EAN guideline on palliative care of people with severe, progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Patients with severe, progressive multiple sclerosis (MS) have complex physical and psychosocial needs, typically over several years. Few treatment options are available to prevent or delay further clinical worsening in this population. The objective was to develop an evidence-based clinical practice guideline for the palliative care of patients with severe, progressive MS. METHODS: This guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Formulation of the clinical questions was performed in the Patients-Intervention-Comparator-Outcome format, involving patients, carers and healthcare professionals (HPs). No uniform definition of severe MS exists: in this guideline, constant bilateral support required to walk 20 m without resting (Expanded Disability Status Scale score > 6.0) or higher disability is referred to. When evidence was lacking for this population, recommendations were formulated using indirect evidence or good practice statements were devised. RESULTS: Ten clinical questions were formulated. They encompassed general and specialist palliative care, advance care planning, discussing with HPs the patient's wish to hasten death, symptom management, multidisciplinary rehabilitation, interventions for caregivers and interventions for HPs. A total of 34 recommendations (33 weak, 1 strong) and seven good practice statements were devised. CONCLUSIONS: The provision of home-based palliative care (either general or specialist) is recommended with weak strength for patients with severe, progressive MS. Further research on the integration of palliative care and MS care is needed. Areas that currently lack evidence of efficacy in this population include advance care planning, the management of symptoms such as fatigue and mood problems, and interventions for caregivers and HPs.

Patient and caregiver involvement in the formulation of guideline questions: findings from the European Academy of Neurology guideline on palliative care of people with severe multiple sclerosis.

BACKGROUND AND PURPOSE: Patient and public involvement in clinical practice guideline development is recommended to increase guideline trustworthiness and relevance. The aim was to engage multiple sclerosis (MS) patients and caregivers in the definition of the key questions to be answered in the European Academy of Neurology guideline on palliative care of people with severe MS. METHODS: A mixed methods approach was used: an international online survey launched by the national MS societies of eight countries, after pilot testing/debriefing on 20 MS patients and 18 caregivers, focus group meetings of Italian and German MS patients and caregivers. RESULTS: Of 1199 participants, 951 (79%) completed the whole online survey and 934 from seven countries were analysed: 751 (80%) were MS patients (74% women, mean age 46.1) and 183 (20%) were caregivers (36% spouses/partners, 72% women, mean age 47.4). Participants agreed/strongly agreed on inclusion of the nine pre-specified topics (from 89% for 'advance care planning' to 98% for 'multidisciplinary rehabilitation'), and <5% replied 'I prefer not to answer' to any topic. There were 569 free comments: 182 (32%) on the pre-specified topics, 227 (40%) on additional topics (16 guideline-pertinent) and 160 (28%) on outcomes. Five focus group meetings (three of MS patients, two of caregivers, and overall 35 participants) corroborated the survey findings. In addition, they allowed an explanation of the guideline production process and the exploration of patient-important outcomes and of taxing issues. CONCLUSIONS: Multiple sclerosis patient and caregiver involvement was resource and time intensive, but rewarding. It was the key for the formulation of the 10 guideline questions and for the identification of patient-important outcomes.

A consensus review on the development of palliative care for patients with chronic and progressive neurological disease.

BACKGROUND AND PURPOSE: The European Association of Palliative Care Taskforce, in collaboration with the Scientific Panel on Palliative Care in Neurology of the European Federation of Neurological Societies (now the European Academy of Neurology), aimed to undertake a review of the literature to establish an evidence-based consensus for palliative and end of life care for patients with progressive neurological disease, and their families. METHODS: A search of the literature yielded 942 articles on this area. These were reviewed by two investigators to determine the main areas and the subsections. A draft list of papers supporting the evidence for each area was circulated to the other authors in an iterative process leading to the agreed recommendations. RESULTS: Overall there is limited evidence to support the recommendations but there is increasing evidence that palliative care and a multidisciplinary approach to care do lead to improved symptoms (Level B) and quality of life of patients and their families (Level C). The main areas in which consensus was found and recommendations could be made are in the early integration of palliative care (Level C), involvement of the wider multidisciplinary team (Level B), communication with patients and families including advance care planning (Level C), symptom management (Level B), end of life care (Level C), carer support and training (Level C), and education for all professionals involved in the care of these patients and families (Good Practice Point). CONCLUSIONS: The care of patients with progressive neurological disease and their families continues to improve and develop. There is a pressing need for increased collaboration between neurology and palliative care.

