Immunomagnetic detection of micrometastatic cells in bone marrow of uveal melanoma patients: a paradox.

PURPOSE: Our objective was to study survival rates with the bone marrow (BM) results in a cohort of uveal melanoma patients with long follow-up. METHODS: Mononuclear cell fractions isolated from BM were examined for tumour cells using our immunomagnetic separation (IMS) method. The patients were classified as BM positive or BM negative. Clinical follow-up, histopathological findings, vital status and cause of death were registered. RESULTS: The study included 328 consecutive patients with uveal melanoma from 1997 to 2006. Tumour cells were found in BM samples in 29% (95% CI, 25-34) at enrolment (96 cases). After a minimum follow-up time of 6 years, 156 (48%) (95% CI, 42-53) melanoma patients had died. The causes were as follows: melanoma metastases 92 (59%), another cancer 20 (13%) and non-cancer 44 (28%). Nine patients were still living with melanoma metastases. Until the latest work-up, 101(31%) (95% CI, 26-36) patients had developed melanoma metastases. Cyto- or histopathological verification of the metastatic lesions was obtained in 85 cases (84%). In the group with melanoma metastases, 28 tested BM positive at study entry (28%) (95% CI, 19-38). In total, 39 of 101 with metastases tested positive at least once after a maximum of three tests (39%) (95% CI, 29-49). The overall median survival from the first BM test was shorter for the BM negative patients (9.5 years) compared with the BM positive (14.4 years), p = 0.02, log rank test. CONCLUSION: Ocular melanoma cells detected in BM seem to have a positive prognostic impact on survival in contrast to our original hypothesis.

Exploring the agreement between questionnaire information and DSM-IV diagnoses of comorbid psychopathology in children with autism spectrum disorders.

Autism spectrum disorders are often comorbid with other psychiatric symptoms and disorders. However, identifying psychiatric comorbidity in children with autism spectrum disorders is challenging. We explored how a questionnaire, the Child Behavior Check List, agreed with a Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV)-based semi-structured interview, the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children (Kiddie-SADS). The sample comprised 55 children and adolescents (age 6 to 18 years) with autism spectrum disorders, including the main autism spectrum disorder subgroups and the broad range of cognitive and language functioning. High rate of psychopathology was found both through questionnaire and interview assessment. Using predefined Child Behavior Check List cutoffs, we found good agreement between the Child Behavior Check List and the Kiddie-SADS for identifying attention deficit/hyperactivity disorder, depressive disorders, and oppositional defiant disorder. However, overall the specificity of the Child Behavior Check List was low. The Child Behavior Check List was not useful for identifying anxiety disorders. The Child Behavior Check List may capture core symptoms of autism spectrum disorders as well as comorbid psychopathology, and clinicians should be aware that the Child Behavior Check List may be unspecific when used in children and adolescents with autism spectrum disorders.

Palliative brachytherapy with or without primary stent placement in patients with oesophageal cancer, a randomised phase III trial.

PURPOSE: To investigate whether a combination of self-expanding metal stent (SEMS) and brachytherapy provided more rapid and prolonged effect on dysphagia without increased pain compared to brachytherapy alone in patients with incurable oesophageal cancer. METHODS: 41 Patients were randomised to SEMS followed by brachytherapy, 8 Gy×3 (n=21) or brachytherapy alone, 8 Gy×3 (n=20). Change in dysphagia and pain three and seven weeks after randomisation (FU1 and FU2) was assessed by patient-reported outcome. Dysphagia, other symptoms and health-related quality of life were assessed every four weeks thereafter. The study was closed before the estimated patient-number was reached due to slow recruitment. RESULTS: Patients receiving SEMS followed by brachytherapy had significantly improved dysphagia at FU1 compared to patients receiving brachytherapy alone (n=35). Difference in pain was not observed. At FU2, patients in both arms (n=21) had less dysphagia. Four patients in the combined treatment arm experienced manageable complications, no complications occurred after brachytherapy alone. CONCLUSION: For the relief of dysphagia, SEMS followed by brachytherapy is preferable and safe for patients in need of immediate alleviation, while brachytherapy with or without preceding SEMS provides relief within a few weeks after treatment.

The impact of ADHD symptoms and global impairment in childhood on working disability in mid-adulthood: a 28-year follow-up study using official disability pension records in a high-risk in-patient population.

