Durable remission in a patient with leptomeningeal relapse of a MYC/BCL6-positive double-hit DLBCL treated with lenalidomide monotherapy

Secondary central nervous system involvement is an uncommon event that typically occurs early in the natural history of diffuse large B-cell lymphoma and presents as leptomeningeal dissemination in two-thirds of cases. The prognosis of this event is dismal, and treatment options are meagre. Although major validated risk factors for central nervous system dissemination are clinical, concomitant MYC/BCL2 rearrangements as well as MYC/BCL2 protein expression have been recently associated with an increased risk of this complication. Here we present the first case, to our knowledge, of a MYC/BCL6-positive double-hit diffuse large B-cell lymphoma relapsing in the leptomeninges that achieved an outstanding durable remission with single-agent lenalidomide following salvage chemotherapy

Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management

The assessment of hormone receptors (HRs) and human epidermal growth factor receptor (HER)-2 is necessary to select patients who are candidates for hormonal and anti-HER-2 therapy. The evaluation of these parameters is generally carried out in primary tumors and it is not clear if reassessment in metastatic lesions might have an impact on patient management. The primary aim of this analysis was to compare HER-2 and HR status in primary tumors versus metastatic sites in breast cancer patients. PATIENTS AND METHODS: Seventy-five patients with available samples from primary tumors and paired metastases were included. HER-2 status was evaluated by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH); HR status was assessed by IHC. RESULTS: Nineteen percent of primary tumors were HER-2 positive; 77% were HR positive. Sites of biopsied or resected metastases were: locoregional soft tissues (n = 30), liver (n = 20), central nervous system (n = 5), bone (n = 5), pleura (n = 4), distant soft tissues (n = 3), abdomen (stomach, colon, peritoneum) (n = 3), bronchus (n = 3), and bone marrow (n = 2). For paired metastases, the HER-2 status was unchanged in 84% of cases; two patients changed from positive to negative, while 10 patients converted from negative to positive (agreement, 84%; kappa = 0.5681). A change in HR status was observed in 16 cases (21%): nine cases from positive to negative and seven cases from negative to positive (agreement, 78.7%; kappa = 0.4158). CONCLUSIONS: Further studies are necessary to better define the level of discordance in HER-2 or HR status between primary tumors and paired metastases. However, a biopsy of metastatic disease can be recommended, if feasible with minimal invasiveness, because treatment options might change for a significant proportion of patient

Evaluation of the effects of cryopreservation on Modena Biobank tissue samples through HR-MAS NMR

The application of high-resolution magic angle spinning (HR-MAS) NMR spectroscopy to the analysis of intact tissue biopsies and surgery samples dates back to 1997. It represents, at present, an actively investigated field, and it is used to obtain the metabolic fingerprints of tissues. It has been shown to differentiate between normal and neoplastic tissue in the case of breast, brain, kidney, colon cancer and other malignancies in the upper gastrointestinal tract. Nevertheless, it is difficult to run HR-MAS analysis immediately after surgical resection or biopsy, and samples are currently frozen in liquid nitrogen and then stored to -80 °C. Some studies reporting the effect of sample ischaemia, spinning time and measurement temperature on the metabolic profile of tissues can be found.1 Nevertheless, another important issue to be addressed is the effect of cryopreservation time on the metabolic profile of tissues. Crypreservation represents a more and more common practice, due to the widespread of tissue BioBanks. To gain a deeper insight into metabolic changes that occur during the storage, samples of Modena BioBank were analyzed through HR-MAS NMR after 1, 6 and 12 months from collection. The results of this study were discussed

Microsatellite and EGFR, HER2 and K-RAS analyses in sclerosing hemangioma of the lung.

Sclerosing hemangioma (SH) is an uncommonpulmonary tumor thought to derive from primitive respiratoryepithelium consisting of 2 cell populations (cuboidal surface andpolygonal stromal cells) and sharing some clinical characteristics(frequent occurrence in nonsmoking women of Asian ethnicity)with bronchioloalveolar carcinoma with which it has beensuggested a possible common origin. We investigated 11 cases ofSH by immunohistochemistry, fluorescence in situ hybridization,and polymerase chain reaction-based microsatellite andmutational analyses with particular emphasis on possiblealterations of microsatellite loci located at tumor suppressorgenes (FHIT, p16, Rb, and p53) involved in lung adenocarcinomagenesis and EGFR, HER2, and K-RAS genes. AlthoughEGFR expression was observed in all tested cases, none showedHER2 immunostaining. Fluorescence in situ hybridization andmutational analysis of EGFR and HER2 and also K-RASsequencing did not reveal molecular alterations, whereas alleliclosses at p16 and Rb loci (4 and 2 out of 9 tested cases,respectively) with an identical microsatellite allelic loss patternin both cuboidal and polygonal cells were observed. The findingof microsatellite alterations in chromosomal regions related togenes deeply involved in early stage lung adenocarcinoma couldsuggest a possible link between SH and bronchioloalveolarcarcinoma, but tumor pathway promoted by EGFR, HER2, andK-RAS does not represent a common molecular mechanism oftumorigenesis. Microsatellite alterations identified in cuboidaland polygonal cells further confirm the clonal and neoplasticnature of both components of SH

