Cem Iyibozkurt

HOXA methylation in normal endometrium from premenopausal women is associated with the presence of ovarian cancer: a proof of principle study.

DNA methylation of polycomb group target (PCGT) genes is an early step in carcinogenesis and could potentially be assayed to determine cancer risk prediction. To assess whether methylation changes in PCGT genes in normal tissue is able to predict the presence of cancer, we studied HOXA gene methylation in normal endometrium from premenopausal ovarian cancer patients and age‐matched healthy controls without ovarian cancer. DNA methylation of HOXA9 and HOXA11 genes in normal endometrium was associated with ovarian cancer in an initial test set and this was subsequently confirmed in independent validation sample sets. The overall risk of ovarian cancer was increased 12.3‐fold by high HOXA9 methylation for all stages, and 14.8‐fold for early stage ovarian cancers, independent of age, phase of the menstrual cycle and histology of the cancer. The results of this proof of principle study demonstrate the potential to detect ovarian cancer via analysis of normal endometrial cells and provide insight into the possible contribution of this novel approach in ovarian cancer risk prediction and prevention.

Diagnostic value of PET/CT is similar to that of conventional MRI and even better for detecting small peritoneal implants in patients with recurrent ovarian cancer.

ObjectiveThe aim of this study was to evaluate the diagnostic value of 2-(fluorine-18)-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT in comparison with MRI for the detection of recurrent ovarian cancer. MethodsForty-seven patients with suspected ovarian cancer recurrence after total ablative or cytoreductive surgery, as well as neoadjuvant or adjuvant chemotherapy, who had undergone 18F-FDG PET/CT imaging were recruited for the present study. All patients also underwent MRI within a month of 18F-FDG PET/CT for the same purpose. Recurrent cancer in the abdomen and pelvis was evaluated in each of the 47 patients and classified as either distant metastasis or local pelvic recurrence involving the vaginal stump, peritoneal implants, supradiaphragmatic region, and/or abdominal and pelvic lymph nodes. Special attention was paid to peritoneal implants. These were divided into five groups according to size of the implants: less than 0.5 cm (group 1), 0.5–1 cm (group 2), 1–2 cm (group 3), 2–3 cm (group 4), and larger than 3 cm (group 5). PET/CT findings were compared with abdominopelvic MR findings. Statistical analysis was carried out using the Wilcoxon signed rank test. ResultsThirty-nine of 47 patients were found to have recurrent ovarian cancer. Both PET/CT and MRI were negative for recurrence in six patients. Overall sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of PET/CT were 97.5, 100, 100, 87.5, and 97.8%, respectively, whereas those of MRI were 95, 85.7, 97.4, 75, and 93.6%, respectively. For the peritoneal implants in groups 2 and 3, the sensitivity, negative predictive value, and diagnostic accuracy values of PET/CT were significantly better than those of MRI (P<0.05). ConclusionThe present study revealed that PET/CT is similar to conventional MRI for the detection of recurrent ovarian cancer. PET/CT has greater accuracy in the detection of small-to-medium-sized (<2 cm) peritoneal implants compared with MRI. This may affect surgical decision making.

Malignant Ovarian Germ Cell Tumors A Single-Institution Experience

Objective:To evaluate the clinicopathologic prognostic factors in malignant ovarian germ cell tumors. Methods:We reviewed the medical records of 70 patients treated from 1990 to 2006 at our center. Clinical data including demographics, stage, surgery, chemotherapy, survival, menses status, and fertility were collected from patients’ charts. Results:Median age was 22 years (range, 9–68). The histologic subtypes included 36 dysgerminomas, 11 yolk sac tumors, 3 immature teratomas, 1 embryonal carcinomas, and 19 mixed types. The most striking clinicopathologic finding was a history of concomitant immunosuppressant therapy, which was observed in 2 patients. Two patients had contralateral sex-cord tumors at presentation and follow-up. During a median follow-up period of 4.6 years, 11 patients had recurrence. The median time to recurrence was 8 months (6–28 months). Recurrences appeared in the abdominopelvic cavity in 9 out of 11 patients. Only one could be salvaged with second-line chemotherapy. Cumulative survival rate was 97% and 60% in patients with dysgerminoma and nondysgerminoma, respectively. Nondysgerminoma histology and residual tumor after surgery were unfavorable prognostic factors (P < 0.001 and P = 0.015). Fertility-sparing surgery was as effective as radical surgery among all eligible patients. Of patients with known menstrual status, 96% had regular menses. Of the 8 patients who opted for conception among these patients, 7 delivered healthy infants. Conclusions:Nondysgerminomas have an aggressive clinical course. New treatment strategies are needed for eradication of abdominopelvic disease at initial diagnosis and recurrent setting. Occurrence of malignant ovarian germ cell tumors may be associated with immunosuppression in some patients. Sex-cord stromal tumors may present with bilateral involvement. It is possible to maintain fertility after fertility-sparing surgery followed by chemotherapy.

