Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer

The association between tumour shrinkage and reduction in kinetic cell activity after primary chemotherapy in human breast cancer is still a matter of investigation. 157 patients with T2-4, N0-1, M0 breast cancer received primary chemotherapy consisting of either the CMF regimen + tamoxifen (the first consecutive 76 cases) or the single agent epirubicin (the subsequent 81). Ki67, p53, bcl2, c-erbB2 and steroid hormone receptors were evaluated immunohistochemically in tumour specimens obtained before chemotherapy and at surgery. Tumour shrinkage of >50% occurred in 72.4% of patients. Ki67 expression significantly decreased after chemotherapy; the reduction correlated with tumour response in both univariate (P < 0.005) and multivariate analysis (P = 0.02). p53, bcl-2, steroid hormone receptor and c-erbB2 immunostaining were scarcely affected. Baseline bcl2 (P = 0.04) and c-erbB2 (P = 0.02) were directly and inversely associated with the reduction in Ki67 immunostaining, respectively. Baseline p53 expression (P < 0.01) was directly related with Ki67 expression at residual tumour, whereas oestrogen receptor expression (P < 0.001) was inversely related. Ki67 at residual tumour was a better predictor for relapse-free survival (RFS) than baseline Ki67. Clinical response (P < 0.03), but not reduction in Ki67, was a significant independent predictor for disease recurrence. Chemotherapy was found to induce tumour shrinkage and to reduce the number of cells in the cell cycle, but its effect on tumour biology/aggressiveness was minimal. Reduction in Ki67 immunostaining correlated with clinical response but failed to be related to RFS. Ki67 expression at surgery rather than at baseline appears to be a better predictor for disease relapse. © 2001 Cancer Research Campaign  http://www.bjcancer.co

A phase II multi-institutional study assessing simultaneous in-field boost helical tomotherapy for 1-3 brain metastases

<p>Abstract</p> <p>Background</p> <p>Our research group has previously published a dosimetric planning study that demonstrated that a 60 Gy/10 fractions intralesional boost with whole-brain radiotherapy (WBRT) to 30 Gy/10 fractions was biologically equivalent with a stereotactic radiosurgery (SRS) boost of 18 Gy/1 fraction with 30 Gy/10 fractions WBRT. Helical tomotherapy (HT) was found to be dosimetrically equivalent to SRS in terms of target coverage and superior to SRS in terms of normal tissue tolerance. A phase I trial has been now completed at our institution with a total of 60 enrolled patients and 48 evaluable patients. The phase II dose has been determined to be the final phase I cohort dose of 60 Gy/10 fractions.</p> <p>Methods/Design</p> <p>The objective of this clinical trial is to subject the final phase I cohort dose to a phase II assessment of the endpoints of overall survival, intracranial control (ICC) and intralesional control (ILC). We hypothesize HT would be considered unsuitable for further study if the median OS for patients treated with the HT SIB technique is degraded by 2 months, or the intracranial progression-free rates (ICC and ILC) are inferior by 10% or greater compared to the expected results with treatment by whole brain plus SRS as defined by the RTOG randomized trial. A sample size of 93 patients was calculated based on these parameters as well as the statistical assumptions of alpha = 0.025 and beta = 0.1 due to multiple statistical testing. Secondary assessments of toxicity, health-related quality-of-life, cognitive changes, and tumor response are also integrated into this research protocol.</p> <p>Discussion</p> <p>To summarize, the purpose of this phase II trial is to assess this non-invasive alternative to SRS in terms of central nervous system (CNS) control when compared to SRS historical controls. A follow-up phase III trial may be required depending on the results of this trial in order to definitively assess non-inferiority/superiority of this approach. Ultimately, the purpose of this line of research is to provide patients with metastatic disease to the brain a shorter course, dose intense, non-invasive radiation treatment with equivalent or improved CNS control/survival and health-related quality-of-life/toxicity profile when compared to SRS radiotherapy.</p> <p>Trial registration</p> <p>Clinicaltrials.gov - <a href="http://www.clinicaltrials.gov/ct2/show/NCT01543542">NCT01543542</a>.</p

Pretreatment haemoglobin levels significantly predict the tumour response to primary chemotherapy in human breast cancer

