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Although anti-CD20 monoclonal antibodies (mAbs) show promise for the treatment of chronic lymphocytic leukemia (CLL), the success of the anti-CD20 mAb rituximab in CLL treatment has been limited. Novel anti-CD20 mAbs with more potent cytotoxic activity have recently been engineered, but so far most have only been tested in vitro with natural killer (NK) cells from healthy donors. Because it is still unclear whether these optimized cytotoxic mAbs will improve NK-cell killing of tumor cells in CLL patients, we characterized the relevant phenotypic and functional features of NK cells from CLL patients in detail. Expression of inhibitory and activating NK-cell receptors and of Fc gamma receptor IIIA (FcγRIIIA) is well preserved in CD16+CD56dim cytotoxic NK cells from these patients, independently of disease progression. These cells are fully functional following cytokine stimulation. In addition, the FcγRIIIA-optimized LFB-R603 anti-CD20 mAb mediates 100 times greater antibody-dependent cell-mediated cytotoxicity by NK cells from CLL patients and healthy donors than rituximab. Enhanced degranulation against autologous B-CLL cells is observed at lower concentrations of LFB-R603 than rituximab, regardless of CLL prognostic factors. These findings strongly justify further clinical development of anti-CD20 mAbs optimized for FcγR engagement in CLL patients. [ABSTRACT FROM AUTHOR]

Human NK cells comprise two main subsets, CD56(bright) and CD56(dim) cells, which differ in function, phenotype, and tissue localization. To further dissect the differentiation from CD56(bright) to CD56(dim) cells, we performed ex vivo and in vitro experiments demonstrating that the CD56(bright)CD16(+) cells are an intermediate stage of NK cell maturation. We observed that the maximal frequency of the CD56(bright)CD16(+) subset among NK cells, following unrelated cord blood transplantation, occurs later than this of the CD56(bright)CD16(-) subset. We next performed an extensive phenotypic and functional analysis of CD56(bright)CD16(+) cells in healthy donors, which displayed a phenotypic intermediary profile between CD56(bright)CD16(-) and CD56(dim)CD16(+) NK cells. We also demonstrated that CD56(bright)CD16(+) NK cells were fully able to kill target cells, both by Ab-dependent cell cytotoxicity (ADCC) and direct lysis, as compared with CD56(bright)CD16(-) cells. Importantly, in vitro differentiation experiments revealed that autologous T cells specifically encourage the differentiation from CD56(bright)CD16(-) to CD56(bright)CD16(+) cells. Finally, further investigations performed in elderly patients clearly showed that both CD56(bright)CD16(+) and CD56(dim)CD16(+) mature subsets were substantially increased in older individuals, whereas the CD56(bright)CD16(-) precursor subset was decreased. Altogether, these data provide evidence that the CD56(bright)CD16(+) NK cell subset is a functional intermediate between the CD56(bright) and CD56(dim) cells and is generated in the presence of autologous T CD3(+) cells.

Tachykinins are a family of structurally related peptides, including substance P (SP), hemokinin-1 (HK-1), neurokinin A (NKA), and neurokinin B. SP and NKA have been shown to modulate hematopoiesis and rat/mouse HK-1 has been found to be involved in the survival and differentiation of mouse B-cells. This study was designed to assess the expression of tachykinins with a focus on human HK-1 (hHK-1) in human B lymphocytes and the role of these peptides in cell differentiation, apoptosis and proliferation. Expression of tachykinin and tachykinin receptor mRNA was determined quantitatively in human B lymphoproliferative malignancies and compared to normal B-cells. Expression of hHK-1 and NK(1) receptor, but not SP, was detected in human B-lymphocytes, and was up-regulated in B-lymphocytes from chronic lymphocytic leukemia and non-Hodgkin's lymphoma, while it was down-regulated in acute lymphoblastic leukemia. Moreover, hHK-1, in contrast to SP, was able to induce proliferation of human pre-B lymphocytes through a NK(1) receptor-independent mechanism. These data suggest a role for hHK-1 in normal and pathological B lymphopoiesis, and open the door to a better understanding of the physiopathological mechanisms leading to lymphoproliferative malignancies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aging is generally associated with an increased predisposition to infectious diseases and cancers, related in part to the development of immune senescence, a process that affects all cell compartments of the immune system. Although many studies have investigated the effects of age on natural killer (NK) cells, their conclusions remain controversial because the diverse health status of study subjects resulted in discordant findings. To clarify this situation, we conducted the first extensive phenotypic and functional analysis of NK cells from healthy subjects, comparing NK cells derived from newborn (cord blood), middle-aged (18-60 years), old (60-80 years), and very old (80-100 years) subjects. We found that NK cells in cord blood displayed specific features associated with immaturity, including poor expression of KIR and LIR-1/ILT-2 and high expression of both NKG2A and IFN-gamma. NK cells from older subjects, on the other hand, preserved their major phenotypic and functional characteristics, but with their mature features accentuated. These include a profound decline of the CD56(bright) subset, a specific increase in LIR-1/ILT-2, and a perfect recovering of NK-cell function following IL2-activation in very old subjects. We conclude that the preservation of NK cell features until very advanced age may contribute to longevity and successful aging.

