirmed. Here, we propose a guideline for the use of metformin, as an adjuvant therapy, to restore cyclicity and ovulation in women with polycystic ovary syndrome.

Type-1 steroid 5 alpha-reductase is functionally active in the hair follicle as evidenced by new selective inhibitors of either type-1 or type-2 human steroid 5 alpha-reductase.

Steroid 5 alpha-reductase catalyzes the reduction of testosterone (T) into the very potent androgen dihydrotestosterone (DHT). The different tissue expression patterns of the two isoforms of 5 alpha-reductase, namely type-1 and type-2 5 alpha-reductase (5 alpha-R1 and 5 alpha-R2, respectively), have prompted studies directed towards the synthesis of selective 5 alpha-R1 or 5 alpha-R2 inhibitors. In this present work, we have performed a structure/activity study on the inhibitory potential of indole carboxylic acids against hair follicle 5 alpha-reductase activity. We have demonstrated that this class of molecules were potent inhibitors of either 5 alpha-R1 or 5 alpha-R2 or both depending on (i) substituents in positions 4, 5 or 6 and (ii) the presence of a free carboxylic group. We have also found that only 5 alpha-R1 or 5 alpha-R1/R2 inhibitors were able to inhibit 5 alpha-reductase activity in plucked hairs from female volunteers or in freshly isolated female hair follicles, selective 5 alpha-R2 inhibitors being inactive.

Recent advances in the design of iron chelators against oxidative damage.

Iron imbalance plays a pivotal role in oxidative damages associated with a wide range of pathological conditions. However, owing to the essential role of iron in biological processes, the beneficial effects of iron chelation therapy against oxidative damage have to be balanced against potential toxicity. The present review briefly introduces iron redox biochemistry and oxidative-stress associated pathologies, surveys recent advances in iron chelating strategies and summarizes some of our recent findings in this field, with a special emphasis on the chemical design constraints one must satisfy in order to synthesize iron chelators which could be beneficial against oxidative stress without inducing iron depletion of the body. The concept of oxidative stress activatable iron chelators is presented as a new paradigm for safe and efficient treatment of oxidative-stress associated conditions.

Protection against oxidative damage by iron chelators: effect of lipophilic analogues and prodrugs of N,N'-bis(3,4,5-trimethoxybenzyl)ethylenediamine- N,N'-diacetic acid (OR10141).

N,N'-Bis(3,4,5-trimethoxybenzyl)ethylenediamine-N,N'-diacetic acid (1) was recently described as a new type of iron chelator for protection against oxidative damage. It has a low affinity for iron, but the corresponding iron complex undergoes a site-specific oxidation by hydrogen peroxide through intramolecular aromatic hydroxylation into a highly stable iron phenolato complex, which does not catalyze hydroxyl radical formation. The purpose of this local activation process is to minimize toxicity compared to strong iron chelators, which may interfere with normal iron metabolism. 1 efficiently protects biological molecules against oxidative damage in vitro but not intact cells because of poor membrane permeability. We show here that, among a series of prodrug esters and lipophilic analogues, membrane-permeant N,N'-bis(3,4,5-trimethoxybenzyl)ethylenediamine-N,N'-diacetic acid diacetoxymethyl ester (7) protects human skin fibroblasts against hydrogen peroxide toxicity with an IC(50) of 3 microM. These results thus demonstrate that, providing sufficient intracellular chelator concentration is reached, 1 efficiently protects cells against the deleterious effects of hydrogen peroxide. This strategy of oxidative activation should help the design of new chelators with better safety margins, which may be useful against oxidative damage under conditions where a prolonged administration is needed.

Keratinocyte-melanocyte co-cultures and pigmented reconstructed human epidermis: models to study modulation of melanogenesis.