Change in HER2 Status in HER2 Positive Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without Anti-HER2 Therapy: Analysis of Two Consecutive Cohorts

Introduction: emerging literature data have shown a change of HER2 expression from primary tumors to metastatic deposits. Tumor heterogeneity, genetic drift as well as selective pressure of adjuvant therapy have been suggested to explain this phenomenon. Aim of the present analysis is to evaluate the change in HER2 expression after neoadjuvant chemotherapy with or without anti-HER2 agents. Methods: two consecutive cohorts of HER2+ breast cancer patients treated with neoadjuvant therapy were identified from a prospectively maintained database including 310 patients. The first cohort (A) includes 38 patients enrolled before 2005, treated with chemotherapy alone. The second cohort (B) includes 48 patients treated with neoadjuvant chemotherapy in combination with antiHER2 agents (trastuzumab or lapatinib). HER2 expression was evaluated by IHC on pre-treatment core biopsy (tru-cut with 14 gauge needle) and on surgical specimen after neoadjuvant therapy. FISH analysis was performed on IHC 2+ samples. Results: The two cohorts were balanced in respect of tumor stage, patient age, and HR expression. In particular, a co-expression of HER2 and HR was observed in 60% of the patients in cohort A and in 70% of the patients in cohort B (p=0.2). Patients in cohort B have a significantly higher rate of pathologic complete response (pCR) in comparison to cohort A (45% vs 11%, p=0.001). A change in HER2 expression from biopsy to post-therapy samples was observed in 39% of the patients in cohort A vs 12% of the patients in cohort B (p=0.02). No patients with pCR have recurred so far vs 25% of the patients with less than pCR (p=0.005). The rate of recurrence was significantly higher for patients experiencing a change in HER2 expression (50% vs 19%, p=0.018). Conclusion: contrary to our expectations, patients not receiving anti-HER2 therapy as part of neoadjuvant therapy were more likely to have a change in HER2 status vs patients receiving anti-HER2 neoadjuvant therapy. The change in HER2 status has a negative prognostic impact

ASSESSMENT OF FREEZING EFFECTS AND DIAGNOSTIC POTENTIAL OF BIOBANK HEALTHY AND NEOPLASTIC BREAST TISSUES THROUGH HR-MAS NMR SPECTROSCOPY

HR-MAS NMR spectroscopy was employed to monitor the metabolic profiles of Modena BioBank breast samples over one year of freezing at -80 °C. The study includes 22 adult female patients living in Modena and its hinterland, who underwent total mastectomy or quadrantectomy in 2011 - 2012. Variations occur, especially affecting phosphocholine and choline. This is not a trivial finding, since many studies base the distinction between neoplastic and healthy tissues or the assessment of tumor grade on the analysis of choline metabolites [1,2]. Despite the changes observed, we established that the diagnostic power of the HR-MAS NMR spectra of frozen samples is preserved, at least as far as the distinction between neoplastic and healthy samples is concerned. Lactate, phosphocholine, phosphoethanolamine, taurine, myo-inositol and glucose are biomarkers that can be used to distinguish healthy from neoplastic tissues, whereas some metabolite ratios, such as Lac+PE+Tau/Glc+Myo, seem to have even higher discrimination potential. Fig. 1. Scores plot of PCA on neoplastic (crosses) vs healthy (triangles) samples. Loadings profiles (right) of PC2 and PC3. References [1

Loss of HER2 positivity and prognosis after neoadjuvant therapy in HER2-positive breast cancer patients