Perioperative Complications in Abdominal Sacrocolpopexy, Sacrospinous Ligament Fixation and Prolift Procedures

BACKGROUND Pelvic organ prolapse is an important problem for women. To overcome this issue, different operational technics are in use, such as abdominal sacrocolpopexy, sacrospinous fixation, and the total Prolift procedure. AIMS This study assessed perioperative complications in abdominal sacrocolpopexy, sacrospinous fixation, and the total Prolift procedure. STUDY DESIGN Retrospective comparative study. METHODS Perioperative complications were defined as any complication occurring during surgery or the first 6 weeks postoperatively. Forty-five patients underwent abdominal procedures, 60 patients underwent sacrospinous fixation, and 43 patients underwent the total Prolift procedure. RESULTS In the abdominal group, one bladder injury, four hemorrhages, and three wound dehiscences occurred. In the sacrospinous group, one rectal injury and one postoperative vault infection occurred. In the Prolift group, one bladder injury and one hemorrhage occurred. Minor complications were more frequent in the abdominal group than the others. The operating time and hospital stay of the abdominal group were significantly longer than the others. The Pro-lift procedure had less operating time and hospital stay than other procedures. CONCLUSION The total Prolift may be a novel alternative for apical prolapse with low perioperative morbidities and complications.

Management and follow-up results of an incidental thyroid carcinoma in a young woman with ovarian teratoma

Abstract Thyroid cancer in ovarian teratoma is reported to be rare and experiences are limited. A 26-year-old woman had undergone bilateral cystectomy and omentectomy for bilateral cystic adnexial masses. Pathological examination showed 1.5 cm follicular variant papillary thyroid carcinoma on the basis of unilateral mature cystic teratoma. Increased CA-125 and CA19-9 levels decreased to normal reference ranges after surgery, but postoperative magnetic resonance imaging indicated multiple abdominal cystic loci. After total thyroidectomy, high dose I-131 was administered to ablate thyroid tissue. Thereafter, levothyroxine was started to achieve subclinical hyperthyroidism. No iodine uptake was detected in post-therapeutic whole body scan (WBS) other than thyroid bed. This finding supported that tumor did not show dissemination to abdomen. No uptake on the first-year evaluation with low-dose I-131 WBS suggested the complete ablation of the thyroid gland. It is recommended that thyroid carcinoma arising from ectopic thyroid tissue in a teratoma should be managed as thyroid carcinoma in thyroid. However, direct dissemination to contiguous regions in abdomen and hematogenous dissemination to distant organs should be in mind. Radical surgery including total abdominal hysterectomy, bilateral salphingo-oopherectomy, pelvic and paraaortic lymph node excision and thyroidectomy is recommended. Fertility preserving surgery may be the surgical procedure as in the present case.

Carney's complex: a successful pregnancy after bilateral adrenalectomy.