Normal human melanocytes were amplified and cultured in a new defined culture medium without phorbol esters or cholera toxin. The medium decreased considerably the doubling time and increased the possible passage number. Melanocytes were co-seeded with normal human keratinocytes into 24 well culture dishes to screen potentially active modulators of melanogenesis. For the assay, the co-cultures were exposed to the compounds under investigation in the presence of 14C-thiouracil and 3H-leucine. Control cultures contain L-tyrosine or kojic acid, modulators which served as internal calibration standards. Changes in the rate of melanin synthesis were measured on the basis of 14C-thiouracil incorporation into newly synthesized melanin. A reduction or increase in 3H-leucine incorporation was taken as an indication of cytotoxicity or induction of proliferation, respectively. The NHK-NHM co-culture screening assay provides a useful tool to compare the activity of known modulators of melanogenesis and to perform structure-activity studies with newly identified modulators to improve their activity. The efficacy of particularly interesting new compounds was further evaluated on reconstructed pigmented epidermis after repeated topical application. The same model was used to assess the anti-pigmenting effect of sunscreens on UV-induced pigmentation. Integration of melanocytes from different ethnic origin resulted in pigmented epidermis reflecting different skin phenotypes, Caucasian, Asian and African.

Protection of U937 cells against oxidative injury by a novel series of iron chelators.

A new series of iron chelators designed to protect tissues against iron-catalysed oxidative damage is described. These compounds are aminocarboxylate derivatives bearing pendant aromatic groups. They were designed to have a relatively low affinity for both ferrous and ferric iron and to be site-specifically oxidizable by hydrogen peroxide through intramolecular aromatic hydroxylation into species with strong iron binding capacity which do not catalyse hydroxyl radical formation. Thus, at the cellular level, oxidative injury is used to convert weak iron chelators into strong iron chelators in order to promote cell survival. The purpose of this local activation process is to minimise toxicity compared to strong iron chelators which may interfere with normal iron metabolism. Compounds within this series were evaluated in vitro in view of their capacity to undergo intramolecular hydroxylation and to protect cultured cells against oxidative injury. Results show that the intramolecular aromatic hydroxylation capacity is critically dependent upon the amino carboxylate chelating moieties and the substituents of the aromatic rings. Cell protection against oxidative injury is only observed with compounds possessing sufficient lipophilicity. The monohydroxylation product of N,N'-dibenzylethylenediamine N,N'-diacetic acid, protects cells against both H2O2 and tBuOOH toxicity with IC50's of 12 and 60 microM, respectively, in agreement with the oxidative activation concept. These results represent the first step toward the development of a new strategy to safe iron chelation for the prevention of oxidative damage.

N,N'-bis-(3,4,5-trimethoxybenzyl) ethylenediamine N,N'-diacetic acid as a new iron chelator with potential medicinal applications against oxidative stress.

N,N'-bis-(3,4,5-trimethoxybenzyl) ethylenediamine N,N,-diacetic acid dihydrochloride (OR10141) is a member of a recently described series of "oxidative stress activatable iron chelators." These chelators have a relatively low affinity for iron but can be site-specifically oxidized, in situations mimicking oxidative stress in vitro, into species with strong iron-binding capacity. It is hoped that this local activation process will minimise toxicity compared to strong iron chelators that may interfere with iron metabolism. The present paper describes the results of experiments aimed at characterising oxidative reactions between iron-OR10141 complexes and hydrogen peroxide. Incubation of ascorbate and hydrogen peroxide with the ferric chelate of OR10141 in neutral aqueous solution yields a purple solution with a chromophore at 560 nm, which is consistent with an o-hydroxylation of one of the trimethoxybenzyl rings. Oxidation of OR10141 also takes place, although more slowly, by incubating hydrogen peroxide with ferric OR10141 complex in the absence of reductant. HPLC analysis shows that OR10141 is consumed during the reaction and transformed principally into N-(2-hydroxy 3,4,5-trimethoxybenzyl) N'-(3,4,5-trimethoxybenzyl) ethylenediamine N,N'-diacetic acid. Minor products are also formed, some of which were identified by mass spectrometry. The protective effect of OR10141 in vitro against DNA single strand breaks, protein damage, and lipid peroxidation induced by Fenton chemistry suggests that this compound is able to compete for iron with biological molecules and, thus, that this strategy of protection against oxidative stress is feasible. In addition, preliminary results showing protective effects of OR10141 dimethyl ester against toxicity induced by hydrogen peroxide in cell culture are described. It is concluded that OR10141 and related prodrugs might be useful in vivo in chronic situations involving oxidative stress.

N,N'-bis-dibenzyl ethylenediaminediacetic acid (DBED): a site-specific hydroxyl radical scavenger acting as an "oxidative stress activatable" iron chelator in vitro.

