Stillbirth due to SARS-CoV-2 placentitis without evidence of intrauterine transmission to fetus: association with maternal risk factors.

OBJECTIVES: To describe the placental pathology, fetal autopsy findings and clinical characteristics of pregnancies that resulted in stillbirth owing to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) placentitis, and to identify potential risk factors. METHODS: This was a prospective multicenter study of non-vaccinated pregnant women affected by coronavirus disease 2019 (COVID-19) in Greece from April 2020 to August 2021. A total of 165 placentas were examined histologically and six cases of stillbirth associated with SARS-CoV-2 placentitis were retrieved. Complete fetal autopsy was performed in three of these cases. Gross, histopathological, immunohistochemical, molecular and electron microscopy examinations were carried out in the stillbirth placentas and fetal organs. The histological findings of cases with SARS-CoV-2 placentitis were compared with those in 159 cases with maternal COVID-19 which resulted in a live birth. Regression analysis was used to identify predisposing risk factors for SARS-CoV-2 placentitis. RESULTS: The placentas of all six stillborn cases showed severe and extensive histological changes typical of SARS-CoV-2 placentitis, characterized by a combination of marked intervillositis with a mixed inflammatory infiltrate and massive perivillous fibrinoid deposition with trophoblast damage, associated with intensely positive immunostaining for SARS-CoV-2 spike protein, the presence of virions on electron microscopy and positive reverse-transcription polymerase chain reaction test of placental tissues. The histological lesions obliterated over 75% of the maternal intervillous space, accounting for intrauterine fetal death. Similar histological lesions affecting less than 25% of the placenta were observed in seven liveborn neonates, while the remaining 152 placentas of COVID-19-affected pregnancies with a live birth did not show these findings. Complete fetal autopsy showed evidence of an asphyctic mode of death without evidence of viral transmission to the fetus. The mothers had mild clinical symptoms or were asymptomatic, and the interval between maternal COVID-19 diagnosis and fetal death ranged from 3 to 15 days. Statistically significant predisposing factors for SARS-CoV-2 placentitis included thrombophilia and prenatally diagnosed fetal growth restriction (FGR). Multiple sclerosis was seen in one case. CONCLUSIONS: SARS-CoV-2 placentitis occurred uncommonly in COVID-19-affected pregnancies of non-vaccinated mothers and, when extensive, caused fetal demise, with no evidence of transplacental fetal infection. Thrombophilia and prenatally detected FGR emerged as independent predisposing factors for the potentially lethal SARS-CoV-2 placentitis. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Chorionic villi derived mesenchymal like stem cells and expression of embryonic stem cells markers during long-term culturing.

Mesenchymal stem cells (MSCs) can be obtained from a variety of human tissues. MSCs derived from placental chorionic villi of the first trimester are likely to resemble, biologically, embryonic stem cells (ESC), due to the earlier development stage of placenta. In the present study long-term cultures of MSC-like cells were assessed in order to evaluate MSCs multipotent characteristics and molecular features during the period of culture. CV-cells obtained from 10 samples of chorionic villus displayed typical fibroblastoid morphology, undergone 20 passages during a period of 120 days, maintaining a stable karyotype throughout long term expansion. The cells were positive, for CD90, CD73, CD105, CD29, CD44, HLA ABC antigens and negative for CD14, CD34, AC133, and HLA DR antigens as resulted from the flow cytometry analysis. CV-cells were differentiated in adipocytes, osteoblasts, chondrocytes and neuronal cells under specific culture conditions. The expression of the ESC-gene markers POU5F1 (Oct-4) and NANOG was observed at earliest stages (4-12 passages) and not at the late stages (14-20 passages) by RT-PCR analysis. ZFP42 and SOX2 expression were not detected. Moreover, CV-cells were found to express GATA4 but not NES (Nestin). Chorionic villi-derived cells possess multipotent properties, display high proliferation rate and self-renew capacity, share common surface antigens with adult MSCs and express certain embryonics stem cells gene markers. These characteristics highlight chorionic villi as an attractive source of MSCs for the needs of regenerative medicine.

Gene receptor polymorphism as a risk factor for BMD deterioration in adolescent girls with anorexia nervosa.