Individualized quality of life of severely affected multiple sclerosis patients: practicability and value in comparison with standard inventories.

PURPOSE: Individualized quality of life (QoL) measures differ from traditional inventories in that QoL domains/weights are not predetermined, but identified by the individual. We assessed practicability of the Schedule for the Evaluation of Individual QoL-Direct Weighting (SEIQoL-DW) interview in severely affected multiple sclerosis (MS) patients; the key QoL dimensions identified; and the correlation of the SEIQoL-DW index score with standard patient-reported outcome measures (PROMs). METHODS: Participants were people with severe MS who performed the baseline visit of the PeNSAMI trial (ISRCTN73082124). The SEIQoL-DW was administered at the patient's home by a trained examiner. Patients then received the following PROMs: the Core-Palliative care Outcome Scale (Core-POS), the Palliative care Outcome Scale-Symptoms-MS (POS-S-MS), the European Quality of Life Five Dimensions-3L (EQ-5D-3L), and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Of 59 enrolled patients, 11 (19 %) did not receive the SEIQoL-DW (and the other PROMs) because of severe cognitive compromise or inability to communicate. SEIQoL-DW administration was completed and deemed valid in all 48 cases (mean age 60 years, 58 % women, median Expanded Disability Status Scale score 8.5). Mean SEIQoL-DW index score was 59.1 (SD 25.5). The most commonly nominated SEIQoL-DW areas were family (94 % of the patients), relationships, and leisure activities (both 65 %). Core-POS and POS-S-MS contained 70 % of the SEIQoL-DW-nominated areas. Nevertheless, correlations between SEIQoL-DW index, Core-POS, and POS-S-MS (and the other PROMs) were negligible. CONCLUSIONS: Individualized QoL can be assessed in severely affected MS patients, providing information that is not tracked by the standard inventories Core-POS, POS-S-MS, EQ-5D-3L, and HADS.

Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial.

BACKGROUND: The prognostic and predictive role of KRAS mutations in advanced nonsmall-cell lung cancer (NSCLC) is still unclear. TAILOR prospectively assessed the prognostic and predictive value of KRAS mutations in NSCLC patients treated with erlotinib or docetaxel in second line. PATIENTS AND METHODS: NSCLC patients from 52 Italian hospitals were genotyped for KRAS and EGFR mutational status in two independent laboratories. Wild-type EGFR patients (N = 218) received first-line platinum-based chemotherapy and were randomly allocated at progression to erlotinib or docetaxel. Overall survival (OS) according to KRAS mutational status was the primary end point. RESULTS: KRAS mutations were present in 23% of TAILOR randomized cases. The presence of a KRAS mutation did not adversely affect progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS = 1.01, 95% confidence interval (CI) 0.71-1.41, P = 0.977; OS = 1.24, 95% CI 0.87-1.77, P = 0.233], nor influenced treatment outcome (test for interaction: OS P = 0.965; PFS P = 0.417). Patients randomized to docetaxel treatment experienced longer survival independently from the KRAS mutational status of their tumors (HR: mutated KRAS 0.81, 95% CI 0.45-1.47; wild-type KRAS 0.79, 95% CI 0.57-1.10). CONCLUSION: In TAILOR, KRAS was neither prognostic nor predictive of benefit for either docetaxel or erlotinib. Docetaxel remains superior independently from KRAS status for second-line treatment in EGFR wild-type advanced NSCLC patients. CLINICAL TRIAL REGISTRATION: NCT00637910.

Two cases of elevated tryptase in abdominal aortic aneurysm.

