Risk factors for chemotherapy-induced neutropenia occurrence in breast cancer patients: data from the INC-EU Prospective Observational European Neutropenia Study

Background: Chemotherapy-induced neutropenia (CIN) places patients at risk of life-threatening infections. While reduction of chemotherapy dose or delay of the subsequent treatment cycle and, consequently, reduction of relative dose intensity (RDI) may limit myelotoxicity, these actions can also impact adversely on treatment outcome and should be avoided in adjuvant settings. Patients and methods: Based on data from 444 breast cancer patients in the INC-EU Prospective Observational European Neutropenia Study, we have evaluated patient-specific and treatment-specific factors that impact on the incidence of grade 4 CIN (absolute neutrophil count <0.5 × 109/L), either during the first or in any cycle of (neo)adjuvant chemotherapy, across a range of regimens and doses. Results: Using multivariate logistic regression analysis, risk factors for grade 4 CIN were identified as older age, lower weight, higher planned dose intensity of doxorubicin, epirubicin, or docetaxel, higher number of planned cycles, vascular comorbidity, lower baseline white blood cell count, and higher baseline bilirubin. Use of colony-stimulating factor before a neutropenic event occurred, dose delays, and dose reductions were protective against grade 4 CIN. Conclusions: By identifying risk factors for grade 4 CIN, CSF prophylaxis may be appropriately targeted to prevent low RDI in patients treated with curative inten

Accelerated growth of orbital schwannomas during pregnancy does not correlate with sex hormone- or growth factor receptor status

Purpose: Until now, three cases of growth of an orbital schwannoma during pregnancy have been published. We aim to provide additional insight in the effect of pregnancy on orbital schwannomas. Methods: We present two additional cases of accelerated growth of orbital schwannomas during pregnancy and investigate receptor expression profiles for estrogen, progesterone, androgen, VEGF, EGF, FGF, PDGF-Rβ and ki-67 in the two pregnant cases and six non-pregnant cases. Results: Case 1: A 26-year-old woman developed unilateral exophthalmos during pregnancy, with normal visual acuity and ocular motility. During a subsequent pregnancy, again the exophthalmos progressed. MRI showed a mass suggestive of schwannoma. After delivery, resection of the lesion was performed through an anterior approach. Pathology confirmed schwannoma. The expression profile was positive for estrogen- and FG

Cellular angiofibroma of the orbit

Cellular angiofibroma is a benign mesenchymal tumor most commonly located in the distal genital tract of both men and women. Although extragenital locations have been reported rarely, this is the first report of cellular angiofibroma of the orbit. A 58-year-old man presented with a mass in the left superomedial orbit since 2 years. Magnetic resonance imaging showed a well-demarcated lesion with a homogeneous intermediate signal intensity on both T1- and T2-weighted images, homogeneous contrast enhancement and high signal intensity on diffusion-weighted images. Complete excision was performed through a medial upper eyelid crease incision. Histopathology showed a vascular CD34-positive and STAT6-negative spindle cell tumor with monoallelic loss of FOXO1, indicating cellular angiofibroma

Histopathological and Molecular Features of a Conjunctival Caruncular Deep Penetrating Nevus

We describe the first presentation of a deep penetrating nevus (DPN) on the lacrimal caruncle. This lesion was seen in an 18-year-old woman presenting with hemorrhage of a long-standing pigmented mass on the caruncle. Histology showed a combined melanocytic neoplasm that consisted of two different melanocytic components. The differential diagnosis, based on histological examination, was a conventional melanocytic nevus, a Spitz nevus, or a combined melanocytic nevus. On the molecular level, one of the components revealed a mutation in the CTNNB

Neutropenic event risk and impaired chemotherapy delivery in six European audits of breast cancer treatment

Goals of work: The aims of this study were to assess chemotherapy treatment characteristics, neutropenic event (NE) occurrence and related risk factors in breast cancer patients in Western Europe. Materials and methods: Six retrospective audits of breast cancer chemotherapy were combined into a dataset of 2,860 individuals. NEs were defined as neutropenia-related hospitalisation, dose reduction ≥15% or dose delay ≥7days. Summation dose intensity (SDI) was calculated to compare different types of chemotherapy regimens on a single scale. Risk factors of NE occurrence and of low relative dose intensity (RDI) ≤85% were identified by multiple logistic regression. Main results: Patient populations were comparable between audits. Until 1998, cyclophosphamide, methotrexate and fluorouracil regimens were most frequently used, but thereafter, anthracycline-based regimens were most common. NEs occurred in 20% of the patients and low RDI in 16%. NE occurrence predicted low RDI and was associated with higher age, bigger body surface area, lower body mass index, regimen type, more chemotherapy cycles planned, normal to high SDI, concomitant radiotherapy and year of treatment. First cycle NE occurrence predicted NEs from cycle 2 onwards. A risk score using age, SDI, number of planned chemotherapy cycles and concomitant radiotherapy differentiated patients with increasing NE risk (9-37%). An alternative score version not using concomitant radiotherapy performed moderately less well. Conclusions: NEs occurred frequently in this combined dataset and they affected treatment delivery. Identifying patients at high NE risk enables targeted prophylaxis and may avoid dose limitation

Diplopia as the First Sign of Gastric Carcinoma

Orbital metastasis may be the initial manifestation of a malignancy of unknown origin. The primary locations of orbital metastasis are usually the lung, prostate, gastrointestinal tract, skin, kidney, eye, or thyroid gland. Metastasis of gastric carcinoma to an extraocular eye muscle is extremely rare. A solitary thickening in an extraocular eye muscle with no inflammatory features is suspect for a tumor. Symptoms such as diplopia, proptosis, ptosis, vision loss, or pain may be associated with an orbital malignancy. Our patient, a 67-year-old man known with radically resected prostate cancer, presented with complaints of vertigo with a tendency to fall, headache, and diplopia when looking to the right. As a coincidental finding, swelling of the rectus lateralis muscle of the left eye was observed on imaging. Extensive additional investigations showed that a gastric carcinoma with intraorbital and leptomeningeal metastasis was the cause. In conclusion, a solitary thickened extraocular eye muscle should be recognized in time and examined further