Anorexia nervosa is a serious eating disorder that is associated with decreased bone mineral density and greater lifetime risk for fractures. This case-controlled study, analyzed single nucleotide polymorphisms of genes encoding vitamin D receptor, estrogen receptor alpha (ESR1), collagen type I and calcitonin receptor (CTR). Relationships between genotype and body mass index, cycling status and lumbar spine bone mineral density (LBMD) were determined in 40 adolescent girls with anorexia nervosa and 10 age-matched controls. The distribution of CTR-AluI genotypes differed between groups, but this polymorphism was not associated with LBMD Z-score. Distribution of ESR1-XbaI genotypes did not differ between groups, but the AA genotype was associated with decreased LBMD Z-score (≤-1) (OR = 24.79, 95% CI, 1.01-606.08). Carriers of the A allele were more likely to have decreased LBMD Z-scores compared with carriers of the G allele (OR = 4.12, 95% CI, 1.23-13.85, p = 0.022). In conclusion, our study shows that anorexic patients with wild-type genotype ESR-XbaI receptor are in greater risk for decreased BMD in relation to those with the mutated gene. Prompt recognition of these patients is crucial because early administration of the proper therapeutic treatment may contribute to the prevention of adverse sequelae on bone metabolism.

Outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC).

OBJECTIVE: To describe the outcomes of surgical management of bowel obstruction in relapsed epithelial ovarian cancer (EOC) so as to define the criteria for patient selection for palliative surgery. METHODS: 90 women with relapsed EOC underwent palliative surgery for bowel obstruction between 1992 and 2008. RESULTS: Median age at time of surgery for bowel obstruction was 57 years (range, 26 to 85 years). All patients had received at least one line of platinum-based chemotherapy. Median time from diagnosis of primary disease to documented bowel obstruction requiring surgery was 19.5 months (range, 29 days-14 years). Median interval from date of completed course of chemotherapy preceding surgery for bowel obstruction was 3.8 months (range, 5 days-14 years). Ascites was present in 38/90(42%). 49/90(54%) underwent emergency surgery for bowel obstruction. The operative mortality and morbidity rates were 18% and 27%, respectively. Successful palliation, defined as adequate oral intake at least 60 days postoperative, was achieved in 59/90(66%). Only the absence of ascites was identified as a predictor for successful palliation (p=0.049). The median overall survival (OS) was 90.5 days (range, <1 day-6 years). Optimal debulking, treatment-free interval (TFI) and elective versus emergency surgery did not predict survival or successful palliation from surgery for bowel obstruction (p>0.05). CONCLUSION: Surgery for bowel obstruction in relapsed EOC is associated with a high morbidity and mortality rate especially in emergency cases when compared to other gynaecological oncological procedures. Palliation can be achieved in almost two thirds of cases, is equally likely in elective and emergency cases but is less likely in those with ascites.

Association of maternal angiotensin II type 1 and type 2 receptor combination genotypes with susceptibility to early-onset preeclampsia.

Allelic variations affecting the activity of the maternal renin-angiotensin system may play a role in the development of hypertensive disorders of pregnancy like preeclampsia, its more severe early-onset form, and intrauterine growth restriction. We examined the association of common allelic variants of angiotensin II type 1 and type 2 receptor genes (AT1R and AT2R) sorted in five AT1R/AT2R receptor combination genotype groups with susceptibility to early-onset preeclampsia (EOP). The occurrence of AT1R (A1166C) and A2TR (C3123A) alleles in wild type (AA, CC), heterozygous (A/C, C/A), and homozygous (C/C, A/A) states was recorded in 84 women with a history of EOP and 84 age-matched controls sorted in five AT1R/AT2R receptor combination genotype (wild type: AA/CC, one mutant: AA/CA, AC/CC, two mutant: AC/CA, AA/AA, CC/CC, three mutants: AC/AA, CC/CA and four mutant: CC/AA) groups, by polymerase chain reaction-RFLP analysis. Three mutant receptor combination genotype carriers were more common in women with a history of EOP than in controls (26.18% vs. 4.76%, p = 0.003, OR = 8.25). Receptor combination genotyping may be of clinical value in: (a) maternal prediction of susceptibility to EOP, (b) disease subtyping for directed studies with receptor signaling antagonists, (c) the broader study of hypertension.

High-risk human papillomavirus DNA test and p16(INK4a) in the triage of LSIL: a prospective diagnostic study.