INTRODUCTION: From the literature, patients with a history of anaphylaxis to hymenoptera venom and positive specific IgE have shown a correlation between elevated tryptase levels and two clinical situations: systemic mastocytosis and an increased risk of reactions to venom immunotherapy or hymenoptera sting. Other clinical scenarios could explain elevated tryptase levels. MATERIAL AND METHODS: A 67 year old male (P1) and a 77 year old male (P2) were evaluated for previous severe anaphylaxis to hymenoptera sting. They underwent standard diagnostic work-up for hymenoptera venom allergy. Having found elevated tryptase levels, these were followed by a bone marrow biopsy to rule out systemic mastocytosis. RESULTS: P1: specific IgE and skin tests were positive for Vespula species; tryptase 52.8 ng/ml; P2: specific IgE and skin tests were positive for Vespa cabro and tryptase 153 ng/ml. Bone marrow biopsy results were negative for mastocytosis. We carried out magnetic resonance imaging, in P1 to better characterize the severe osteoporosis and in P2 because during physical examination a pulsating mass had been identified in the mesogastrium, and an aneurysm of the abdominal aorta which required surgical intervention in both patients was detected. Eight months after surgery, tryptase levels had diminished significantly (P1: 11.6 ng/ml and P2: 14.5 ng/ml). DISCUSSION: The elevated tryptase levels were correlated to abdominal aneurysm in both patients. In fact, post-surgery tryptase levels dramatically decreased. These two cases demonstrate that high tryptase levels in subjects with a history of hymenoptera venom anaphylaxis can be associated to undiagnosed aneurysmatic disease.

Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Self-reported sleep disorders in secondary school students: an epidemiological and risk behavioural analysis.

PURPOSE: To estimate the prevalence of self-reported sleep disorders (SD), to examine associations among demographic characteristics and familiar factors with SD, between SD and daytime sleep-related disorders (DD) and between evening habits and SD. METHODS: An anonymous questionnaire was proposed to 1563 students (aged 14-21 years, mean age 16.5 +/- 1.5; 42.8% males, 57.2% females) attending all classes of two high schools in Verona (North-East of Italy). Data were analyzed by some personal and familial characteristics, by definition of three sleeper groups (non problem, occasional problem or problem-sleepers). Moreover SD were put in relation with DD and with some personal evening attitudes. RESULTS: The 75.5% of the subjects report at least one SD. Difficulty falling asleep is the most frequent SD. The DD concern 91.2% of the sample. Females are more involved than males in SD and DD. All SD result strongly associated with the referred DD, except for sleepiness. Sport is significantly correlated with a minor prevalence of SD. Smoking and studying appear to be associated with SD. CONCLUSIONS: Since SD in youth constitute an important Public Health matter with a severe social impact they would be accurately studied to offer youth appropriate counselling given the importance of lifestyle in determining good sleep.

Successful CD34+ cell mobilization by intermediate-dose Ara-C in chronic lymphocytic leukemia patients treated with sequential fludarabine and Campath-1H.

Chronic lymphocytic leukemia (CLL) cells could be undetectable by flow cytometry or polymerase chain reaction after sequential treatment with fludarabine and Campath-1H. Concern has been raised regarding the ability to mobilize sufficient peripheral blood progenitor cells (PBPCs) for autografting after purine analogues, and there are few data about PBPC collection after Campath-1H. In all, 16 CLL patients responding to sequential chemo-immunotherapy entered the study. In 10, mobilization regimen consisted of granulocyte colony-stimulating factor (G-CSF) 5-10 microg/kg/die. Patients failing mobilization or not achieving the target of 2.5 x 10(6) CD34+ cells/kg underwent a second attempt using intermediate-dose (ID) Ara-C, 800 mg/m(2) every 12 h for six doses+G-CSF. PBPC collection after G-CSF alone was successful in two out of 10 patients. An adequate number of CD34+ cells were collected after ID Ara-C+G-CSF in eight patients failing the mobilization with G-CSF alone and in five out of six who did not receive G-CSF before. Greater yields of PBPCs were collected with Ara-C+G-CSF compared with G-CSF alone (13.8 vs 3.3). The extrahematologic toxicity was manageable. In conclusion, PBPC collection is feasible in CLL patients treated with sequential therapy including fludarabine and Campath-1H. Excellent yields were obtained in 92.8% of patients primed with ID Ara-C+G-CSF.