Carneys complex is a rare inherited disease of multicentric tumours of multiple organs. It is inherited in autosomal dominant fashion. Primary pigmented nodular adrenocortical dysplasia (PPNAD) is a component of Carneys complex [1]. Primary pigmented nodular adrenocortical dysplasia is an exceedingly rare cause of Cushings syndrome in young adults. It is characterized by non-adrenocorticotropic hormone-dependent hypersecretion of cortisol by multiple, pigmented nodules of hyperplastic adrenocortical cells. Treatment for PPNAD involves bilateral adrenalectomy because of high recurrence risk after unilateral or partial adrenalectomy. Cohen et al. reported a successful pregnancy after unilateral adrenalectomy for PPNAD [2]. Kidney stones were reported in about 15% of Cushings syndrome cases [3]. The susceptibility of the patients to nephrolithiasis is probably due to the synergic effect of several lithogenic factors, such as increased urinary excretion of calcium, phosphorus, potassium, uric acid, cystine, and oxalate and decreased urinary excretion of citrate. Chronically elevated urinary excretion of these elements represents a direct and/or indirect risk factor for kidney stone formation. Unlike these factors, citrate and potassium are protective factors by inhibiting urinary crystal formation. The prevalence of nephrolithiasis in the patients remained still higher than in the general population after disease remission, even if lithogenic factors had normalized [4]. All Cushings syndrome patients must be evaluated very carefully for lithogenic factors and kidney disease. Here we present a successful pregnancy three years after bilateral adrenalectomy due to Cushings syndrome secondary to Carney complex in a 28-year-old nulliparous woman. A 24-year-old previously healthy female presented with a 4-week history of fatigue, weight gain and alopecia. Clinical examination revealed central obesity, plethora, moon face, buffalo hump, atrophy in muscles of extremities, pigmented skin lesion, arrhythmia and severe hypertension. Serum ACTH level was low and cortisol was high at 09:00 h. Serum cortisol at 09:00 h also failed to suppress with either low-dose or high-dose dexamethasone suppression tests according to standard criteria [5]. Her plasma electrolytes, fasting glucose, thyroid function tests and liver function tests were in the normal range. Electrocardiogram (ECG) showed sinus tachycardia and Wolf Parkinson White syndrome which subsequently responded well to propafenone 150 mg tid. Echocardiogram was reported to be normal. Magnetic resonance imaging (MRI) of pituitary and hypothalamus revealed a cyst of Rathkes cleft around a millimetre in size. An abdominopelvic MRI showed bilateral multinodular appearance in adrenal glands, supporting a diagnosis of hyperplasia, and bilateral renal calculi. She had a right femoral neck fracture secondary to osteoporosis whilst under therapy for Cushing syndrome. Surgery for this fracture was planned after bilateral adrenalectomy. Preoperatively she received metyrapone for 6 weeks in order to normalize her serum cortisol in preparation for surgery. The pathology report for the bilateral adrenalectomy specimen revealed PPNAD. This pathological finding, combined with the presence of pigmented skin lesions, established the diagnosis of Carney complex. The post-operative course of the patient was unremarkable while she was on prednisolone 5 mg bid and fludrocortisone 0.1 mg daily replacement therapy. A prosthesis for femoral neck fracture was inserted 6 months after bilateral adrenalectomy. She subsequently had extracorporeal shock wave lithotripsy (ESWL) for multiple calculi. One year later her weight was decreased to 51 kg and 2 years later she had normal serum Ca, P and PTH levels along with a bone density which was appropriate for her age. She had regular menses 1 year after bilateral adrenalectomy and she was married at 26 years. Her ACTH levels were stable and Nelson syndrome did not complicate the course. She got pregnant under replacement therapy at the age of 27 years. She had an uncomplicated pregnancy until 32 weeks of gestation. At this stage she was hospitalized for the diagnosis of suspected preterm premature rupture of membranes (PPROM) and intrauterine growth retardation (IUGR). Preterm premature rupture of membranes was not confirmed but the fetus was monitored for IUGR. The fludrocortisone dose was stable throughout pregnancy but the prednisolone dose was increased 1.5 times at the third trimester. Signs and symptoms of neither hypo/hypercortisolism nor electrolyte imbalance were noted during pregnancy. Gestational diabetes did not develop. She was given a stress dose of 100 mg of IV hydrocortisone before caesarean section for breech presentation and hydrocortisone weaning was scheduled for the following 3 days. The dose regimen prior to pregnancy for fludrocortisone and prednisolone was resumed 3 days after the operation. A 2850 g healthy male infant was delivered at gestational age of 37 years. No fetal or maternal complications were observed. Although women with Cushings syndrome rarely conceive, successful pregnancies have been reported [6]. But maternal and fetal mortality and morbidity rates of such pregnancies are high [7]. Such mothers are prone to diabetes mellitus, hypertensive disorders of pregnancy, cardiac failure, pulmonary oedema and even death, and their fetuses are also prone to abortion, and intrauterine and neonatal death [7]. Primary pigmented nodular adrenocortical dysplasia is a rare cause of Cushings syndrome and is generally treated with bilateral total adrenalectomy due to high recurrence risk following partial or unilateral adrenalectomy. The main risks of bilateral adrenalectomy are hypoadrenalism and adrenal crisis. Pregnancy planning in patients with PPNAD requires meticulous multidisciplinary medical care and detailed patient information because hypoadrenalism after operative treatment may also be associated with maternal and fetal complications during pregnancy and puerperium. Cohen et al. reported a PPNAD case managed with unilateral adrenalectomy in order to preserve adrenal function for an anticipated pregnancy [2]. The pregnancy was uneventful and the fetal development was normal without any steroid therapy. But he also emphasized the need for long-term meticulous follow-up due to the fact that remission might be temporary. The long-term outcome of this case was not available. Successful pregnancy outcomes in women with Addisons disease have been reported by several authors since the mid-1960s [8]. Many cases of bilateral adrenalectomy have also been reported, but no data related to their fertility after the procedure are available in the English literature. On the other hand, scarce case reports of bilateral adrenalectomy during pregnancy are available. Berends et al. first reported a case of bilateral adrenalectomy due to bilateral pheochromocytoma during pregnancy but they did not give further details on postoperative follow-up of the case [9]. Phupong et al. also reported a case of bilateral adrenalectomy during pregnancy [10]. But this case received glucocorticoid replacement only and a growth-retarded fetus was delivered due to fetal compromise at gestational age of 31 years. Glucocorticoid treatment during pregnancy reduces birth weight in animal models, including non-human primates and humans [11–14]. Birth weight reduction is most notable when glucocorticoids are administered in the latter stages of pregnancy [12], presumably reflecting the catabolic actions of these steroids, actions most likely to become manifest as reduced birth weight during the period of maximum fetal somatic growth. In some studies, antenatal glucocorticoids are associated with a reduction in birth weight [13]. Compared with betamethasone and dexamethasone, which cross the placental barrier in ratios of 3 : 1 and 2 : 1, respectively, only 10% of prednisolone crosses the placenta to reach the fetus. Glucocorticoid treatment is known to accelerate organ maturation at the expense of organ size, so it was also reassuring to find no difference in birth weight and head circumference [14]. Growth retardation also complicated our case despite additional mineralocorticoid replacement. Although the patient underwent physiological prednisolone replacement therapy, steroid replacement may cause growth retardation. The patient was not married and was not considering pregnancy just before the operation and an unexpected fracture of the femoral neck necessitated definitive curative treatment before she got married and pregnant. Signs of both inadequate and excessive steroid treatment such as lethargy and hypotension during pregnancy must be monitored in these patients because plasma renin activity and plasma cortisol level are not used for dose titration of prednisolone and fludrocortisone in pregnancy [15]. Our case was normotensive and developed no electrolyte imbalance throughout pregnancy under both glucocorticoid and mineralocorticoid therapy. In spite of the absence of signs of lethargy in our case, the dose of prednisolone was increased 1.5 times at the third trimester in order to catch up with normally increasing serum cortisol levels as pregnancy progresses. Addisonian crisis is a life-threatening event in pregnant women and usually accompanies stressful conditions such as hyperemesis gravidarum, infection and labour. A stress dose of hydrocortisone, owing to its glucocorticoid and mineralocorticoid activities, should be administered in such situations. Following the stress dose and three-day hydrocortisone weaning in the postoperative period, the dose regimen prior to pregnancy was resumed in our case. Maternal and fetal successful outcomes could also be obtained with meticulous multidisciplinary management in cases which have undergone bilateral adrenalectomy secondary to PPNAD.