Plasma MMP1 and MMP8 expression in breast cancer: Protective role of MMP8 against lymph node metastasis

<p>Abstract</p> <p>Background</p> <p>Elevated levels of matrix metalloproteinases have been found to associate with poor prognosis in various carcinomas. This study aimed at evaluating plasma levels of MMP1, MMP8 and MMP13 as diagnostic and prognostic markers of breast cancer.</p> <p>Methods</p> <p>A total of 208 breast cancer patients, of which 21 with inflammatory breast cancer, and 42 healthy controls were included. Plasma MMP1, MMP8 and MMP13 levels were measured using ELISA and correlated with clinicopathological characteristics.</p> <p>Results</p> <p>Median plasma MMP1 levels were higher in controls than in breast cancer patients (3.45 vs. 2.01 ng/ml), while no difference was found for MMP8 (10.74 vs. 10.49 ng/ml). ROC analysis for MMP1 revealed an AUC of 0.67, sensitivity of 80% and specificity of 24% at a cut-off value of 4.24 ng/ml. Plasma MMP13 expression could not be detected. No correlation was found between MMP1 and MMP8 levels. We found a trend of lower MMP1 levels with increasing tumour size (p = 0.07); and higher MMP8 levels with premenopausal status (p = 0.06) and NPI (p = 0.04). The median plasma MMP1 (p = 0.02) and MMP8 (p = 0.007) levels in the non-inflammatory breast cancer patients were almost twice as high as those found in the inflammatory breast cancer patients. Intriguingly, plasma MMP8 levels were positively associated with lymph node involvement but showed a negative correlation with the risk of distant metastasis. Both controls and lymph node negative patients (pN0) had lower MMP8 levels than patients with moderate lymph node involvement (pN1, pN2) (p = 0.001); and showed a trend for higher MMP8 levels compared to patients with extensive lymph node involvement (pN3) and a strong predisposition to distant metastasis (p = 0.11). Based on the hypothesis that blood and tissue protein levels are in reverse association, these results suggest that MMP8 in the tumour may have a protective effect against lymph node metastasis.</p> <p>Conclusion</p> <p>In summary, we observed differences in MMP1 and MMP8 plasma levels between healthy controls and breast cancer patients as well as between breast cancer patients. Interestingly, our results suggest that MMP8 may affect the metastatic behaviour of breast cancer cells through protection against lymph node metastasis, underlining the importance of anti-target identification in drug development.</p

Meta-analyses of Phase 3 randomised controlled trials of third generation aromatase inhibitors versus tamoxifen as first-line endocrine therapy in postmenopausal women with hormone receptor-positive advanced breast cancer

Background Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8%–55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. MethodsAnonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. FindingsThe OR for clinical benefit rate was 1·56, in favour of AIs (p[less than] 0·001). The duration of clinical benefit was not significantly increased by AIs (hazard ratio [HzR] 0·88; p=0·08). For PFS the HzR (0·82) was in favour of AIs (p=0·007). However, for OS the HzR (1·05) was not significantly different between AIs and tamoxifen (p=0·42).InterpretationAlthough third generation AIs put significantly more patients into ‘clinical benefit’, their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS

The Gene expression Grade Index: a potential predictor of relapse for endocrine-treated breast cancer patients in the BIG 1–98 trial

<p>Abstract</p> <p>Background</p> <p>We have previously shown that the Gene expression Grade Index (GGI) was able to identify two subtypes of estrogen receptor (ER)-positive tumors that were associated with statistically distinct clinical outcomes in both untreated and tamoxifen-treated patients. Here, we aim to investigate the ability of the GGI to predict relapses in postmenopausal women who were treated with tamoxifen (T) or letrozole (L) within the BIG 1–98 trial.</p> <p>Methods</p> <p>We generated gene expression profiles (Affymetrix) and computed the GGI for a matched, case-control sample of patients enrolled in the BIG 1–98 trial from the two hospitals where frozen samples were available. All relapses (cases) were identified from patients randomized to receive monotherapy or from the switching treatment arms for whom relapse occurred before the switch. Each case was randomly matched with four controls based upon nodal status and treatment (T or L). The prognostic value of GGI was assessed as a continuous predictor and divided at the median. Predictive accuracy of GGI was estimated using time-dependent area under the curve (AUC) of the ROC curves.</p> <p>Results</p> <p>Frozen samples were analyzable for 48 patients (10 cases and 38 controls). Seven of the 10 cases had been assigned to receive L. Cases and controls were comparable with respect to menopausal and nodal status, local and chemotherapy, and HER2 positivity. Cases were slightly older than controls and had a larger proportion of large, poorly differentiated ER+/PgR- tumors. The GGI was significantly and linearly related to risk of relapse: each 10-unit increase in GGI resulted in an increase of approximately 11% in the hazard rate (p = 0.02). Within the subgroups of patients with node-positive disease or who were treated with L, the hazard of relapse was significantly greater for patients with GGI at or above the median. AUC reached a maximum of 78% at 27 months.</p> <p>Conclusion</p> <p>This analysis supports the GGI as a good predictor of relapse for ER-positive patients, even among patients who receive L. Validation of these results, in a larger series from BIG 1–98, is planned using the simplified GGI represented by a smaller set of genes and tested by qRT-PCR on paraffin-embedded tissues.</p