Epidermal growth factor receptor expression and activation in nonseminomatous germ cell tumors.

PURPOSE: The goal of this work was to study the expression of epidermal growth factor receptor (by use of monoclonal antibody EGFR 1) and HER-2/neu (by use of monoclonal antibody EGFR 2), as well as EGFR activation [phosphorylated EGFR (P-EGFR)] and autocrine stimulation [ligand transforming growth factor-alpha (TGF-alpha)] markers in a series of 24 testicular tumors [18 nonseminomatous germ cell tumors (GCTs), 1 Leydig cell tumor, and 5 seminomatous GCTs]. EXPERIMENTAL DESIGN: Paraffin-embedded sections of tumors were studied immunohistochemically for beta-human chorionic gonadotropin (beta-HCG), EGFR 1, HER-2/neu, TGF-alpha, and P-EGFR expression. In one case of pure choriocarcinoma, fresh-frozen tumor sections were also evaluated. The presence of EGFR mRNA was studied in the Jar choriocarcinoma cell line using reverse transcription-PCR. RESULTS: Staining for cell membrane EGFR was detected immunohistochemically in the 16 beta-HCG-positive components of 18 nonseminomatous GCTs as well as in the control Jar choriocarcinoma cell line and normal placenta. In contrast, 1 Leydig cell tumor, 5 seminomatous GCTs, and beta-HCG-negative components of 18 GCTs, as well as control B and T lymphoma cell lines, did not express EGFR. Expression of HER-2/neu, TGF-alpha, and P-EGFR was detected in 25, 36, and 27% of EGFR-positive, nonseminomatous GCTs, respectively. EGFR mRNA was detected in the Jar choriocarcinoma cells. CONCLUSIONS: We report data, for the first time, that document EGFR and HER-2/neu expression and indicate EGFR activation and autocrine stimulation in beta-HCG-positive, nonseminomatous GCTs. These findings may be clinically relevant in relation to the recent availability of active EGFR- and HER-2/neu-targeted pharmaceutical agents and to the extensively described negative prognostic significance of beta-HCG expression in mixed GCTs.

Prognostic value of p21(WAF1) and p53 expression in breast carcinoma: an immunohistochemical study in 261 patients with long-term follow-up.

p21 protein (p21) inhibitor of cyclin-dependent kinases is a critical downstream effector in the p53-specific pathway of growth control and can also be induced by p53-independent pathways in relation to terminal differentiation. We investigated p21 immunoreactivity in 261 breast carcinomas (141 node negative and 120 node positive) with long-term follow-up (median, 73 months; range, 37-119). p21 was seen in 214 (82%) infiltrating tumors, staining was nuclear and heterogeneous, and the p21 labeling index ranged from 0 to 90%. Sixty-eight (32%) patients showed p21 overexpression (>10% of reactive tumor cells). p21 overexpression was associated with large tumor size, positive nodal status, high histological grade, and high mitotic count and was related to short disease-free survival (DFS) in the whole series of patients (P = 0.04), in the node-negative subgroup (P = 0.004), and in the group of patients who did not undergo systemic adjuvant therapy (P = 0.003). In patients treated with systemic adjuvant therapy, bivariate analysis of the combined p21 and p53 phenotypes showed that p21+/p53+ tumors were associated with long DFS and overall survival (OS), whereas p21-/p53+ tumors had the worst prognosis. In treated patients, multivariate analysis showed that the p21-/53+ phenotype was independently associated with short DFS and OS. Our present data support the hypothesis that p21/p53 heterogeneous expression may be of clinical relevance for the therapeutic response to chemotherapy/hormonotherapy. The p21-/p53+ phenotype could correspond to a situation where p53 overexpression really reflects complete abrogation of p53 function. These cases with disrupted p53 function should have impaired the G1 checkpoint and may not be able to activate the apoptotic cascade in response to DNA-damaging drugs.