OBJECTIVE: The detection of high-grade cervical intraepithelial neoplasia (CIN) amongst patients with low-grade cytology (LSIL) is challenging. This study evaluated the role of high-risk HPV (HR-HPV) DNA test and p16(INK4a) immunostaining in identifying women with LSIL cytology at risk of harboring CIN2 or worse (CIN2+) and the role of p16(INK4a) in the triage of a population of HR-HPV positive LSIL. METHODS: We conducted a prospective study including women with LSIL cytology. Detection of HR-HPV was carried out by means of a polymerase chain reaction based assay. p16(INK4a) immunostaining was performed using the Dako CINtec cytology kit. All patients had colposcopically directed punch biopsies or large loop excision of the transformation zone of the cervix. The endpoint was detection of a biopsy-confirmed CIN2+. RESULTS: A series of 126 women with LSIL cytology were included. HR-HPV test had sensitivity 75% and specificity 64% for an endpoint of CIN2+. p16(INK4a) had significantly higher specificity of 89% (p=0.0000) but low sensitivity of 42%. The role of p16(INK4a) immunostaining in the triage of LSIL positive for HR-HPV was also evaluated. p16(INK4a) triage had 70% positive predictive value (PPV); however, this was not significantly higher than the PPV (56%) of HR-HPV test alone (p=0.4). CONCLUSIONS: The results indicate that HR-HPV or p16(INK4a) cannot be used as solitary markers for the assessment of LSIL. The addition of p16(INK4a) immunostaining led to an increase in HR-HPV specificity; however, the biomarker needs to be assessed further to establish its role as an adjunct test in the triage of LSIL.

Alterations in human papillomavirus-related biomarkers after treatment of cervical intraepithelial neoplasia.

OBJECTIVE: This study aims to assess the alterations in various HPV-related biomarkers 6 months post-treatment and how these relate to various risk factors and individual characteristics; their role for the prediction of treatment failure was also evaluated. DESIGN: Prospective observational study. POPULATION: Women planning to undergo treatment for cervical intraepithelial neoplasia. INTERVENTION: A liquid-based cytology sample was taken pre-operatively. This was tested for HPV genotyping, Nucleic Acid Sequence Based Amplification, flow cytometric evaluation and p16 immunostaining. A repeat LBC sample was obtained 6 months post-treatment and was tested for the same biomarkers. OUTCOMES: The alterations of the biomarkers 6 months post-treatment were recorded. Their relation to individual characteristics and risk factors (age, smoking, sexual history, use of condom, CIN grade, excision margin status, crypt involvement) as well as their role for the prediction of residual/recurrent disease were assessed. ANALYSIS: The accuracy parameters (sensitivity, specificity, positive and negative predictive value and the likelihood ratios) of each biomarker for the prediction of recurrent/residual CIN were calculated. RESULTS: A total of 190 women were recruited. All biomarkers had significantly higher negativity rates post-treatment compared to pre-treatment ones. Multivariate analysis demonstrated that consistent condom use post-treatment significantly reduces the high-risk HPV positivity rates in comparison to no use (OR=0.18; 95% CI: 0.09-0.38). Sensitivity and specificity for all high risk HPV DNA testing were 0.5/0.62, respectively; the relevant values for only type 16 or 18 DNA typing were 0.5/0.92, for NASBA 0.5/0.94, for flow 0.5/0.85 and for p16 0.25/0.93. CONCLUSION: CIN treatment reduces positivity for all HPV-related biomarkers. Consistent condom use significantly reduces high-risk HPV positivity rates. More cases of treatment failures are required in order to specify whether different combinations of HPV-related biomarkers could enhance the accuracy of follow up, possibly in the form of a Scoring System that could allow tailored post-treatment surveillance.

Different patterns of p16 immunoreactivity in cervical biopsies: correlation to lesion grade and HPV detection, with a review of the literature.

p16 is one extensively studied marker in gynecological pathology. However, its routine application in the diagnosis of squamous intraepithelial lesions of the uterine cervix may present difficulties for the general pathologist. The aim of the present study was to examine a series of 100 cervical biopsies/LEEP specimens, with detailed HPV-typing, for patterns of p16 immunoreactivity and possible correlations with morphology and HPV types. Four patterns of immunopositivity were recognized, according to the distribution of positively stained cells, and these correlated to lesion grade. A review of the pertinent literature concerning p16 immunoreactivity in squamous intraepithelial lesions and nonneoplastic epithelia of the uterine cervix is included in an effort to summarize the existing data and the remaining questions at both the practical and theoretical level.

