The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment.

The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines for HER2 assessment have increased the number of HER2 equivocal breast carcinomas following in situ hybridization reflex testing, that is, HER2 "double equivocal" (equivocal protein expression and equivocal gene copy number). Forty-five double-equivocal carcinomas were subjected to Prosigna analysis. Twenty-seven cases were investigated for the expression of genes found to be differentially expressed between estrogen receptor (ER)-positive/HER2-positive (N=22) and ER-positive/HER2-negative (N=22) control cases. Twenty-nine of the 45 cases were also analyzed by targeted sequencing using a panel of 14 genes. We then explored the pathologic complete response rates in an independent series of double-equivocal carcinoma patients treated with trastuzumab-containing chemotherapy. All cases were ER-positive, with a mean Ki67 of 28%. Double-equivocal carcinomas were predominantly luminal B (76%); 9 cases (20%) were luminal A, and 2 cases (4%) HER2-enriched. The majority (73%) showed a high risk of recurrence by Prosigna, even when the carcinomas were small (<2 cm), node-negative/micrometastatic, and/or grade 2. Double-equivocal carcinomas showed TP53 (6/29, 20%), PIK3CA (3/29, 10%), HER2 (1/29, 3%), and MAP2K4 (1/29, 3%) mutations. Compared with grade-matched ER-positive/HER2-negative breast carcinomas from METABRIC, double-equivocal carcinomas harbored more frequently TP53 mutations and less frequently PIK3CA mutations (P<0.05). No significant differences were observed with grade-matched ER-positive/HER2-positive carcinomas. Lower pathologic complete response rates were observed in double-equivocal compared with HER2-positive patients (10% vs. 60%, P=0.009). Double-equivocal carcinomas are preferentially luminal B and show a high risk of recurrence. A subset of these tumors can be labeled as HER2-enriched by transcriptomic analysis. HER2 mutations can be identified in HER2 double-equivocal cases.

[A case of pulmonary artery sarcoma and review of the literature]. / Un caso di angiosarcoma polmonare e revisione della letteratura.

Pulmonary artery sarcoma (PAS) is a highly malignant tumor that originates in the pulmonary artery. This disease has a poor prognosis. Early diagnosis followed by radical surgical resection constitutes the only chance of survival for patients. However, owing to the rare and nonspecific clinical manifesta-tions and imaging findings, PAS is frequently misdiagnosed as various pulmonary thromboembolic diseases. We report the case of a 49-year-old woman who presented to our emergency department for dyspnea, hemoptysis, cough, and asthenia. A diagnosis of pulmonary thromboembolism was initially postulated. However, the rapid clinical progression of the disease, characterized by multiorgan involvement, together with the persistence of pulmonary filling defects despite appropriate anticoagulation therapy, induced to a late diagnosis of metastasized PAS. The peculiarity of our case consists of two main factors: the first is the atypical clinical presentation characterized by severe neurological impairment that finally led to patient's death; the second is the histopathological aspect of the lesion with a prevalent histiocytic cell component that is described in the literature as the less frequent pathological variant of this tumor.

Does accelerated hypofractionated adjuvant whole-breast radiotherapy increase mammographic density or change mammographic features?

OBJECTIVE: To compare mammographic features before and after accelerated hypofractionated adjuvant whole-breast radiotherapy (AWB-RT) and to evaluate possible appearance of modifications. METHODS: A retrospective review of 177 females before and after an AWB-RT treatment (follow-up ranging from 5 to 9 years) was performed by four radiologists focused in breast imaging who independently evaluated diffuse mammographic density patterns and reported on possible onset of focal alterations; modifications in density and fibrosis with parenchymal distortion were deemed as indicators of AWB-RT treatment impact in breast imaging. RESULTS: Prevalent mammographic density (D) patterns in the 177 females evaluated were according to the American College of Radiology-Breast Imaging Reporting and Data System (ACR-BIRADS): D1, fibroadipose density (score percentage from 55.9% to 43.5%); and D2, scattered fibroglandular density (from 42.9% to 32.7%). No change in diffuse mammographic density and no significant difference in mammographic breast parenchymal structure were observed. "No change" was reported with score percentage from 87% to 79.6%. Appearance of fibrosis with parenchymal distortion was reported by all radiologists in only two cases (1.1%, p = 0.3); dystrophic calcification was identified with percentage score from 2.2% to 3.3% (small type) and from 9.6% to 12.9% (coarse type). CONCLUSION: No statistically significant changes in follow-up mammographies 5-9 years after AWB-RT were detected, justifying large-scale selection of AWB-RT treatment with no risk of altering radiological breast parameters of common use in tumour recurrence detection. ADVANCES IN KNOWLEDGE: The hypofractionated radiotherapy (AWB-RT treatment) is a new proven, safe and effective modality in post-operative patients with early breast cancer with excellent local control and survival. In our study, the absence of changes in mammographic density patterns and in breast imaging before and after AWB-RT treatment (up to 5-9 years after radiotherapy) justifies large-scale use of AWB-RT treatment without hindrance in tumour recurrence diagnosis.

