Edgar Petru

Nongenital cancers metastatic to the ovary

Abstract We review our experience with 82 patients with nongenital cancers metastatic to the ovary. All patients were referred for evaluation of an ovarian mass. The patients had primary carcinoma of the breast ( n = 28), colon ( n = 23), stomach ( n = 22), pancreas ( n = 7), or gallbladder ( n = 2). The overall actuarial 5-year survival rate was 10%. Five-year survival in patients with metastatic colon cancer was significantly higher (23%) than that in patients with metastatic cancer of the breast, stomach, gallbladder, or pancreas, all of whom died within 58 months ( P p = 0.003). Five-year survival in patients with disease limited to the pelvis was significantly higher than that in those with abdominal spread (22% vs 6%; P 2 cm in diameter was 18% or 4%, respectively ( P = 0.002). This pattern applied mainly to differences in patients with primary cancer of the breast or colon ( P

Prospective validation study of a predictive score for operability of recurrent ovarian cancer: The multicenter intergroup study DESKTOP II. A project of the AGO kommission OVAR, AGO study group, NOGGO, AGO-Austria, and MITO

Purpose: The DESKTOP I trial proposed a score for the prediction of complete cytoreduction in recurrent ovarian cancer. Resectability was assumed if 3 factors were present: (1) complete resection at first surgery, (2) good performance status, and (3) absence of ascites. The DESKTOP II trial was planned to verify this hypothesis prospectively in a multicenter setting. Methods: Participating centers prospectively enrolled all consecutive patients with platinum-sensitive first or second relapse. The score was applied to all patients, but centers were free to decide on therapy. All further therapies were documented, and the outcome of patients was analyzed. A 75% complete resection rate in 110 prospectively classified patients had to be achieved to confirm a positive predictive value of 2 or higher of 3 with 95% probability. Results: A total of 516 patients were screened within 19 months; of these, 261 patients (51%) were classified as score positive, and 129 patients with a positive score and first relapse were operated on. The rate of complete resection was 76%, thus confirming the validity of this score regarding positive prediction of complete resectability in 2 or more of 3 patients. Complication rates were moderate including second operations in 11% and perioperative mortality in 0.8%. Conclusions: This score is the first prospectively validated instrument to positively predict surgical outcome in recurrent ovarian cancer. It can aid in the selection of patients who might benefit from secondary cytoreductive surgery and will be enrolled in the recently started randomized prospective DESKTOP III trial investigating the role of surgery in recurrent platinum-sensitive ovarian cancer.

Establishment of tumor‐specific copy number alterations from plasma DNA of patients with cancer

With the increasing number of available predictive biomarkers, clinical management of cancer is becoming increasingly reliant on the accurate serial monitoring of tumor genotypes. We tested whether tumor‐specific copy number changes can be inferred from the peripheral blood of patients with cancer. To this end, we determined the plasma DNA size distribution and the fraction of mutated plasma DNA fragments with deep sequencing and an ultrasensitive mutation‐detection method, i.e., the Beads, Emulsion, Amplification, and Magnetics (BEAMing) assay. When analyzing the plasma DNA of 32 patients with Stage IV colorectal carcinoma, we found that a subset of the patients (34.4%) had a biphasic size distribution of plasma DNA fragments that was associated with increased circulating tumor cell numbers and elevated concentration of mutated plasma DNA fragments. In these cases, we were able to establish genome‐wide tumor‐specific copy number alterations directly from plasma DNA. Thus, we could analyze the current copy number status of the tumor genome, which was in some cases many years after diagnosis of the primary tumor. An unexpected finding was that not all patients with progressive metastatic disease appear to release tumor DNA into the circulation in measurable quantities. When we analyzed plasma DNA from 35 patients with metastatic breast cancer, we made similar observations suggesting that our approach may be applicable to a variety of tumor entities. This is the first description of such a biphasic distribution in a surprisingly high proportion of cancer patients which may have important implications for tumor diagnosis and monitoring.