BACKGROUND: Individuals with ADHD have been associated with more employment difficulties in early adulthood than healthy community controls. To examine whether this association is attributable specifically to disturbance of activity and attention (ADHD) or to psychopathology in general, we wanted to extend existing research by comparing the rate of mid-adulthood working disabilities for individuals diagnosed with ADHD as children with the rate for clinical controls diagnosed with either conduct disorder, emotional disorder or mixed disorder of conduct and emotions. METHODS: Former Norwegian child-psychiatric in-patients (n = 257) were followed up 17-39 years after hospitalization by record linkage to the Norwegian national registry of disability pension (DP) awards. Based on the hospital records, the patients were re-diagnosed according to ICD-10. Associations between the diagnoses, other baseline factors and subsequent DP were investigated using Kaplan-Meier survival analyses and logrank testing. RESULTS: At follow-up, 19% of the participants had received a DP award. In the logrank testing, ADHD was the only disorder associated with a subsequent DP, with 30% being disabled at follow-up (p = 0.01). Low psychosocial functioning (assessed by the Children's Global Assessment Scale) at admission uniquely predicted future DP (p = 0.04). CONCLUSIONS: ADHD in childhood was highly associated with later receiving a DP. Our finding of worse prognosis in ADHD compared with other internalizing and externalizing disorders in mid-adulthood supports the assumption of ADHD being specifically linked to working disability. Assessment of psychosocial functioning in addition to diagnostic features could enhance prediction of children who are most at risk of future disability.

Neoadjuvant chemotherapy, interval debulking surgery or primary surgery in ovarian carcinoma FIGO stage IV?

OBJECTIVES: The aim of this study was to investigate the impact of surgical approach, the extent of surgery and chemotherapy on overall survival in patients with ovarian carcinoma (OC) stage IV. METHODS: We retrospectively collected population-based data from the Norwegian Radium Hospital code registry on the diagnosis and surgery of 238 patients diagnosed with OC stage IV from 1996-2005. All patients received platinum-based chemotherapy. Surgical approach was registered as primary debulking surgery (PDS), interval debulking surgery (IDS) and delayed primary surgery (DPS). Surgery level was classified as radical surgery (RS), standard surgery (SS) or suboptimal surgery (SUBS). Univariate and multivariate analyses identified prognostic factors in PDS, IDS and DPS groups and subgroups. RESULTS: There were no differences in overall survival between the PDS, IDS and DPS groups. Surgery level was significantly associated with overall survival in the whole cohort (p<0.001), the PDS and IDS groups, but not in the DPS group. More patients with RS achieved no residual tumour (RT), but overall survival was not superior compared to no RT in the SS group. In 66 patients with no RT there were no differences in overall survival between those who underwent PDS, IDS and DPS. Chemotherapy with platinum/paclitaxel tended to improve survival. RT, World Health Organisation (WHO) performance status and histology were prognostic factors for overall survival in the whole cohort. CONCLUSION: No RT remains the objective, whether PDS, IDS or DPS is performed, and no differences in overall survival were found in the three treatment groups.

Predicting platinum resistance in primary advanced ovarian cancer patients with an in vitro resistance index.

PURPOSE: We aimed to identify primary platinum resistance in epithelial ovarian cancer (OC) patients with FIGO stage III-IV disease by an in vitro drug-response assay and to correlate the findings with clinical response. We considered whether neoadjuvant chemotherapy or anatomic sample site and tumor heterogeneity would influence the results. METHODS: We combined the ATP-based tumor-chemosensitivity and the extreme drug resistance assays for testing of 85 biopsies from 58 patients. Tumors were classified as sensitive or resistant by a resistance index (RI). We did separate analyses of primary tumors and metastases and compared chemo-naïve samples with samples obtained after neoadjuvant chemotherapy. Results were analyzed for association with clinical platinum resistance, progression-free survival (PFS), and overall survival (OS). RESULTS: RI · 250 predicted primary platinum resistance, without misclassification of sensitive patients. The test sensitivity for primary tumors was 15/15, specificity 3/10, negative predictive value 3/3, and positive predictive value 15/22. Patients with in vitro platinum-resistant samples had shorter PFS compared with patients with sensitive samples (3.4 vs. 10.0 months, p = 0.02). Comparing patient-matched primary and metastatic samples, there was about 1/3 mismatch in resistance. RI for platinum was lower in primary tumors exposed to neoadjuvant chemotherapy than in chemo-naïve tumors (p < 0.01). CONCLUSIONS: This in vitro assay predicted primary platinum resistance, without misclassification of sensitive OC patients, and the results were significantly associated with PFS. We suggest that samples from primary tumor and metastatic samples have different responses to chemotherapy and that exposure to chemotherapy might induce in vitro platinum resistance.