During oxidative stress, iron traces are supposed to be released from normal storage sites and to catalyse oxidative damage by Fenton-type reactions. This type of damage is difficult to prevent in vivo except by the use of strong iron chelators such as deferoxamine (affinity constant for Fe(III): log K = 30.8). However, strong iron chelating agents are also suspected to mobilize iron from various storage and transport proteins thereby leading to toxic effects. In contrast, N,N'-bis-dibenzyl ethylenediaminediacetic acid (DBED) is an iron chelator with relatively low affinity for iron (affinity constant for Fe(III): log K < 15). In the present paper, we show that, in situations mimicking oxidative stress in vitro, DBED is site-specifically oxidized into new species with strong iron binding capacity. Indeed, in the presence of ascorbate as a reductant, the iron chelate of DBED reacts with H2O2 in aqueous solution to yield a purple chromophore with minor release of free HO. in the medium, as measured by aromatic hydroxylation assay. The formation of these purple species is not suppressed by the presence of HO. scavengers at high concentration. The visible spectrum of these species is consistent with a charge transfer band from a phenolate ligand to iron. N-2-hydroxybenzyl N'-benzyl ethylenediaminediacetic acid (HBBED) was identified in the medium as one of the oxidation products of DBED. Therefore, these results suggest that the iron chelate of DBED undergoes an intramolecular aromatic hydroxylation by HO. leading to 2-OH derivatives and hence that DBED is a site-specific HO. scavenger. Moreover, since the measured affinity for Fe(III) of HBBED (log K = 28) is at least 13 orders of magnitude higher than that of DBED and since ferric HBBED chelate is not a catalyst of Fenton chemistry, DBED may be looked as an "oxidative stress activatable" iron chelator, e.g. which increase in affinity for iron is triggered in the presence of H2O2 and an electron donor. Therefore it is proposed that DBED and related derivatives may be interesting as protective compounds against oxygen radicals toxicity, especially for chronic use.

A potentiometric and spectroscopic study of the proton, and copper (II) and zinc (II) complexes formed by fibrinopeptide A.

Results are reported for a potentiometric and spectroscopic (visible, CD, and EPR) study of the complexes of fibrinopeptide A (Ala-Asp-Ser-Gly-Glu-Gly-Asp-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg) with H+, Cu2+ and Zn2+. They show that the peptide forms stable complexes with Cu2+, largely as a result of the Asp2 residue, and that its coordination behavior is almost identical to that of the N-terminal tetrapeptide fragment, Ala-Asp-Ser-Gly. Hence the influence of the remaining amino acid residues on coordination to Cu2+ is insignificant.

Ethylene formation from methionine as a method to evaluate oxygen free radical scavenging and metal inactivation by cosmetics.

Synopsis It has been proposed that oxygen free radicals are involved in skin aging. This paper describes a new method for the evaluation of oxygen free radical scavenging by cosmetic products. It is based on the measurement, by gas chromatography, of ethylene produced during the oxidation of methionine by the hydroxyl radical. OH. is produced by an iron catalyzed superoxide-driven Fenton reaction in which superoxide is obtained by photochemical oxygen reduction. The cosmetic is applied, together with methionine, riboflavine, NADH, FeCl(3) and EDTA, on a glass microfibre filter and submitted to UVA exposure through a quartz cell. Ethylene is then measured from aliquots of the atmosphere inside the cell. Catalase or Desferal completely inhibits ethylene production. SOD or high concentrations of hydroxyl radical scavengers (Mannitol, DMSO etc.) afford a partial protection. Thus the efficiency of O(2) (-)., H(2)O(2) and OH. scavengers and iron chelators can be measured. The main advantage of this test is that it is performed in conditions which simulate skin during UV exposure (e.g. air and UV exposed thin layer). Furthermore, as it is non-invasive, it can also be applied to human skin in vivo.

Recurrent osteoid osteoma. Case report with a ten-year asymptomatic interval.

Osteoid osteoma has been accepted as a distinct clinical and pathologic entity for more than 50 years. Surgical curettage will often cure the lesion, although en bloc excision is now the preferred treatment. The development of local recurrence after surgery, although rare, has been well documented after both curettage and en bloc excision. Symptomatic recurrence of an osteoid osteoma was seen ten years after surgical curettage. Its occurrence at the same site as the original lesion is consistent with the concept that it had originated from residual tissue and is in keeping with the concept of osteoid osteoma as a benign tumor.