Anhydramnios associated with administration of trastuzumab and paclitaxel for metastatic breast cancer during pregnancy

A 38-year-old women in her second pregnancy presented with symptomatic metastatic spinal-cord compression 7 years after undergoing lumpectomy and axillary dissection for stage I primary breast cancer. Immunohistochemistry analysis of the tumour had shown that it was oestrogen-receptor negative, progesterone-receptor positive, and overexpressed ERBB2. The patient had received six cycles of cyclophosphamide, methotrexate, and fl uorouracil followed by radiotherapy and then tamoxifen, which she had taken for 5 years. 86 months after primary diagnosis the patient developed paresthesia and hypoesthesia of the left arm and pain in the cervical vertebrae. MRI showed diff use metastatic infi ltration of the corpus of the second cervical vertebra (fi gure 1) with spinal-cord compression. Additional lesions in the fourth thoracic vertebra and the left femur were also seen with bone scintigraphy, but no other signs of metastatic disease were identifi ed by clinical examination, chest radiograph, or abdominal ultrasound. At this time the patient was 17 weeks pregnant with normal fetal development. After counselling the patient decided to continue pregnancy and was started on hydromorphone hydrochloride. Palliative radiotherapy of 46 Gy given in 23 fractions was administered to the cervical vertebra, which resulted in clinically improved neurological symptoms and pain. Cervical radiotherapy was undertaken with lead shielding of the uterus to protect the fetus. At 25+6 weeks’ gestation the patient received trastuzumab (8 mg/kg loading dose) combined with 175 mg/m of paclitaxel, followed by another cycle at 28+5 weeks with the dose of trastuzumab reduced to 6 mg/kg and the dose of paclitaxel kept the same. Close fetal surveillance was undertaken. Between 26 weeks’ gestation and 32 weeks’ gestation, during two cycles of trastuzumab and paclitaxel, fetal abdominal circumference stopped increasing and the volume of amniotic fl uid decreased to almost anhydramnios (fi gure 2). The mother was of normal constitutional size with normal weight gain of 11 kg during pregnancy and no other risk factors for restriction of intrauterine growth. Tests for premature rupture of the membranes were negative. At 31+6 weeks the volume of both fetal kidneys was decreased below the fi fth percentile. Additionally, the urinary bladder was barely visible, suggesting reduced renal function, and doppler sonography showed increased resistance indices of both the renal arteries (fi gure 3). Doppler sonography of the fetal umbilical and maternal uterine arteries was normal, which suggested healthy placental function. Serial ultrasound measurements of femur length, biparietal diameter, and head circumference were all within normal limits. As a result of the evidence of fetal renal failure and cessation of abdominal growth, fetal lung maturation was induced with corticosteroids after two cycles of trastuzumab and paclitaxel, and a caesarean section was done at 32+1 weeks’ gestation. The male newborn infant weighed 1460 g (tenth percentile), had a body length of 39 cm, and had a head circumference of 29.5 cm. The pH value of the umbilical artery was 7.31. The placenta weighed 290 g and placental histology was normal. The newborn infant showed signs of bacterial sepsis with hypotension, transient renal failure, respiratory failure necessitating mechanical ventilation, and positive laboratory fi ndings (C-reactive protein 30 mg/dL). With antibiotic treatment blood pressure normalised after 2 days and mechanical ventilation was ended on day 6. Diuresis was adequate with serum creatinine slightly increased (1.6 mg/dL) until day 14. Ultrasonography of the fetal kidneys showed transient hyperechodensities in the renal parenchyma that resolved by day 28. These transient hyperechodensities are often noted in newborn infants with transient renal failure as a result of decreased renal perfusion. Echocardiography and cranial ultrasound examinations were normal. The infant was discharged at age 6 weeks weighing 2335 g and in healthy condition. Development at 12 weeks was normal. Lancet Oncol 2007; 8: 79–81

Preoperative CA 125: An independent prognostic factor in patients with stage I epithelial ovarian cancer