Prognostic significance of residual tumor in patients with epithelial ovarian carcinoma stage IV in a 20 year perspective.

OBJECTIVE: We aimed to evaluate prognostic factors impacting on overall survival during a 20 year period with substantial changes in surgical approach and chemotherapy management of patients with epithelial ovarian carcinoma stage IV. DESIGN: A retrospective population-based study. SETTING: The Norwegian Radium Hospital during 1985-2005. POPULATION: Three hundred and ninety-four patients with epithelial ovarian carcinoma stage IV treated at the Norwegian Radium Hospital. METHODS: The cohort was divided into two groups (1985-1995 and 1996-2005), and clinical and pathological characteristics were compared. Univariate and multivariate analyses were performed to identify prognostic factors during 1985-1995, 1996-2005 and 1985-2005. MAIN OUTCOME MEASURES: Prognostic factors and overall survival in the three periods. RESULTS: Median overall survival improved from 1985-1995 to 1996-2005 (from 1.3 to 2.1 years). More patients had macroscopic radical surgery (28 vs. 11%), received neoadjuvant chemotherapy and were treated with platinum-taxane combination therapy from 1996-2005 compared to 1985-1995. Patients with primary surgery had improved median overall survival from 1996-2005 compared to 1985-1995. In multivariate analyses, surgical approach was not a prognostic factor for overall survival, but chemotherapy was during 1985-2005. Postoperative residual tumor was a prognostic factor for overall survival in all periods. CONCLUSIONS: Macroscopic radical surgery is a strong prognostic factor for overall survival and is achievable in a subset of patients with epithelial ovarian carcinoma stage IV. Improved selection criteria for what treatment algorithm to choose for patients with epithelial ovarian carcinoma stage IV are warranted.

The impact of ADHD and conduct disorder in childhood on adult delinquency: a 30 years follow-up study using official crime records.

BACKGROUND: Few longitudinal studies have explored lifetime criminality in adults with a childhood history of severe mental disorders. In the present study, we wanted to explore the association between adult delinquency and several different childhood diagnoses in an in-patient population. Of special interest was the impact of disturbance of activity and attention (ADHD) and mixed disorder of conduct and emotions on later delinquency, as these disorders have been variously associated with delinquent development. METHODS: Former Norwegian child psychiatric in-patients (n = 541) were followed up 19-41 years after hospitalization by record linkage to the National Register of Criminality. On the basis of the hospital records, the patients were re-diagnosed according to ICD-10. The association between diagnoses and other baseline factors and later delinquency were investigated using univariate and multivariate Cox regression analyses. RESULTS: At follow-up, 24% of the participants had been convicted of criminal activity. In the multivariate Cox regression analysis, conduct disorder (RR = 2.0, 95%CI = 1.2-3.4) and hyperkinetic conduct disorder (RR = 2.7, 95% CI = 1.6-4.4) significantly increased the risk of future criminal behaviour. Pervasive developmental disorder (RR = 0.4, 95%CI = 0.2-0.9) and mental retardation (RR = 0.4, 95%CI = 0.3-0.8) reduced the risk for a criminal act. Male gender (RR = 3.6, 95%CI = 2.1-6.1) and chronic family difficulties (RR = 1.3, 95% CI = 1.1-1.5) both predicted future criminality. CONCLUSIONS: Conduct disorder in childhood was highly associated with later delinquency both alone or in combination with hyperactivity, but less associated when combined with an emotional disorder. ADHD in childhood was no more associated with later delinquency than the rest of the disorders in the study population. Our finding strengthens the assumption that there is no direct association between ADHD and criminality.

Radiotherapy or surgery for spine metastases?