Solitary thyroid metastasis from colon cancer: fine-needle aspiration cytology and molecular biology approach.

Thyroid gland is one of the most vascularized organs of the body, nevertheless clinical and surgical series report an incidence of secondary malignancies in this gland of only 3%. Colorectal carcinoma metastatic to the thyroid gland is not as uncommon as previously believed, infact the number of cases seems to be increased in recent years due to the more frequent use of fine-needle aspiration cytology (FNAC) guided by ultrasonography. Although kidney, breast and lung metastases to the thyroid are frequent, metastasis from colon cancer is clinically rare with 52 cases reported in the literature in the last 5 decades and three cases described as solitary thyroid metastasis from the colon cancer without any other visceral metastases. To the best of our knowledge, we report the fourth case of solitary, asymptomatic thyroid metastasis from colon cancer without involvement of other organs. We discuss the importance of FNAC to detect metastatazing process as a compulsory step of the diagnostic and therapeutic management algorithm, combined with a molecular biology approach. A review of the last 5 decades literature, to update the number of cases described to date, is also included.

Inhibition of telomerase activity by a cell-penetrating peptide nucleic acid construct in human melanoma cells.

We investigated the effect of two peptide nucleic acids (PNAs), which are complementary to the RNA component of human telomerase, on the catalytic activity of the enzyme. PNAs induced a dose-dependent reduction of telomerase activity in cell extracts from human melanoma cell lines and surgical specimens. To down-regulate telomerase in intact cells, we generated a chimeric molecule synthesized by coupling the 13-mer PNA to the Antennapedia peptide. The PNA construct induced a dose- and time-dependent inhibition of telomerase activity. However, a 20-day exposure to the PNA construct only caused a slight increase in melanoma cell doubling time and failed to induce any telomere shortening.

Reliability of a primary culture system to test cytotoxic drug activity in human-malignant melanoma.

Optimal conditions have been defined to grow primary cultures of malignant melanoma suitable for in vitro pharmacological studies. A feasibility of primary cultures was observed in 60% of 62 clinical melanoma lymph node metastases. The neoplastic nature of the cells grown in culture, as assessed by the highly specific monoclonal antibodies anti-S100 and HMB45, was confirmed in 100% and 65% of the cases, respectively. Flow cytometric analysis showed a high stability of DNA content profiles observed in clinical samples through all the methodologic steps used to obtain in vitro cultures. The intertumor variability of the degree of the antiproliferative effect of melphalan and its relation with DNA interstrand cross-links (DNA ISC) provided preliminary evidence of the reliability of the experimental system for in vitro evaluation of anticancer drug activity.

Prognostic value of estrogen receptor status can be improved by combined evaluation of p53, Bcl2 and PgR expression: an immunohistochemical study on breast carcinoma with long-term follow-up.

Steroid receptor analysis is the only widely accepted prognostic/predictive marker in breast cancer (BC) treatment. In the present study we evaluated the prognostic role of ER/PgR with p53 and Bcl2, in a series of 277 BC (153 pN1/2, 122 pNO, 2 pNx) with a long-term follow-up (67 months for DFS, 75 months for OS). Our results, besides confirming the usefulness of ER immunohistochemical expression as a prognostic marker, showed that PgR expression alone had a borderline/not significant prognostic value in the whole series (p=0.08 for DFS and p=0.09 for OS), while showed to be prognostic in N+ cases (p=0.02 for DFS and p=0.03 for OS). PgR prognostic value, however, was not independent at the multivariate analysis. By combining ER with PgR, p53 and Bcl2, we showed that ER/p53 and ER/Bcl2 phenotypes had a better discriminant role than ER/PgR phenotype. The ER+/p53+ phenotype was at higher risk of relapse/death as compared with ER+/p53- phenotype. Conversely ER-/p53+ phenotype showed the most unfavourable prognosis. Similar results could be observed concerning ER/Bcl2 phenotypes. Our study showed that the combined evaluation of ER/PgR weakly enhanced the prognostic/predictive power of ER status alone. On the contrary, the combined evaluation of ER/p53 and ER/Bcl2, improved this prognostic/predictive capability and allowed the separation of ER positive and ER negative cases into subgroups with different prognosis.