Objective To evaluate the prognostic importance of preoperative CA 125 levels in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I epithelial ovarian cancer in comparison with the established prognostic factors: degree of differentiation, FIGO substage, and age. Methods In a retrospective analysis, the traditional prognostic factors and CA 125 levels (cutoff value 65 U/mL) were studied in 201 patients who were treated in five centers during 1984–1993. Patients with borderline tumors or nonepithelial ovarian carcinomas were excluded, as were women in whom CA 125 had not been determined preoperatively. Results In univariate analysis (Mantel test), overall survival decreased significantly in patients positive for CA 125 (P < .001). Substage (P = .004) and histologic grade (P = .01) also significantly influenced survival prognosis. When the effects of preoperative CA 125 levels were correlated with histologic grade, all three subgroups with CA 125 levels equal to or greater than 65 U/mL were associated with a decreased survival probability (grade 1, P = .04; grade 2, P = .003; grade 3, P = .01). Multivariate analysis (Cox model) identified preoperative CA 125 as the most powerful prognostic factor for survival (P < .001), the risk of dying of disease being 6.37 times higher (95% confidence interval 2.39–16.97) in CA 125-positive patients. Although FIGO substage retained its significant influence on survival (P = .03), histologic grade and age were not prognostically important. Conclusion Randomized trials investigating the efficacy of adjuvant treatment in patients with FIGO stage I epithelial ovarian cancer should also include stratification by preoperative CA 125 levels.

Gynecologic Cancer Intergroup (GCIG) proposals for changes of the current FIGO staging system

The FIGO has invited the GCIG to make contributions for possible changes of the FIGO staging system. We report on the consensus within the GCIG committee to propose the following changes in the current FIGO classification. Cervical cancer: Since fertility-preserving surgery is increasingly used in early disease, stage IB1-A may include tumors of up to 2 cm in diameter. Endometrial cancer: Positive peritoneal cytology alone should not classify this patient to be allotted to stage IIIA disease. Lymphadenectomy should be recommended in high-risk clinical stage I patients and in those with adverse histologies. Ovarian cancer: In early stage disease, grading and in advanced disease, the amount of residual disease should be reported. Vulvar cancer: The lymph node status should always be reported. In the case of enlarged inguinal nodes, histology should be obtained by any means. Vaginal cancer: Besides bladder and rectal tumor involvement urethral mucosal involvement should be added. Gestational trophoblastic disease: The modified WHO scoring system which is widely accepted should be adopted.

Pelvic and paraaortic lymphocysts after radical surgery because of cervical and ovarian cancer

To determine the incidence and clinical import of lymphocysts after radical gynecologic surgery including lymphadenectomy, we reviewed the records of 173 patients with cervical cancer and 135 patients with ovarian cancer who were followed up by computed tomography. Lymphocysts were found in 35 (20%) and 43 (32%) of the patients, respectively. Patients with cervical cancer and positive lymph nodes had a significantly higher rate of lymphocyst formation than did those with negative nodes (29% versus 14%, respectively, p less than 0.02). Age, type of lymphadenectomy, volume of fluid furthered by postoperative drains, disease stage, and tumor histology were not related to lymphocyst development. We saw no complications strictly attributable to lymphocysts. The clinical import and treatment possibilities are discussed.

The dynamic range of circulating tumor DNA in metastatic breast cancer

IntroductionThe management of metastatic breast cancer needs improvement. As clinical evaluation is not very accurate in determining the progression of disease, the analysis of circulating tumor DNA (ctDNA) has evolved to a promising noninvasive marker of disease evolution. Indeed, ctDNA was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. However, at present little is known about the dynamic range of ctDNA in patients with metastatic breast cancer.MethodsIn this study, 74 plasma DNA samples from 58 patients with metastasized breast cancer were analyzed with a microfluidic device to determine the plasma DNA size distribution and copy number changes in the plasma were identified by whole-genome sequencing (plasma-Seq). Furthermore, in an index patient we conducted whole-genome, exome, or targeted deep sequencing of the primary tumor, metastases, and circulating tumor cells (CTCs). Deep sequencing was done to accurately determine the allele fraction (AFs) of mutated DNA fragments.ResultsAlthough all patients had metastatic disease, plasma analyses demonstrated highly variable AFs of mutant fragments. We analyzed an index patient with more than 100,000 CTCs in detail. We first conducted whole-genome, exome, or targeted deep sequencing of four different regions from the primary tumor and three metastatic lymph node regions, which enabled us to establish the phylogenetic relationships of these lesions, which were consistent with a genetically homogeneous cancer. Subsequent analyses of 551 CTCs confirmed the genetically homogeneous cancer in three serial blood analyses. However, the AFs of ctDNA were only 2% to 3% in each analysis, neither reflecting the tumor burden nor the dynamics of this progressive disease. These results together with high-resolution plasma DNA fragment sizing suggested that differences in phagocytosis and DNA degradation mechanisms likely explain the variable occurrence of mutated DNA fragments in the blood of patients with cancer.ConclusionsThe dynamic range of ctDNA varies substantially in patients with metastatic breast cancer. This has important implications for the use of ctDNA as a predictive and prognostic biomarker.

Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo

BackgroundUterine sarcomas are very rare malignancies with no approved chemotherapy protocols. Histone deacetylase (HDAC) inhibitors belong to the most promising groups of compounds for molecular targeting therapy. Here, we described the antitumor effects of suberoylanilide hydroxamic acid (SAHA; vorinostat) on MES-SA uterine sarcoma cells in vitro and in vivo. We investigated effects of vorinostat on growth and colony forming ability by using uterine sarcoma MES-SA cells. We analyzed the influence of vorinostat on expression of different HDACs, p21WAF1 and activation of apoptosis. Finally, we examined the antitumor effects of vorinostat on uterine sarcoma in vivo.ResultsVorinostat efficiently suppressed MES-SA cell growth at a low dosage (3 μM) already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 μM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours. HDACs class I (HDAC2 and 3) as well as class II (HDAC7) were preferentially affected by this treatment. Vorinostat significantly increased p21WAF1 expression and apoptosis. Nude mice injected with 5 × 106 MES-SA cells were treated for 21 days with vorinostat (50 mg/kg/day) and, in comparison to placebo group, a tumor growth reduction of more than 50% was observed. Results obtained by light- and electron-microscopy suggested pronounced activation of apoptosis in tumors isolated from vorinostat-treated mice.ConclusionsOur data strongly indicate the high therapeutic potential of vorinostat in uterine sarcomas.

T1 breast cancer: identification of patients at low risk of axillary lymph node metastases.

AbstractObjective. The status of the axillary lymph nodes is one of the most important prognostic factors in patients with breast cancer. A panel of molecular markers of tumor aggressiveness in addition to conventional clinical and histopathologic features were analyzed in an attempt to identify a subgroup of patients with a low risk of axillary lymph node metastases. Material and methods. Data from 358 patients with T1 breast cancer who underwent level I/II axillary lymph node dissection (ALND) were investigated. Hormone receptor status, Ki-67, S-phase fraction, DNA ploidy, HER-2/neu, p53, epidermal growth factor receptor, urokinase type plasminogen activator, plasminogen activator inhibitor-1, bone marrow micrometastases as well as patient age, menopausal status, tumor site, tumor size, histologic type, tumor grade, carcinoma in situ, multifocality, and lymph vascular invasion (LVI) were studied to predict axillary lymph node status. Results. In a multivariate logistic regression analysis LVI (present v.s. not present), Ki-67 (≥18% v.s. <18%), tumor size (1.1–2 cm v.s. ≤1 cm), and histologic grade (G3 v.s. G1/2) were identified as independent predictive factors of axillary lymph node metastases. Approximately 13% of patients (n = 47) with well or moderately differentiated tumors less than or equal to 1 cm, no lymph vascular invasion, and a low Ki-67 staining were identified as having a low risk of axillary lymph node metastases of 4.3%. However, 20 patients with all four unfavorable predictive factors had a 75% incidence of axillary lymph node involvement. Conclusion. Primary tumor characteristics can be used to identify a subgroup of patients with a low risk of axillary lymph node metastases in T1 breast cancer. Preoperative risk assessment might be used to omit routine ALND in those patients at low risk of axillary lymph node metastases.