The Use of Human Epididymis 4 and Cancer Antigen 125 Tumor Markers in the Benign or Malignant Differential Diagnosis of Pelvic or Adnexal Masses

Background: Ovarian cancer is one of the highest mortality cancers in gynaecology. Discrimination of benign masses from malignant ones may sometimes become a challenge for the clinician since there is not a reliable tumour marker, thus some unnecessary, highly morbid operations can be performed. Aims: To explore the efficacy of human epididymis 4 (HE 4) and cancer antigen 125 (CA 125) markers in differentiating malignant and benign pelvic masses of ovarian origin and to identify the cut-off points for those markers. Study Design: Prospective study. Methods: Fifty-one patients who were diagnosed and planned to undergo surgery for ovarian mass between June 2008 and December 2008 were enrolled into this study. Preoperative venous blood samples were taken and frozen for marker investigation and final diagnoses were concluded by histopathological examination. After recruitment of all cases CA 125 and HE 4 levels were evaluated. Results: The statistical analysis did not indicate any statistically significant difference between the CA 125 levels of the patients with malignant and benign adnexal masses (p=0.105). The HE 4 levels of the patients with malignant adnexal masses were higher at a statistically significant level compared to the patients with benign adnexal masses (p=0.002). For HE 4 tumour marker and at the cut-off point of >25 pM, sensitivity was 1, specificity 0.40, positive cut-off value 0.19, negative cut-off value 1, accuracy 0.47 and positive likelihood ratio 1.65. Conclusion: Human epididymis 4 is a better diagnostic tool than CA 125 in benign-malignant discrimination of adnexal masses. The cut-off value of 25 pmol/L for human epididymis 4 will contribute to providing proper guidance to patients with adnexal masses and applying the proper treatment method.

Laparoscopic management of a spontaneous 12th week heterotopic tubal pregnancy: a case report

Here we present a spontaneously-developed case involving 12th week heterotopic tubal pregnancy. In the preoperative period, the diagnosis was confirmed both by ultrasonographic examination and magnetic resonance imaging (MRI). The patient was treated successfully using a laparoscopic salpingectomy technique without jeopardizing the intrauterine pregnancy.