Introduction: The treatment of reference of congenital toxoplasmosis combines two folate synthesis inhibitors, pyrimethamine and an antibacterial sulfamide (sulfadiazine or sulfadoxine). Despite the efficacy of this combination, the possibility of eventually severe side effects must also be taken into account., Observation: A pancytopenia occurred at 37 weeks of amenorrhea during antenatal treatment for congenital toxoplasmosis in a tripara. The outcome was positive following administration of strong doses of parenteral folinic acid combined with platelet transfusion and broad-spectrum antibiotics., Discussion: Each of the molecules (pyrimethamine and antibacterial sulfamide) used for the treatment of congenital toxoplasmosis can lead to acute haematological problems. The occurrence of maternal pancytopenia however remains exceptional. It is principally related to pyrimethamine and is usually observed in the presence of factors enhancing folate deficiency.

Massive fetomaternal hemorrhage is rare. Without risk factors, early diagnosis is difficult to establish. The clinical and paraclinical manifestations are not specific and depend on fetal compensatory reactions; the Kleihauer test will confirm the diagnosis. Two cases of massive fetomaternal hemorrhage preceded by decreased fetal movements are presented here. An emergency delivery by cesarean section saved one child. Despite a favorable clinical and laboratory evaluation, one fetal death could not be avoided. Early diagnosis and specialised management are essential to improve prognosis. These observations indicate that it is mandatory to carry out a Kleihauer test whenever a decrease of fetal movements is observed.

In spite of many references to carcinoma arising from endometriosis, there are few documented cases in the literature of endometrioid adenocarcinoma developed in association with adenomyosis. We report a case of endometrioid adenocarcinoma arising from adenomyosis. Carcinogenic and prognostic factors as well as the therapeutic consequences of this unusual situation are discussed. The use of hormonal replacement therapy by patients with a prior history of adenomyosis is also examined.

We report a case of an isolated persistent right umbilical vein which was diagnosed on an ultrasound examination performed in the third trimester of pregnancy. This was made possible by the contribution of color flow Doppler and real-time ultrasound. Having isolated the anomaly no further fetal monitoring was instituted. Delivery was at term and the infant is doing well. Persistent right umbilical vein results from an anomaly of organogenesis. It represents the main intra abdominal anomaly of this vein. Its incidence is estimated at approximately 1 case for 500 antenatal ultrasound examinations. Ultrasonographic diagnosis is relatively easy and can be performed near the end of the first trimester. After insertion in the abdominal wall, the umbilical vein passes round the gallbladder from the right before connecting to the portal vein in the intra-hepatic form; right atrium, inferior vena cava, superior vena cava or iliac vein in extra-hepatic form. Diagnosis is affirmed by color flow Doppler, which emphasizes a continuity of blood flow between the extra and intra abdominal segment of the umbilical vein, and real-time ultrasound, which shows a venous blood flow. Prognosis depends essentially on the existence of congenital malformations, which are observed in 10 to 25% of cases. When isolated, persistent right umbilical vein is generally associated with favorable outcome and must be considered as a normal fetal anatomical variant.

Placental chorioangioma is a benign vascular tumor found in about 1% of pregnancies at routine histological examination of the placenta. The large placental tumor may cause serious fetal complications. We report 4 cases of placental chorioangioma diagnosed during the second trimester. Three pregnancies with rapidly growing tumors measuring more than 4 cm led to fetal hydrops and perinatal death despite thoracocentesis and cesarean delivery at 33 weeks (1 case) and repeated amniodrainage (1 case). The only surviving infant presented with a 3.3cm tumor which grew progressively to 8 cm at 38 weeks and did not induce polyhydramnios or hydrops. Although aggressive prenatal management of placental chorioangioma has been reported using amniodrainage, intrauterine transfusions, embolization, or ligation of the tumor vessel supply, prognosis remains poor for large tumors and largely depends on fetal hemodynamic tolerance.