The purpose of this study was to evaluate whether tumour response to primary chemotherapy in human breast cancer is influenced by baseline haemoglobin (Hb) status. A total of 157 patients with T2-4, N0-1 M0 breast cancer were treated with chemotherapy consisting of either the CMF regimen + tamoxifen (the first 76 cases) or the single-agent epirubicin (the subsequent 81) before definitive surgery. In total, 144 patients were fully assessable. Ki67, p53, bcl-2, c-erbB2, steroid hormone receptor, and microvessel density were evaluated immunohistochemically in tumour specimens obtained before chemotherapy and at surgery. Tumour shrinkage >50% occurred in 72.1% of patients. Responding patients had higher baseline Hb levels and red blood cell counts than nonresponders (P<0.01 and <0.003, respectively). The distribution of disease response according to increasing cutoffs of baseline Hb status showed that from 12.5 mg l(-1) onwards, patients with Hb levels above the cutoff obtained a greater response rate than those with lower Hb values. The difference attained the statistical significance at 12.5 (76.1 vs 59.5%, P<0.05) and 13.0 g/dl(-1) (81.0 vs 57.6%, P<0.002) cutoffs, respectively. The predictive role of Hb levels was maintained in multivariate analysis after adjustment for clinical and biological characteristics and treatment regimen. Patients with baseline Hb levels </=13 g dl(-1) showed a lower treatment-induced reduction in Ki67 expression (P<0.04) and a higher Ki67 expression at postoperative evaluation (P<0.02) than their counterparts. In conclusion, low Hb levels may negatively influence the response rate of chemotherapy in breast cancer patients. Inhibition of antiproliferative activity could be a possible mechanism

Proton Therapy for Intracranial Meningioma for the Treatment of Primary/Recurrent Disease Including Re-Irradiation

Meningeal tumors represent approximately 10–25% of primary brain tumors and occur usually in elderly female patients. Most meningiomas are benign (80–85%) and for symptomatic and/or large tumors, surgery, with or without radiation therapy (RT), has been long established as an effective means of local tumor control. RT can be delivered to inoperable lesions or to those with non-benign histology and for Simpson I–III and IV–V resection. RT can be delivered with photons or particles (protons or carbon ions) in stereotactic or non-stereotactic conditions. Particle therapy delivered for these tumors uses the physical properties of charged carbon ions or protons to spare normal brain tissue (i.e. Bragg peak), with or without or a dose-escalation paradigm for non-benign lesions. PT can substantially decrease the dose delivered to the non-target brain tissues, including but not limited to the hippocampi, optic apparatus or cochlea. Only a limited number of meningioma patients have been treated with PT in the adjuvant or recurrent setting, as well as for inoperable lesions with pencil beam scanning and with protons only. Approximately 500 patients with image-defined or WHO grade I meningioma have been treated with protons. The reported outcome, usually 5-year local tumor control, ranges from 85 to 99% (median, 96%). For WHO grade II or III patients, the outcome of only 97 patients has been published, reporting a median tumor local control rate of 52% (range, 38–71.1). Only 24 recurring patients treated previously with photon radiotherapy and re-treated with PT were reported. The clinical outcome of these challenging patients seems interesting, provided that they presented initially with benign tumors, are not in the elderly category and have been treated previously with conventional radiation dose of photons. Overall, the number of meningioma patients treated or-re-irradiated with this treatment modality is small and the clinical evidence level is somewhat low (i.e. 3b–5). In this review, we detail the results of upfront PT delivered to patients with meningioma in the adjuvant setting and for inoperable tumors. The outcome of meningioma patients treated with this radiation modality for recurrent tumors, with or without previous RT, will also be reviewed.</jats:p

Proton Therapy for Intracranial Meningioma for the Treatment of Primary/Recurrent Disease Including Re-Irradiation

Meningeal tumors represent approximately 10-25% of primary brain tumors and occur usually in elderly female patients. Most meningiomas are benign (80-85%) and for symptomatic and/or large tumors, surgery, with or without radiation therapy (RT), has been long established as an effective means of local tumor control. RT can be delivered to inoperable lesions or to those with non-benign histology and for Simpson I-III and IV-V resection. RT can be delivered with photons or particles (protons or carbon ions) in stereotactic or non-stereotactic conditions. Particle therapy delivered for these tumors uses the physical properties of charged carbon ions or protons to spare normal brain tissue (i.e. Bragg peak), with or without or a dose-escalation paradigm for non-benign lesions. PT can substantially decrease the dose delivered to the non-target brain tissues, including but not limited to the hippocampi, optic apparatus or cochlea. Only a limited number of meningioma patients have been treated with PT in the adjuvant or recurrent setting, as well as for inoperable lesions with pencil beam scanning and with protons only. Approximately 500 patients with image-defined or WHO grade I meningioma have been treated with protons. The reported outcome, usually 5-year local tumor control, ranges from 85 to 99% (median, 96%). For WHO grade II or III patients, the outcome of only 97 patients has been published, reporting a median tumor local control rate of 52% (range, 38-71.1). Only 24 recurring patients treated previously with photon radiotherapy and re-treated with PT were reported. The clinical outcome of these challenging patients seems interesting, provided that they presented initially with benign tumors, are not in the elderly category and have been treated previously with conventional radiation dose of photons. Overall, the number of meningioma patients treated or-re-irradiated with this treatment modality is small and the clinical evidence level is somewhat low (i.e. 3b-5). In this review, we detail the results of upfront PT delivered to patients with meningioma in the adjuvant setting and for inoperable tumors. The outcome of meningioma patients treated with this radiation modality for recurrent tumors, with or without previous RT, will also be reviewed