Hypoxia inducible factor-1 alpha and vascular endothelial growth factor in biopsies of small cell lung carcinoma.

Neoangiogenesis has been documented in small cell lung carcinoma (SCLC). In addition, antiangiogenic therapies are being tested in clinical trials that involve SCLC. However, study of the underlying mechanisms has been performed almost exclusively in cell lines. In the current study, we immunostained 30 biopsy samples of SCLC with antibodies to hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), vascular endothelial growth factor-receptor 1 (VEGF-R1/flt-1) and vascular endothelial growth factor-receptor 2 (VEGF-R1/flk-1). The immunoreactivity was analyzed using a bivariate Spearman correlation test and linear regression analysis. We found significant correlation between HIF-1 alpha nuclear staining and VEGF staining. Moreover HIF-1 alpha+/VEGF+ cases were associated with poor survival. We also found a positive correlation between VEGF and VEGF-R2 expression. We suggest that a HIF-1 alpha/VEGF angiogenic pathway may exist in vivo in SCLC, similar to that in non-SCLC. Our data also suggest a potential VEGF/VEGFR-2 autocrine pathway in SCLC. The inclusion of novel inhibitors to HIF-1 alpha and other factors may optimize antiangiogenic interventions in SCLC.

Behaviour of the pandemic H1N1 influenza virus in Andalusia, Spain, at the onset of the 2009-10 season.

In Andalusia, Spain, the pandemic influenza A(H1N1)v virus has spread throughout the community, being the dominant influenza strain in the season so far. The current objective of the Andalusia Health Service is focussed on the mitigation of the health and social impact by appropriate care of the patients at home or in health centres. The 2009-10 seasonal influenza epidemic started early compared with to previous seasons. This article analyses the influenza A(H1N1)v situation in Andalusia until the week 39/2009.

Immature teratoma in pregnancy: a case report and literature review.

BACKGROUND: The management of a Stage I immature teratoma during pregnancy with a review of the literature is reported. CASE REPORT: A growing adnexal mass was removed at 12 weeks of gestation. Although the frozen section was negative, because of intraoperative clinical suspicion, a right salpingo-oophorectomy and surgical staging were performed. Histological examination revealed a Stage Ia, grade 1 immature ovarian teratoma. Appropriate surgical staging enabled avoidance of chemotherapy despite the unexpected histological diagnosis. The pregnancy was terminated because of fetal distress, with cesarean section at 34 weeks of gestation. At that time the peritoneal cavity was inspected and biopsies were taken as in second-look laparotomy. Two years after the first operation the patient remains disease free. CONCLUSION: For adnexal masses removed during pregnancy frozen section is useful but when there is clinical suspicion surgical staging must be performed.

Fascin can be an auxiliary immunomarker of ovarian granulosa cell tumors: comparison with calretinin and inhibin-alpha.

The histopathologic diagnosis of granulosa cell tumor adult type (AGCT) can be supported by the use of established immunomarkers such as inhibin-alpha and calretinin. Previously unreported data is presented on the detection of fascin in AGCT, in nonneoplastic granulosa cells and in other types of sex-cord stromal tumors. In addition, by staining a panel of various tumors, potentially included in the differential diagnosis of AGCT, we assessed the value of fascin as an auxiliary AGCT immunomarker. Intense and strong fascin staining may assist in cases with ambiguous calretinin or inhibin-alpha staining. On the contrary, absence of fascin should question a provisional morphologic diagnosis of AGCT.

L1 (CAM) (CD171) in ovarian serous neoplasms.

PURPOSE OF THE INVESTIGATION: The evaluation of L1 (CAM) as a tumor progression marker and as a prognostic factor in serous ovarian tumors. METHODS: L1 (CAM) protein expression was assessed by immunohistochemistry and Western blot in serous ovarian tumors [cystadenomas (n = 20), borderline tumors (n = 14) and carcinomas (n = 47)], and was correlated with stage,grade, progression-free survival time (PFS) and overall survival. RESULTS: L1 (CAM) immunoreactivity correlated significantly with stage and grade. It increased from benign tumors to early carcinomas and to advanced stage carcinomas progressively and significantly. In Stage III G3 carcinoma patients, low L1 (CAM) expressing tumors exhibited better response to chemotherapy and were associated with statistically significantly longer PFS (p = 0.002). CONCLUSION: L1 (CAM) expression represents a novel diagnostic marker in serous ovarian neoplasms that shows characteristics of tumor progression. L1 expression was associated with chemotherapy response.