We report a case of a patient with carnitine palmityl deficiency in active labour. We discuss the metabolic and energetic implications of obstetrical labour in regard with the mitochondrial myopathy and we propose an optimal management. Neuroaxial analgesia and glucose infusion are indicated in early labour because it is necessary to alleviate stress and pain in order to avoid rhabdomyolysis associated with CPT deficiency. Combined spinal epidural analgesia using intrathecal opioid alone then epidural naropein should be a relevant choice because of a minimal motor blockage. Monitoring of myolysis using serum creatinine phosphokinase levels must take in account CK and MB fractions releases to the circulation during obstetrical labour.

The "limb body wall complex" or LBWC is a rare polymalformative syndrome. Two distinct phenotypes of which were recently described: one form with "placento-cranial" adhesion and the other with "placento-abdominal" adhesion. Coelosomia is found in all cases, it variably coexists with encephalic, vertebral, visceral or limb anomalies. Three pathogenesis are proposed: the "early amnion rupture" theory and the "vascular" theory can explain the form with "placento-cranial" adhesion, conversely, the "defective folding process" allows for a better explanation of the form with "placento-cranial" adhesion. These theories do not exclude each other if we accept that this syndrome could be split: the first form would then be the original "LBWC" et could belong to "amniotic band syndrome", the mechanism of which is not precisely known, whereas the second could be named "body stalk syndrome" - "syndrome du cordon court". In any case, this syndrome should be better known so as to be studied and give a prognosis for a later pregnancy, because there is no recurrence.

Objective: The aim of this study was to assess the factors of success in abdominal colposacropexy (CSP) procedures., Patients and Methods: We performed 271 consecutive CSP between 1986 and 1997 (mean age: 48.8 years +/- 11.1). We reviewed 217 patients (80.1%). Mean duration of follow-up was 5.5 years (1-136 months). We performed: 18 CSP with Goretex mesh, 3 with resorbable mesh and 196 with Mersilene; 179 CSP with posterior colporraphy and 38 without; 208 CSP with culdoplasty (Moschowitz's procedure) and 9 without; 182 CSP with anterior and posterior meshes, 26 with posterior mesh only and 9 with anterior mesh only., Results: 97.7% (212/217) of patients were cured for prolapse. 58% (125/217) had urinary stress incontinence totally cured and 82% (178/217) had urinary stress incontinence improved. Rejected grafts were 16.7% (3/18) with Goretex mesh and 1.1% with Mersilene mesh (p = 0.004). Recurrent prolapses were 1.1% (2/196) with CSP with posterior colporrhaphy and 7.9% (3/38) in CSP without (p = 0.009; OR = 0.14, CI = 0.02-0.86); 4/208 with CSP with culdoplasty and 1/9 with CSP without (p = 0.04; OR = 0.17, CI = 0.02-1.58). Recurrent stress incontinence was observed in 4/9 cases with CSP with anterior mesh only and 28/182 with CSP with anterior and posterior meshes (p = 0.03; OR = 0.34, CI = 0.12-0.97)., Conclusion: CSP must use anterior and posterior Mersilene mesh. The CSP must be systematically combined with posterior colporraphy and culdoplasty (Moschcowitz's procedure).

Testing for syphilis during pregnancy reveals a positive serologic status in 0.02% of cases. However, a 66% rate of stillbirths is noted in women who are infected and who have not benefited from any treatment. Routine screening is at present performed during the early stages of pregnancy but a second serologic test during the third trimester is useful in the diagnosis of a late infection especially in drug users or HIV (human immunodeficiency virus) positive patients. Congenital syphilis is diagnosed in utero when a positive maternal serologic status is associated with ultrasound images showing fetal abnormalities; these include hepatosplenomegaly, hyperechogenic bowel, signs of bowel obstruction or fetal hydrops. Maternal syphilis is treated by delayed action penicillin and is indicated even for patients allergic to the antibiotic which in this particular case is delivered after desensitization. First line therapy by intravenous penicillin is indicated when confronted with the following high risk factors of congenital syphilis: an elevated titre of VDRL (venereal disease research laboratory) at the time of diagnosis or delivery, unknown date of the precise onset of the infection, the appearance of a rash or of a chancre during pregnancy, ultrasound fetal abnormalities or late therapy during the third trimester. Treatment of the new-born child will depend on the results of clinical, serologic and X-ray evaluation. Long term follow-up for at least a year is mandatory.

Five cases of non-Hodgkin malignant lymphoma (NHML) presenting as ovarian tumours are reported. All corresponded to disseminated lymphomatous disease, none was of low grade. Ultrasound showed a solid, most often homogeneous, hypoechoic, bilateral mass in 4 of 5 cases. Its association with many lymph nodes and mainly parenchymal localisation suggested of the NHML. Only histologic and immunohistochemical findings may provide the final diagnosis. The biopsy for those studies should be obtained as least invasively as possible because treatment of NHML is chemotherapy.