Gene status in HER2 equivocal breast carcinomas: impact of distinct recommendations and contribution of a polymerase chain reaction-based method.

BACKGROUND: The primary objectives of this study on carcinomas with equivocal HER2 expression were to assess the impact of distinct recommendations with regard to identifying patients eligible for anti-HER2 agents by fluorescence in situ hybridization (FISH) and to elucidate whether multiplex ligation-dependent probe amplification (MLPA) may be of support in assessing HER2 gene status. METHODS: A cohort of 957 immunohistochemistry-evaluated HER2-equivocal cases was analyzed by dual-color FISH. The results were assessed according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) 2007 and 2013 guidelines for dual- and single-signal in situ hybridization (ISH) assays. A subgroup of 112 cases was subjected to MLPA. RESULTS: HER2 amplification varied from 15% (ASCO/CAP 2007 HER2/CEP17 ratio) to 29.5% (FDA/EMA HER2 copy number). According to the ASCO/CAP 2013 interpretation of the dual-signal HER2 assay, ISH-positive carcinomas accounted for 19.7%. In contrast with the ASCO/CAP 2007 ratio, this approach labeled as positive all 32 cases (3.34%) with a HER2/CEP17 ratio <2 and an average HER2 copy number ≥6.0 signals per cell. In contrast, only one case showing a HER2 copy number <4 but a ratio ≥2 was diagnosed as positive. MLPA data correlated poorly with FISH results because of the presence of heterogeneous HER2 amplification in 33.9% of all amplified carcinomas; however, MLPA ruled out HER2 amplification in 75% of ISH-evaluated HER2-equivocal carcinomas. CONCLUSION: The ASCO/CAP 2013 guidelines seem to improve the identification of HER2-positive carcinomas. Polymerase chain reaction-based methods such as MLPA can be of help, provided that heterogeneous amplification has been ruled out by ISH.

[Neurendocrine tumours of the appendix, colon and rectum: current surgical aspects]. / Attualità nella chirurgia dei tumori neuroendocrini dell'appendice, del colon e del retto.

Neuroendocrine tumours (NET) are a heterogeneous group of neoplasms deriving from a system of diffuse neuroendocrine cells in organs and tissues, defined as the "diffuse neuroendocrine system". Over the period from 1996 to 2005 42 patients with gastroenteropancreatic (GEP) NET were observed (M.F ratio: 1.5:1; mean age 58 years; > 60 years for all localisations except the appendix [< 39 years]). Twenty-three were tumours of the appendix, colon and rectum, corresponding to 55% of all those affecting the digestive tract: 8 appendix (35%), 6 right colon (26%), 4 left colon (17%) and 5 rectum (22%). The NET diagnosis was formulated in all cases on the basis of histological and immunohistochemical examinations. The mean follow-up period was 5 years (range: 1-10). In the RO-RI cases no relapses occurred and those who were not disease-free were treated with somatostatin analogues and/or chemotherapy. NET of the appendix, colon and rectum are rare, despite being the most frequent among the GEP tumours, and are difficult to diagnose, and therefore sometimes pose problems of surgical therapy, which, when performed in time, may be curative. NET of the appendix measuring <2 cm, localised in the distal part without local infiltration, can be treated by simple appendicectomy and removal of the mesenteriole; otherwise, right hemicolectomy is indicated. The surgical treatment of tumours of the colon, except for well differentiated cases measuring <2 cm with a pedunculate structure such as to allow safe endoscopic removal, consists in radical hemicolectomy with lymphadenectomy. Carcinoids of the rectum measuring <1 cm and 1 cm to 2 cm, in the absence of other negative prognostic factors, can be treated locally by transanal endoscopic microsurgery (TEM) or minimally invasive transanal surgery (MITAS). Tumours measuring >2 cm or presenting muscular invasion and/or lymph-node metastases (malignant carcinoids), regardless of tumour diameter, are submitted to radical operations, as in the case of carcinoma of the rectum. Extensive disease which is no longer curable with surgery alone is treated with chemotherapy and bio-chemotherapy, but it is above all treatment with somatostatin analogues that plays a major role in symptom control.