BACKGROUND AND PURPOSE: Radiotherapy (RT) remains the cornerstone of management of spine metastases (SM), even though surgery is a well-established treatment for selected patients. We compared the use of RT and surgery in a population-based cohort of patients with SM, investigated pre-treatment factors that were associated with use of these treatment modalities, and examined survival. PATIENTS AND METHODS: 903 patients in the south-eastern Norway who were admitted for RT or surgery for SM for the first time during an 18-month period in 2007-2008 were identified and their medical records were reviewed. RESULTS: The primary treatment was surgery in 58 patients and RT in 845 patients, including 704 multiple-fraction (MF) and 141 single-fraction (SF) RT schedules. 11 of 607 patients without motor impairment (2%) and 47 of 274 patients with motor impairment (17%) underwent primary operations. 11 of 58 operated patients and 244 of 845 irradiated patients died within 2 months after the start of treatment. 26% of those who received multiple-fraction RT or surgery died within 2 months. INTERPRETATION: Motor impairment was the main indication for surgery. Better identification of patients with short survival is needed to avoid time-consuming treatment (major surgery and long-term RT).

Nuclear S100A4 is a novel prognostic marker in colorectal cancer.

Current staging classifications in colorectal cancer are not able to accurately predict patient outcome, and the need for novel prognostic markers is evident. S100A4 is a Ca(2+)-binding protein which promotes metastasis in several tumour types, and the aim of the present study was to investigate the prognostic impact of S100A4 expression in colorectal cancer. Two hundred and forty two patients with curatively resected adenocarcinoma of the colon or rectum were prospectively included in the study at the time of surgery. S100A4 expression was analysed by immunohistochemistry, and associations with clinicopathological variables and patient outcome were investigated. Nuclear expression of S100A4 was observed in 29% and cytoplasmic expression was observed in 64% of the tumours. In univariate analysis, nuclear S100A4 was a negative predictor of metastasis-free (P=0.006) and overall survival (P=0.01), whereas cytoplasmic S100A4 was not associated with patient outcome. In multivariate analysis, nuclear localisation was inversely associated with metastasis-free (P=0.03) and overall survival (P=0.02). Interestingly, the prognostic impact was largely confined to TNM stage II, and stage II patients with tumours expressing nuclear S100A4 had a similar prognosis as stage III patients. In conclusion, nuclear expression of S100A4 is a novel prognostic marker in colorectal cancer, and the prognostic value in TNM stage II suggests that nuclear S100A4 could be used in the stratification of stage II patients for adjuvant treatment.

Radical treatment for oesophageal cancer patients unfit for surgery and chemotherapy. A 10-year experience from the Norwegian Radium Hospital.

BACKGROUND: Over a 10-year period from 1990, 445 patients with carcinoma of the oesophagus were admitted to the Norwegian Radium Hospital and 184 of these patients received treatment with curative intent. Even though surgery is the treatment of choice for these patients, many of them suffer from medical conditions that increase the risk for postoperative mortality and morbidity. In a retrospective study, the effect of the curative treatment offered to patients was explored with a particular focus on patients unfit for surgery. METHODS: Medical data of the 184 patients treated with curative intent were reviewed and additional clinical information was retrieved from local hospitals and general practitioners. Preoperative radiotherapy followed by surgery was the standard curative treatment for operable patients. Medically inoperable patients were offered radical split-course hyperfractionated radiotherapy followed by a brachytherapy boost. RESULTS: More than 50% (103/184) received non-surgical treatment only. Patients who received radical surgery (n = 81) were younger, had better performance status, less weight loss and dysphagia compared to patients treated with radical radiotherapy (n = 102). One patient received only photodynamic therapy. The 3-year survival was 29% for patients treated with radical surgery, and 8% for patients who received radical radiotherapy. The overall median crude survival for the two groups of patients were 20 months and seven months respectively. CONCLUSION: The hyperfractionated radiotherapy provided symptom relief without extensive toxicity and with a possibility for cure for patients with oesophageal cancer who are unfit for surgery and chemoradiotherapy. The literature supports the curative potential of high dose accelerated hyperfractionated radiotherapy even though the optimal radiotherapy regimen still needs to be explored.

Bone marrow micrometastases in advanced stage non-small cell lung carcinoma patients.