We report three cases of caudal regression syndrome diagnosed in utero. Caudal regression syndrome (CRS) is a rare condition associating vertebral agenesia and urinary and digestive tract malformations. Pathogenesis is not clear but, as in our three cases, the CRS is often associated with poorly controlled maternal diabetes. Antenatal ultrasound examinations may reveal the disease in major forms with a non-viable foetus. In our 3 cases, a femoral "V" was associated with sudden interruption of the spine. Minor forms may not be recognized until childhood. Prognosis depends essentially on the extent of spinal involvement and associated malformations. Sirenomelus was considered for many years to be the most severe form of caudal regression, but recently acquired evidence suggests that these two conditions are separate entities.

We report a case of acute toxoplasmosis during the first trimester of pregnancy in which antenatal diagnosis was negative. Except for non-specific signs of liver failure, assessment by repeated ultrasound scans, testing of fetal blood for toxoplasmic specific antibodies and competitive PCR to isolate the parasite, had ruled out fetal infection. In spite of early treatment with spiramycin, and although the infant was assumed to be non-contaminated, severe hydrocephalus was noted at 3 and half months of life, arising soon after therapy had been stopped. This case focuses attention on the problem of the shortcomings of the diagnostic techniques currently used, and leads us to question our practical course of action. Several questions are thus raised: how reliable are indirect signs of fetal compromise, what is the real sensitivity of the PCR test and how useful are repeated amniocentesis and inoculation of the amniotic fluid to mice.

Steinert's disease or myotonic dystrophy is a heredo-degenerative neuroendocrinal dystrophy. It is an autosomal dominant disorder. The arising of a congenital myotonic dystrophy of one of the new-born children of the maternity hospital enabled to diagnose the Steinert's disease of his mother. A review of the international literature enabled us to recall its interactions with pregnancy. There is an aggravation of myotonia and multiple obstetric complications such as miscarriage, premature onset of labor, polyhydramnios, stillbirth, difficulties during the evacuation, atonic postpartum hemorrhage, anesthetic-accidents. The congenital variant of myotonic dystrophy (6 to 30% of the cases) is a severe disease with a high mortality. It is only seen in the offspring of mothers who themselves have myotonic dystrophy. The myotonic dystrophy gene has been isolated and the mutation-causing myotonic dystrophy was found to result from a series of trinucleotide (CTG) repeats located in the 3' untranslated region of the gene. The direct diagnosis is henceforth possible both on the fetus and parents. Steinert's disease and its association with pregnancy are rare, especially when the affected parent has hypogonadism. The diagnosis of the congenital form is difficult because of the mother is unaware of the disorder. Family and personal history may give hints: hydramnios, appearance delay and reduced fetal movements, and the association at birth of generalized hypotonia with neonatal respiratory distress.

During pregnancy 50% of all cases with a ventriculo-peritoneal shunt malfunction. This is because of anatomo-physiological changes associated with the pregnant state, and shows itself as a rise in intracranial tension. There were no acute neurological complications at term; with the malfunction of the shunt distally, vaginal delivery is preferable. It is not necessary routinely to carry out instrumental delivery.

The authors followed 187 pregnancies in which metrorrhagia had occurred in the first trimester, but which had not resulted in abortion. In these patients, the authors studied particularly changes in hormone levels in the urine and the relation between these levels and fetal prognosis. If hormonal deficit is related to fetal prognosis, the relationship does not appear to be a direct one: estrogen deficiency is discovered more often than luteal deficiency; the more serious the estrogen deficiency the more often is it associated with severe progesterone deficiency; The number of fetal malformations did not seem to be any higher in patients who had presented metrorrhagia in first trimester than in patients whose pregnancy was normal. Any higher in patients who had presented metrorrhagia in the pregnancy on one hormone analysis, whether or not it is abnormal. The examinations should be repeated so that the evolution may be followed carefully.

With reference to a 25-year-old patient who developed manifestations of clinical and paraclinical hyperthyroidism during the course of a molar pregnancy, the authors studied correlations between the two conditions. Hyperthyroidism is the result of hyperstimulation, of placental origin, and disappears when the hyperstimulation disappears. The placenta is capable of producing a TSH-like factor. HENNEN and HERSCHMAN established the existence of human chorionic thyrotropin which has hormonal and physicochemical properties similar to those of TSH, and which has just been isolated by Japanese workers. In fact during the development of a mole, it is molar HCT (or MHCT) that constitutes either a precursor or a subunit of HCT. However, hyperthyroidism remains rare during the course of molar pregnancies, a fact that has not yet been explained.