Bcl-2 and p53 expression in node-negative breast carcinoma: a study with long-term follow-up.

Bcl-2 and p53 gene products (Bcl-2, p53) are important regulators of apoptosis and cell proliferation, and their immunohistochemical expression may help to identify high-risk breast cancer patients. The authors evaluated p53 and Bcl-2 immunoreactivity in 178 node-negative breast cancers (NNBC) with long-term follow-up (median, 60 months). Bcl-2 was seen in 111 (62%) cases, and was significantly associated with small tumor size, nonductal morphology, low tumor grade, estrogen-receptor (ER) positivity, and p53 negativity. p53 overexpression (ie, > 15% reactive nuclei) was observed in 31 (17%) cases, and was associated with lower age, large tumor size, ductal morphology, high tumor grade, negative ER status, and lack of Bcl-2 immunoreactivity. In univariate analysis, the variables associated with short relapse-free survival (RFS) were large tumor size (P = .002), high histological grade (P = .01), high mitotic count (P = .03), and high Nottingham prognostic index (NPI) (P = .0002). In multivariate analysis (final model), only the NPI was of independent prognostic value concerning RFS.

Immunocytochemical detection of progesterone receptors. A study in a patient with primary pulmonary hypertension.

Primary pulmonary plexogenic arteriopathy (PPPA) is one of the principal conditions in which pulmonary hypertension may be clinically unexpected. It occurs in the lung vessels in the absence of any demonstrable cause. Its high incidence in women of childbearing age combined with reports of disease following delivery of a child or assumption of oral contraceptives suggest that hormonal factors may play a role in the pathogenesis of PPPA. The suspicion that the pulmonary vascular lesions occurring in PPPA could represent the effect of a hormonal mediated vascular hyperreactivity prompted the evaluation of the steroid hormone receptor status on lung tissue obtained from a women suffering from this disease who had a double-lung transplantation. By the immunocytochemical method performed on formalin fixed, paraffin-embedded lung tissue, we showed the presence of progesterone receptors (PR) in the nuclei of the myofibroblasts forming the arterial obstructive intimal proliferations and of the spindle cells present in the walls of the plexiform lesions. To enhance the staining and to facilitate the observation, we used a microwave-based antigen unmasking technique. The lack of estrogen receptors and the presence of PR could have increased, in the case, the sensitivity of the pulmonary muscular arteries to vasoconstrictory compounds. We hypothesize that on this substrate of a presumptive steroid-mediated vasoconstriction the sequence of the histologic lesions characteristic of pulmonary vascular hypertensive disease could have developed.

Detection of Ki-67 proliferation rate in breast cancer. Correlation with clinical and pathologic features.

In situ determination of proliferative activity was performed on 203 breast cancers by use of Ki-67 monoclonal antibody and immunohistochemical methods. Tumor proliferation rate was analyzed and correlated to tumor size and nodal status. The relationship between Ki-67 proliferative activity and nuclear estrogen receptor content was also investigated on adjacent tissue sections. Ki-67 values ranged from 1 to 75%, with a median value of 10%. Premenopausal patients had greater Ki-67 values (median value, 14.1%) than postmenopausal ones (median value, 9.8%). The authors observed no correlation with lymph nodal involvement, whereas a statistically significant relationship with tumor size was found (P less than 0.01). An inverse correlation (Spearman's coefficient = -0.56; P less than 0.001) was seen between Ki-67 values and nuclear estrogen receptor content. These results, similar to those reported for other kinetic measurements, suggest that in situ detection of Ki-67 proliferation rate is a useful method for obtaining cell cycle information. Follow-up studies will be needed to assess an eventual prognostic relevance.