Xanthogranulomatous salpingitis: report of three cases and comparison with a case of pseudoxanthomatous salpingitis.

Xanthogranulomatous inflammation, an uncommon form of chronic inflammation, has been described in several organs including those of the female genital tract. A rare condition described as pseudoxanthomatous salpingitis or pseudoxanthomatous salpingiosis, which is often associated with endometriosis, has been distinguished from xanthogranulomatous inflammation of the fallopian tube based on its histological features. In the present report three cases of xanthogranulomatous salpingitis and one case of pseudoxanthomatous salpingitis are presented and their clinical, pathological and histochemical features are compared.

Retinoid receptor alpha and Beta expression in serous ovarian tumors.

The expression of retinoid acid receptors alpha (RARalpha) and beta (RARbeta) and estrogen receptor alpha (ERalpha) was assessed by immunohistochemistry and Western blotting in normal ovaries, serous cystadenoma (n = 20), serous borderline (n = 14), and serous ovarian cancer (n = 47) and was correlated in cancer cases with stage, grade, progress-free survival (PFS), and survival. RARalpha was increasingly expressed in benign cystadenomas, borderline, and low-stage and advanced-stage neoplasms (p < 0.001). In stage III, G3 serous carcinoma, increased RARalpha expression was an independent prognostic factor associated with lower chemoresponse to first-line chemotherapy (taxol and carboplatin) and shorter PFS (p < 0.002).RARbeta and ERalpha expression did not correlate with RARalpha tumor characteristics or PFS and survival.

Diabetes mellitus mortality in Spanish cities: Trends and geographical inequalities.

AIM: To analyze the geographical pattern of diabetes mellitus (DM) mortality and its association with socioeconomic factors in 26 Spanish cities. METHODS: We conducted an ecological study of DM mortality trends with two cross-sectional cuts (1996-2001; 2002-2007) using census tract (CT) as the unit of analysis. Smoothed standardized mortality rates (sSMR) were calculated using Bayesian models, and a socioeconomic deprivation score was calculated for each CT. RESULTS: In total, 27,757 deaths by DM were recorded, with higher mortality rates observed in men and in the period 1996-2001. For men, a significant association between CT deprivation score and DM mortality was observed in 6 cities in the first study period and in 7 cities in the second period. The highest relative risk was observed in Pamplona (RR, 5.13; 95% credible interval (95%CI), 1.32-15.16). For women, a significant association between CT deprivation score and DM mortality was observed in 13 cities in the first period and 8 in the second. The strongest association was observed in San Sebastián (RR, 3.44; 95%CI, 1.25-7.36). DM mortality remained stable in the majority of cities, although a marked decrease was observed in some cities, including Madrid (RR, 0.67 and 0.64 for men and women, respectively). CONCLUSIONS: Our findings demonstrate clear inequalities in DM mortality in Spain. These inequalities remained constant over time are were more marked in women. Detection of high-risk areas is crucial for the implementation of specific interventions.

Evaluation of high-risk human papillomavirus types PCR detection in paired urine and cervical samples of women with abnormal cytology.

BACKGROUND: During the last decade, increasing efforts have focused on HPV detection in self-obtained samples, to increase the overall proportion of patients participating in cervical cancer screening procedures. OBJECTIVES: A clinical evaluation study of an optimized protocol for PCR detection of high-risk human papillomavirus (HPV) types in urine compared with cervical samples in consecutive women referred to the colposcopy clinic with abnormal cervical cytology. STUDY DESIGN: Paired urine and cervical specimens were collected from 100 consecutive women referred to the colposcopy clinic with abnormal cervical cytology and normal urine parameters. In-house and a commercial PCR method for the detection of HPV types 16 and 18, and a commercial multiplex PCR for HPV types 6, 11, 16, 18, and 33 were performed. All HPV cervix-positive/urine-negative paired urine samples were spiked with serial dilutions of cell lines infected with HPV 16 or 18 to test the sensitivity of HPV detection in these urine samples. RESULTS: In all but two cases HPV type 16 was detected. In cancer cases, the urine/cervix HPV detection sensitivity was 88.8%; in cases with high-grade lesions it was 76.5%; and in cases with low-grade lesions it was 45.5%. In all concordant cases the same HPV type was detected in both samples. The urine/cervix HPV detection sensitivity was higher when urine samples contained two or more epithelial cells per field in urine microscopy. HPV detection in 9 cervix-positive but urine-negative urine samples spiked with serial dilutions of HPV-positive cell lines showed that in these cases urine PCR inhibitors did not affect PCR amplification. CONCLUSIONS: A higher urine/cervix HPV detection sensitivity in cancer and high-grade lesions suggests that urine testing could be used to detect HPV mainly when these lesions are present.