The authors review the literature in relation to a detailed study of an ovarian arrhenoblastoma operated on in a young patient who subsequently became pregnant twice, one of these pregnancies developing to full term. This review makes it possible to formulate certain anatomopathological ideas, and above all makes it clear that complete endocrine studies are infrequently carried out. It has been shown in cases of arrhenoblastoma that some of the anomalies of steroidogenesis are secondary to the enzyme disorders, the impression being that, with this kind of tumour, the tumour parenchyma begins to secrete like a normal testicle.

The authors draw attention to the fact that the possible effects of drugs containing iodine are often neglected during pregnancy. As an example, they report the following observation : "A young woman with benign asthma, treated for 14 years Asthmasedine and Asthmaligne, gave birth, on the 36th week of pregnancy, to a child apparenty dead but who was able to be reanimated. The child showed two types of signs : respiratory distress due to higher neurological disorders and a multinodular, non-compressing goiter. These two complications were caused by a congenital hypothyroidism corroborated by laboratory tests and due to the prolonged absorption of iodinated drugs by the mother". In conclusion, in cases of women receiving during pregnancy high doses of drugs containing iodine (250 such drugs are recorded in the Vidal), it is desirable to control the effect on the fetus and to propose an intra-amniotic therapy with L-Thyroxine, thus allowing a cerebral development close to normal.

With reference to 207 observations of lesions associated with uterine fibronias. the authors have tried to discover a distinct anatomo-pathological entity. Associated lesions are found in 31 percent of cases. and this frequency should be particularly noted, when the classical view emphasizes particularly the occurrence of complications. The lesions found in association with this type of fibroma are listed below in order of frequency of occurrence: infectious lesions, ovarian dystrophies, hormonal disorders, benign or malignant tumoral lesions, and endometriosis. Attempts at pre-operative diagnosis have been rather disappointing, as only 41 percent of the cases have been diagnosed. The presence of these associated lesions leads more readily to the use of surgery but it is not easy to determine whether this is because of the existence of the lesions or because they are misunderstood. if the associated lesions are diagnosed before the operation, medical treatment of the lesions, particularly in the case of infectious lesions or endometriosis, does not avoid the need for surgery but often make it easier.

The study was based on 15 cases of haemostasis hysterectomy: 7 cases after caesarian section, 8 cases after normal delivery. The etiological circumstances varied, the haemorrhage being due to uterine rupture, to an accident during delivery related to uterine atony, to placenta accreta, or to a coagulation disorder. In these circumstances, the most satisfactory operation seems to be total hysterectomy with bilateral ovariectomy, conservation of the ovaries being justified in younger women. The authors describe the precautions that they feel are essential during labour or during a caesarian section to avoid such complications.

With reference to 70 patients, the authors studied the pathology of the stump of the cervix left after subtotal hysterectomy. The wide range of disorders presented by women after partial hysterectomy included metrorrhagia (44.2 percent of cases), pelvic pain, leucorrhoea, cervical pain, and functional disorders related to prolapse. Lesions found on the stump of the cervix included: cancer in 15.7 percent of cases, of which the clinical symptoms were not specific to the stump of the cervix: however, the methods of treating such cancers, of the usual methods are used, raise complex problems; prolapse was found after subtotal hysterectomy in 27.1 percent of cases and the symptomatology was not unusual. Here also, the absence of the uterus increases the difficulties of surgery. Thus subtotal hysterectomy appears to present more dangers than advantages and, except in particular cases, the authors prefer total hysterectomy.

A new technique for the treatment of uterine septa is described. The septum is divided by the transcervical route, using 4 mm endoscopic scissors. Simultaneously, real-time ultrasonography confirms the diagnosis of septate uterus and ensures the safety of this blind procedure. Ultrasonic guidance also enables the septum to be divided along the medial antero-posterior plane and the distance between the upper limit of the section and the fundus uteri to be measured. The operation is rapid, carries a limited risk, leaves no uterine or abdominal scar and requires no special equipment. The elective indication for section of uterine septa is habitual abortion. This convenient method can also be used in women who have never been pregnant during coelioscopy for sterility or section of a vaginal septum.

Although there are certain advantages of amniofetography they must be considered against the risk of fetal hypothyroidism "in utero" with its prognostic danger. The authors report six case histories which illustrate this risk and they draw attention to the possible effect on the thyroid gland "in utero". Amniofetography should therefore be reserved solely for those cases in which the indications exist and there are no other possible means of diagnosis. If it is indicated means must be found of treating the possible transitory iatrogenic hypothyroidism.