BACKGROUND: The clinical relevance of bone marrow micrometastases in non-small cell lung cancer (NSCLC) is undetermined, and the value of such analyses in advanced stage patients has not been assessed previously. METHODS: Immunomagnetic selection with the MOC31 (anti-EpCam) antibody was performed to isolate and detect tumor cells in bone marrow aspirates obtained from 196 patients with NSCLC, and the patients were subjected to follow-up for the assessment of survival. Repeated bone marrow samples, 2-7 samples per patient, were obtained from 13 long-term survivors. RESULTS: MOC31 positive tumor cells were detected in 107 of 196 (55%) samples, a frequency similar to results reported in low-stage patients prior to curative surgical resection for NSCLC. No association was found between the presence of bone marrow micrometastases and disease stage or histological subgroup, and survival was similar in patients with and without detectable tumor cells in bone marrow. Repeated bone marrow analysis revealed, for the first time in this group of patients, the continued presence of tumor cells regardless of the given therapy and treatment response. CONCLUSION: The immunomagnetic method utilized is a feasible strategy for the detection of bone marrow micrometastases in NSCLC. In advanced stage patients, the presence of MOC31 positive cells in bone marrow does not predict survival. Repeated analyses of bone marrow samples from long-term survivors revealed tumor cells in bone marrow which may represent dormant cells of particular interest for further characterization and follow-up.

Tobramycin once versus three times daily, given with penicillin G, to febrile neutropenic cancer patients in Norway: a prospective, randomized, multicentre trial.

OBJECTIVES: Penicillin G with an aminoglycoside is the standard initial empirical treatment in febrile neutropenia in Norway. It has been argued that giving the aminoglycoside once daily to neutropenic patients with Gram-negative bacteraemia may be hazardous when penicillin G is the beta-lactam antibiotic. We questioned this argument and hypothesized that tobramycin once daily was as efficacious as three times daily. METHODS: We conducted a randomized prospective multicentre study, comparing the efficacy of tobramycin 6 mg/kg once (arm A) versus three times (arm B) daily, plus penicillin G 5 million IU x 4, in febrile neutropenic cancer patients. PRIMARY OUTCOME: modification of the antibiotic regimen. RESULTS: One hundred and seventy-four patients were evaluable for intention-to-treat analyses. One hundred and fifty-five patients had lymphoma or leukaemia as the underlying cancer diagnosis. In arm A, 35 of 88 patients and in arm B, 34 of 86 patients, that is 40% in both arms had no modification of the antibiotic regimen. No patients died while participating in the study. Upon modification of the antibiotic regimen, all patients were successfully treated. The increase in serum creatinine was modest and similar in the two treatment groups. CONCLUSIONS: When administered with penicillin G, tobramycin given once daily was as efficacious and safe as tobramycin given three times daily in cancer patients with febrile neutropenia in Norway, provided the regimen was modified according to the clinical response.

Weekly docetaxel and prednisolone versus prednisolone alone in androgen-independent prostate cancer: a randomized phase II study.

BACKGROUND: Due to its palliative effect and prostate-specific antigen (PSA) decrease, many clinicians have considered prednisolone monotherapy to be the standard systemic treatment in patients with androgen-independent prostate cancer (AIPC). This approach should be compared with docetaxel (Taxotere)+prednisolone. METHODS: A total of 109 eligible patients were entered into a randomized phase II study (arm A: Taxotere+prednisolone [30 mg m(-2) weekly during 5 of 6 wk+prednisolone 5 mg x 2 per os daily]; arm B: prednisolone [5 mg x 2 per os daily]). Biochemical response (confirmed > or = 50% PSA reduction of the baseline level at 6 wk) was the primary endpoint with subjective progression, quality of life, and progression-free and overall survival as secondary outcomes. RESULTS: Biochemical response at 6 wk was recorded in 29 of 54 evaluable patients in arm A (54%; 95% CI: 40-67%) and 13 of 50 patients in arm B (26%; 95% CI: 14-38%), with similar response rates at 12 wk and if based on all eligible patients. Median progression-free survival was 11 mo (95% CI: 5.8-16.2 mo) in arm A and 4 mo in arm B (95% CI: 2.4-5.6 mo). Median overall survival was 27 mo in arm A (95% CI: 19.8-34.1 mo) and 18 mo in arm B (95% CI: 15.2-20.8 mo). Pain relief and quality-of-life assessment indicated superiority of the arm A treatment, without unacceptable toxicity. CONCLUSION: Docetaxel+prednisolone should become the first-line systemic standard treatment for AIPC as a more effective treatment than prednisolone monotherapy. Weekly applications of docetaxel are well tolerated.