The “mystery” of the train station: The importance of a forensic approach to a rare case of survival after a train-pedestrian collision

In the early morning a 28-year-old man was found lying on the tracks of a railway station with head injuries and fractures of the cervical spine resulting in permanent quadriplegia. He was in a club about 1 km away until about 2&nbsp;h earlier and did not have any recollection of what could have happened. Was he the victim of an assault, did he fall down or was he hit by a passing train? The solution to this "mystery" came from a forensic evaluation that included the forensic branches of pathology, chemistry, merceology and genetics as well as the scene evaluation. Through these different steps, the role of a railway collision in determining the injuries was ascertained and a possible dynamic was postulated. The presented case is an expression of the importance of the different forensic disciplines and the difficulties the forensic pathologist encounters when analysing such peculiar and rare cases

Abstract P3-12-13: Breast Cancer Genomic Profile in a Consecutive Series of a Breast Healthcare Service in South Brazil

Abstract Background: Prognostic factors, such as breast cancer (BC) genomic profile, are cornerstone for the understanding of the disease, especially in the orientation of its treatment. The majority of studies reporting BC genomic profile were conducted in developed countries. Research in the developing world is needed, in order to investigate if BC profile in these countries is similar to the one seen in the developed world. Moreover, it is important to evaluate possible differences in the genomic profile between pre-and post-menopausal women. Finally, it is also important to appraise if there was any temporal trend in BC genomic profile in the last decade. Methods: A consecutive sample of patients who were diagnosed with BC between 2000 and 2010 were analyzed. All patients were diagnosed and treated at Núcleo Mama Moinhos, a specialized BC service in South Brazil. Comparisons were made between women below and above the age of 50, and between the period of 2000-2005 and 2006-2010. The Fisher exact test was used for comparisons. Ki-67 was considered as positive when &amp;gt; 5%. Results: 439 patients were included. Mean age was 55 ± 13 years, 37% of the sample was younger than 50 years old and 10% than 40 years old. 57% were diagnosed between 2000-2005 and 43% between 2006-2010. Tumor staging was as follows: 61% stage 0/I, 22% stage IIA, 9% stage IIB, 7% stage III and 1% stage IV. Median tumor size was 1.6 cm (IQR 1.0 — 2.5), 26% of patients had positive lymph nodes. 75% were invasive ductal carcinomas and 10% were in situ ductal carcinomas. Tumor histologic grades were as follows: 15% grade I, 42% grade 2 and 22% grade 3. Surgery type was mastectomy in 43.5% and setorectomy in the remainder. 56% of patients were submitted to chemotherapy, of which 25% were neoadjuvant. Regarding the genomic profile, 82% of the sample had positive estrogen receptor (ER) or progesterone receptor (PR), 18% were HER2 positive, and 11% were triple negative. Ki 67 was positive in 68% of the sample, median value was 10% (IQR 5% — 20%); p53 mutation was seen in 26%. When compared to patients diagnosed between 2000-2005, the sample from 2006-2010 had a lower prevalence of hormone receptors (76% vs 86%, p = 0.01) and a higher proportion of triple negative cases (16% vs 8%, p=0.01). This difference was more marked in women below the age of 50 (6% until 2005 and 18% afterwards, p = 0.02). There were no other temporal trends in the other evaluated variables (staging, histologic grade and type, age, HER2, type of surgery). In the comparison of women diagnosed after versus before 50 years of age, the former had a more favorable staging: 86% were in stages 0/I/IIA, as compared to 78% in the latter (p=0.03). Conclusions: The profile seen in this population has some similarities with other series from developed countries. The increase in triple negative and hormone negative tumors in women older than 50 is worrisome and does not reflect the common sense that the large majority of cases in this age group are hormone sensible. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-13.</jats:p