Air pollution and cardiovascular admissions association in Spain: results within the EMECAS project.

OBJECTIVE: To evaluate the short term effect of air pollution on cardiovascular admissions in 14 Spanish cities METHODS: The period under study was from 1995 to 1999. Daily emergency admissions for all cardiovascular diseases (CVD) and heart diseases (HD) were obtained from hospital records, and the corresponding daily levels of particulates, SO2, NO2, CO, and ozone were recorded. The magnitude of association was estimated using Poisson generalised additive models controlling for confounding and overdispersion. For each cause, lagged effects, up to three days, of each pollutant were examined and combined estimates were obtained. For ozone the analyses were restricted to the warm period. One and two pollutant models were performed. RESULTS: Associations were more consistent in lag 0 (concurrent day) and 1 (lag 0-1), except in the case of ozone where there was a more delayed relation (lag 2-3). For combined estimates an increase of 10 microg/m3 in the PM10 levels in lag 0-1 was associated with an increase of 0.9% (95% CI: 0.4 to 1.5%) in the number of hospital admissions for CVD, and 1.6% (0.8 to 2.3%) for HD. For ozone the corresponding estimates for lag 2-3 were 0.7% (0.3 to 1.0) for CVD, and 0.7% (0.1 to 1.2) for HD. An increase of 1 mg/m3 in CO levels was associated with an increase of 2.1% (0.7 to 3.5%) in CVD admissions, and 4.2% (1.3 to 7.1%) in HD admissions. SO2 and NO2 estimates were more sensitive in two pollutant models CONCLUSIONS: A short term association between increases in daily levels of air pollutants and the number of daily admissions for cardiovascular diseases, with specificity for heart diseases, has been described in Spanish cities.

Polymerase chain reaction-based detection of circulating melanoma cells as an effective marker of tumor progression. Melanoma Cooperative Group.

PURPOSE: Reverse transcriptase (RT) polymerase chain reaction (PCR) with multiple markers has been demonstrated to be highly sensitive in detecting circulating cells from patients with malignant melanoma (MM). We evaluated the clinical significance of the presence in peripheral blood of specific PCR-positive mRNA markers as an expression of circulating melanoma cells. PATIENTS AND METHODS: Total cellular RNA was obtained from the peripheral blood of 235 patients with either localized (n = 154) or metastatic (n = 81) melanoma. We performed RT-PCR using tyrosinase, p97, MUC18, and MelanA/MART1 as gene markers. The PCR products were analyzed by gel electrophoresis and Southern blot hybridization. In addition, 20 healthy subjects and 21 patients with nonmelanoma cancer were used as negative controls. RESULTS: Although detected at various levels among assessable patients, each mRNA marker was significantly correlated with disease stage. A significant correlation with disease stage was demonstrated for patients who were positive to all four markers (P < .0001) or to at least three markers (P < .001). Univariate analysis showed a significant correlation between risk of recurrence (evaluated in stage I, II, and III patients) and increasing number of PCR-positive markers (P = .0002). Logistic regression multivariate analysis indicated that each single marker (except tyrosinase) and, more especially, the presence of four PCR-positive markers remained statistically independent prognostic factors for tumor progression. CONCLUSION: Our data establish the existence of a significant correlation among clinical stages, tumor progression, and presence of circulating melanoma-associated antigens in peripheral blood of MM patients. Preliminary assessment of a subset of patients with a higher risk of recurrence needs longer follow-up and further studies to define the role of RT-PCR in monitoring MM patients.

Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study.

PURPOSE: Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT). PATIENTS AND METHODS: Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort. RESULTS: Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability. CONCLUSION: CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.