CD10 protein expression in tumor and stromal cells of malignant melanoma is associated with tumor progression.

CD10 antigen is a 100-kDa-cell surface zinc metalloendopeptidase expressed in a variety of normal and neoplastic lymphoid and nonlymphoid tissues including melanomas. It was recently shown that metastatic melanomas express more CD10 than primary tumors. We evaluated CD10 expression in tumor and stromal cells in 70 biopsies with primary and 28 with metastatic malignant melanomas. Ki-67, Bcl-2, and Bax were also examined to investigate whether CD10 expression is associated with tumor proliferation index or factors of apoptosis. Formalin-fixed/paraffin-embedded tissues were studied by immunohistochemistry. More advanced primary tumors had higher CD10 expression in the tumor cells (r = 0.27, P = 0.03 for Clark levels and r = 0.29, P = 0.02 for Breslow) and higher Ki-67 proliferation fraction (r = 0.32, P = 0.007 for Clark levels and r = 0.32, P = 0.001 for Breslow). Similarly, CD10 expression in the intratumoral stromal cells was also higher in primary tumors with higher Clark level (P = 0.04, linear-by-linear association) and tumor thickness according to Breslow (r = 0.33, P = 0.01). The presence of CD10+ peritumoral stromal cell cuffs was also positively associated with tumor thickness according to Breslow (r = 0.27, P = 0.05). Also, expression of CD10 and Ki-67 were significantly higher in metastatic than in primary tumors (P = 0.01 and 0.02 respectively), but Bcl-2 expression was higher in primary melanomas (P = 0.02). We conclude that CD10 expression in malignant melanoma is associated with tumor progression.

Occult metastases in axillary lymph nodes as a predictor of survival in node-negative breast carcinoma with long-term follow-up.

Increased detection rate in the lymph nodes is seen with serial sectioning or immunohistochemistry (IHC), but the importance of occult metastases is not resolved. IHC is still not recommended in routine examination of lymph nodes. Axillary lymph nodes from 385 node-negative breast cancer patients with a median follow-up of 25 years were examined with IHC for cytokeratins, applied on routine sections. The association between classic histopathologic prognostic factors and the presence of occult metastases was evaluated. Metastases were found in 45 of 385 cases (12%), 21 metastases (47%) measured < or =0.2 mm, 8 (18%) were larger than 2 mm; 14 metastases were located in the subcapsular sinus, 22 in the parenchyma of the lymph node; and 51% (23/45) of the metastases were recognized on hematoxylin-eosin staining on "second look." The detection of metastases was significantly associated with the number of sectioned lymph nodes (6% metastases for one to five lymph nodes examined versus 17% for more than five lymph nodes) and with histologic subtype (metastases in 11% of the ductal versus 33% of the lobular carcinomas). No significant association was found between occult metastases and age, tumor size, histologic grade, estrogen or progesterone receptor status, p53, or c-erbB-2. Metastases larger than 2 mm predicted a poorer recurrence-free survival rate for the whole series. A subcapsular location of the metastases was a strong predictor of overall survival. Whether or not the metastases could be identified on hematoxylin-eosin sections did not have any prognostic significance. In the multivariate analysis, histologic grade, tumor size of the primary tumor, progesterone receptor status, and the presence of occult metastasis in the lymph nodes had a prognostic impact on survival with a 25-year follow-up.

The prognostic impact of cyclin dependent kinase inhibitors p21WAF1, p27Kip1, and p16INK4/MTS1 in adenocarcinomas of the uterine cervix: an immunohistochemical evaluation of expression patterns in population-based material from 142 patients with international federation of gynecology and obstetrics stage I and II adenocarcinoma.