Background: Emerging literature data are showing that a change in human epidermal growth factor receptor (HER2) status adversely affects breast cancer patient’s prognosis. The aim of this study was to evaluate the prognostic impact of HER2 loss in patients with HER2-positive disease treated with neoadjuvant therapy with or without anti-HER2 agents. Methods: One hundred and seven consecutive HER2-positive patients were identified from a prospectively maintained database. The first cohort includes 40 patients treated with chemotherapy (CT) alone. The second cohort includes 67 patients treated with neoadjuvant CT plus anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression was evaluated by immunihistochemistry or fluorescence in situ hybridization on pretreatment core biopsy and on surgical specimen after therapy. Results: The rates of pathologic complete response (pCR) and breast-conserving surgery were higher in the CT + anti- HER2 cohort. A loss of HER2 expression was observed in 40% of the patients with residual disease after CT alone versus 14.7% of the patients after CT + anti-HER2 agents (P = 0.019). Patients not achieving a pCR have a significant increase in the risk of relapse when compared with those achieving a pCR (hazard ratio [HR] 9.55, P = 0.028). Patients with HER2 loss tended to have a higher risk of relapse as comparing to patients with maintained HER2 positivity (HR 2.41, P = 0.063). Conclusion: The pCR is confirmed as a powerful predictor of long-term outcome. The rate of HER2 loss is higher in patients receiving neoadjuvant CT without anti-HER2 agents. HER2 status on residual disease after preoperative therapy can be helpful in selecting patients at different risk of relapse, to be included in prospective trial exploring further adjuvant therapy

Prognostic role of HER2 loss after neoadjuvant therapy in patients with HER2-positive operable breast cancer

Background: Emerging literature data are consistently showing that a change in HER2 status adversely affect the prognosis of breast cancer patients. Aim of the present analysis is to evaluate the prognostic impact of HER2 loss in breast cancer patients with HER2 positive disease treated with neoadjuvant therapy with or without anti-HER2 agents. Methods: A total of 94 HER2 positive patients were identified from a prospectively maintained database. The first cohort (A) includes 40 patients treated with chemotherapy alone (enrolled before 2005). The second cohort (B) includes 54 patients treated with neoadjuvant chemotherapy in combination with anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression was evaluated by IHC or FISH on pre-treatment core biopsy and on surgical specimen after neoadjuvant therapy. Patients were considered as having HER2 positive disease in case of IHC 3+ or FISH amplification. Results: No imbalance in terms of age, stage at diagnosis, tumor grade and expression of hormone receptor was observed in the two cohorts. In detail, 67% and 61% of the patients have a co-expression of HER2 and hormone receptor in cohort A and B, respectively. The rate of breast conservation was significantly higher in cohort B (chemotherapy+anti-HER2 agents) as compared to cohort A (chemotherapy alone) (59% vs 38%, p=0.048). Similarly, the rate of pathologic complete response (pCR) was significantly higher in cohort B (42.6% vs 7.5% in cohort A, p<0.001). A change in HER2 expression from biopsy to post-therapy samples was observed in 35% of the patients in cohort A vs 9% of the patients in cohort B (p=0.04). No patients achieving a pCR have recurred so far vs 25% of the patients with less than pCR (p=0.005). The rate of recurrence was significantly higher for patients experiencing a change in HER2 expression (47% vs 15% in patients with no change, p=0.007). At 5 years, 53% of the patients with Her2 change and 75% of the patients without Her2 change were alive and free of recurrence (log rank test: p=0.03). Conclusions: The rate of HER2 loss was significantly higher in patients not receiving anti-HER2 agents as a part of the neoadjuvant therapy. In this series, the change in HER2 status has a negative prognostic impact

EGFR polysomy in squamous cell carcinoma of the thyroid. Report of two cases and review of the literature

AIMS AND BACKGROUND:Primary squamous cell carcinoma of the thyroid gland (PSCCT) is an uncommon malignancy characterized by a poor prognosis. A radical surgical approach combined with radiotherapy or chemotherapy is the generally accepted treatment for this tumor. The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor modulating the cell proliferation and biological progression of many human epithelial tumors. The EGFR overexpression in PSCCT suggests an additional therapeutic option for the treatment of this tumor.METHODS AND STUDY DESIGN:The clinicopathological features and immunohistochemical profiles of two cases of primary squamous cell carcinoma of the thyroid in a 66-year-old and an 83-year-old woman are presented. EGFR status was valued in both cases.RESULTS:Overexpression of EGFR protein was detected in 50% and 75% of the tumor cell membranes. EGRF gene polysomy was detected in both tumors.CONCLUSIONS:Pharmaceuticals targeting EGFR may help to provide the rationale for an additional, novel therapeutic option for this rare tumor, especially when other therapeutic options have been exhausted