Extremely low frequency-modulated static magnetic fields to treat cancer: A pilot study on patients with advanced neoplasm to assess safety and acute toxicity.

Results of a toxicity pilot human study approved by the competent ethical Committee are reported. Eleven patients with heavily pre-treated advanced cancer were enrolled in a pilot study with different schedules of time exposure to static magnetic fields (MF), amplitude modulated by ELF. An area including the neck, thoracic and abdomen was MF exposed daily, 5 days/week for 4 weeks according to two different schedules: 20 min daily (4 patients) and 70 min daily (7 patients). ECOG performance status was 1 (2 patients), 2 (8 patients), 3 (1 patient). Toxicity was assessed according to WHO criteria. ECG, Chest X-ray, physical examination, blood cell count and complete blood chemistry were performed before and at the end of the treatment. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation (grade 2 toxicity) in 1 patient and microscopic urinary abnormalities in 5 patients were the only negative effects observed. We conclude that MF can be safely administrated according to the MF exposure schedules.

Impact of the AutoPap (currently Focalpoint) primary screening system location guide use on interpretation time and diagnosis.

BACKGROUND: AutoPap (currently Focalpoint) is a computerized scanning system for the primary screening of cervicovaginal smears. For smears indicated to require further review, the system provides maps (PapMaps) to identify the most abnormal areas of the smear. METHODS: To study the effect of PapMaps on diagnosis, 481 smears (from 4656 successfully processed smears using AutoPap) were first classified by conventional manual interpretation and then reinterpreted blind by the same cytologist who limited his examination to only the fields of view marked by the PapMaps. The interpretation time with and without PapMaps was measured on another simple random sample of 188 smears. RESULTS: The interpretation time was reduced significantly, by approximately 40% using PapMaps (average reduction, 136 seconds per smear, 95% confidence interval [CI], 123-150). No cases manually classified as low-grade squamous intraepithelial lesions (LSIL) or worse and 20% of those manually classified as atypical squamous cells of undertermined significance (ASCUS) were judged as completely normal on the basis of fields of visions marked by PapMaps. In none of the latter was a histologically confirmed intraepithelial lesion identified. In relation to detailed diagnosis, the weighted kappa between manual and PapMap-aided interpretation was 0.745 (95% CI 0.687-0.804). Systematic differences were found (symmetry chi-square(10d.f) =19.11, P = 0.039): 48% of smears classified as ASCUS and 23% classified as LSIL by conventional diagnosis were classified as less severe (including normal) on the basis of PapMaps. CONCLUSIONS: Use of PapMaps resulted in a substantial reduction in interpretation time. PapMaps showed good sensitivity (100% for squamous intraepithelial lesions and 80% for ACSUC) for selecting abnormal slides. The latter require full examination: detailed diagnosis based only on areas marked by PapMaps could lead to under-grading.

Increased mouse survival, tumor growth inhibition and decreased immunoreactive p53 after exposure to magnetic fields.

The possibility that magnetic fields (MF) cause antitumor activity in vivo has been investigated. Two different experiments have been carried out on nude mice bearing a subcutaneous human colon adenocarcinoma (WiDr). In the first experiment, significant increase in survival time (31%) was obtained in mice exposed daily to 70 min modulated MF (static with a superimposition of 50 Hz) having a time average total intensity of 5.5 mT. In the second independent experiment, when mice bearing tumors were exposed to the same treatment for four consecutive weeks, significant inhibition of tumor growth (40%) was reported, together with a decrement in tumor cell mitotic index and proliferative activity. A significant increase in apoptosis was found in tumors of treated animals, together with a reduction in immunoreactive p53 expression. Gross pathology at necroscopy, hematoclinical/hematological and histological examination did not show any adverse or abnormal effects. Since pharmacological rescue of mutant p53 conformation has been recently demonstrated, the authors suggest that MF exposure may obtain a similar effect by acting on redox chemistry connected to metal ions which control p53 folding and its DNA-binding activity. These findings support further investigation aimed at the potential use of magnetic fields as anti-cancer agents.