BACKGROUND: The authors assessed the prognostic significance of abnormal cyclin dependent kinase inhibitor (CDKI) expression in adenocarcinomas of the uterine cervix. METHODS: Population-based, archival material from patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I and II cervical adenocarcionmas from 2 5-year periods (1976-1980, n = 82 patients; 1986-1990, n = 142 patients) was examined for expression of p21(WAF1), p27(Kip1), and p16(INK4/MTS1) using immunohistochemical techniques. RESULTS: Rates of tumors with low levels of nuclear expression of p27 and p16 were lower during the period 1976-1980 (P < 0.01), suggesting bias due to unbuffered formalin. Analyses that were restricted to patients from 1986-1990 showed positive associations between all three CDKIs (P < 0.05). Low p16 expression was associated with higher FIGO stage (P = 0.01), age older than 55 years (P = 0.01), and deep invasion (P = 0.003). No significant associations with stage, age, or histopathologic parameters were found for p21 or p27. Significant associations with tumor differentiation were not seen for any CDKI. Kaplan-Meier plots showed diverging survival curves for p21 and p27 expression, but the differences were not significant. In multivariate analysis, low p27 expression and high p16 expression were strong predictors of a poor prognosis (p27: < 40% nuclear staining; P = 0.001; hazard ratio, 3.18; p16: < 40% nuclear staining; P < 0.001; hazard ratio, 0.16). Low p27 expression was of prognostic significance only if it was analyzed together with p16 expression. Further evaluation indicated that patients with different phenotypic p27/p16 combinations may have different outcomes. CONCLUSIONS: Aberrant expression patterns of CDKIs were predictors of prognosis for patients with FIGO Stage I or II cervical adenocarcinoma. Analysis of CDKI expression in this patient group may prove clinically useful.

Selective iron supplementation based on serum ferritin values early in pregnancy: are the Norwegian recommendations satisfactory?

BACKGROUND: The aims of the present study were to evaluate the recommendations by comparing compliance and adequacy of iron status at 6 weeks postpartum between one group given advice only and one group given advice plus iron supplement. In the latter group the efficacies of two iron preparations of different strengths and types were compared. METHODS: Ninety-three women had been given advice only (Group I) and were enrolled in the project at 6 weeks postpartum. Two hundred and thirty-three women enrolled at their second antenatal visit and were given advice plus iron supplement; those with s-ferritin <60 microg/L were randomized to a daily dose of 1) 60 mg Fe2+ (Ferromax) or 2) 3.6 mg heme iron plus 24 mg Fe2+ (Hemofer), and started taking the supplement at once if s-ferritin <20 microg/L or at 20 weeks if 20-60 microg/L. In addition to hemoglobin as routine, s-ferritin was measured in all the women at 6 weeks postpartum. RESULTS: At 6 weeks postpartum median s-ferritin was 28 and 34 microg/L in Groups I and II, respectively, and a significantly higher mean s-ferritin (46.5 vs. 37.3 microg/L; p < 0.05) was found in women taking the highest dose. There were no correlations between s-ferritin in early pregnancy and at 6 weeks postpartum. Peripartum blood loss was the main indicator for iron status at 6 weeks postpartum. CONCLUSION: Iron supplementation based on iron status early in pregnancy, with 60 mg ferrous iron or 27 mg iron containing heme, resulted in adequate iron stores at 6 weeks postpartum among 75% or 70% of the women, respectively. However, 6 weeks were not sufficient to rebuild iron stores in women with large peripartum blood loss.

The prognostic impact of hormone receptors and c-erbB-2 in pregnancy-associated breast cancer and their correlation with BRCA1 and cell cycle modulators.

A population-based series of 122 patients with pregnancy-associated breast carcinomas was histologically revised and the relationship between hormone receptors, c-erbB-2, BRCA1, p27, cyclin E, and cyclin D1 was studied. The 5-year overall survival was 41%; 70% had tumor size >20 mm; 72% had metastasized to regional lymph nodes; 95% were histologic grade II or III; 66% and 75% were negative for estrogen and progesterone receptor, respectively; and c-erbB-2 expression was high (44%). BRCA1 expression was reduced in 33% of the cases. The expression of p27, cyclin D1, and cyclin E was low, 11%, 9%, and 16%, respectively. Cyclin D1 was positively associated with the hormone receptors (p< or =0.01). In multivariate analysis, lymph node status, progesterone receptor, and c-erbB-2 were significant prognostic factors. In subdividing the group according to lymph node status, c-erbB-2 and progesterone receptor retained a prognostic significance in the node positive group only. In conclusion, pregnancy-associated breast carcinomas are aggressive tumors, with low expression of hormone receptors, BRCA1, p27, and cyclin E and D1, and high expression of c-erbB-2.