The influence of breast cancer subtypes on the response to anthracycline neoadjuvant chemotherapy in locally advanced breast cancer patients.

PURPOSE: The objective of neoadjuvant chemotherapy (NACT) for locally advanced breast cancer (LABC) is downstaging to achieve resectability. According to the protocol for the treatment of LABC more than 10 years ago, the routine NACT for LABC in Serbia consisted of 4 cycles of FAC (fluorouracil, doxorubicin, cyclophosphamide). The aim of this analysis was to assess the influence of biologic subtypes of BC on the response to NACT and on the disease outcome in these patients. METHODS: We analyzed 190 patients with median age of 52 years (range 26-74), diagnosed with LABC between Jun/2002 and Dec/2005 and treated with 4 cycles of FAC. Patients with clinical response to NACT (162/192;85.26%) were subjected to radical mastectomy after which the majority of them received 3 cycles of adjuvant FAC, adjuvant tamoxifen if HR-positive disease, and postoperative radiotherapy. We retrospectively determined by immunohistochemistry estrogen receptor (ER)/ progesterone receptor (PgR)/HER2 status from BC biopsies in all patients who were divided in 4 subgroups. Pathological complete remission (pCR) was defined as ypT0N0. The main end points were disease-free survival (DFS) and overall survival (OS). Statistics included Fisher's exact test, KaplanMeier product-limit method and Log-rank test. RESULTS: After a median follow up of 76 months (range 3-128) 104/190 patients (54.74%) experienced disease relapse, while 78/190 (41.05%) died. Of 157 patients with known receptor status the numbers of 4 subtypes were as follows: 31/190 (16.32%) triple negative (TN) BC, 22/190 (11.58%) HR-/HER2+, 97/190 (51%) HR+/HER2- and 17/190 (8.95%) HR+/HER2+. Ten out of 190 patients (6.17%) achieved pCR and had significantly longer DFS (Log-rank test, p=0.042), and a trend to prolonged OS (Log-rank test, p=0.092). There was a significant difference (Fisher exact test, p=7.7 × 10-6) between pCR rates among 4 BC subtypes: 3/31 (9.68%) in TNBC, 6/22 (27.27%) in HR-/HER2+, 0/97 in HR+/HER2- and 1/17 (5.88%) in HR+/HER2+ patients. This difference was achieved on the account of the difference between TNBC and HR-/HER2+ BC subtypes (Fisher's exact test, p=6.85×10-6, Bonferroni correction: 0.05/6=0.0083). There were no differences in DFS and OS between the 4 BC subtypes. CONCLUSION: Although there was a significantly higher number of patients achieving pCR among HR-/HER2+ subtype compared to other BC subtypes, this did not translate into improvement in long-term disease outcome of these patients.

Exploring the role of TNF-α, TGF-ß, and IL-6 serum levels in categorical and noncategorical models of mood and psychosis.

Psychotic and mood disorders are discussed as part of the same continuum. The potential role of immune dysregulation in defining their clinical presentations, however, remains unclear. Differences in TNF-α, IL-6 and TGF-ß levels were investigated in 143 patients with schizophrenia (SCH = 63) and bipolar disorder (BD = 80), in remission. Cytokines were evaluated against the dimensional assessment of psychosis and affective symptoms using the schizo-bipolar scale, together with the severity of the same symptom domains measured by the brief psychiatric rating scale (BPRS). Lower TGF-ß was associated with more lifetime episodes, family risk for psychosis, and more severe mood and psychotic symptoms in all patients. BPRS Affect symptoms domain correlated with lower TGF-ß levels in BD, and higher TGF-ß levels in SCH patients. Using moderated mediation analysis, TGF-ß was a relevant predictor only in the setting of non-categorical symptom distribution, with familial risk for psychosis confirmed as a significant moderator. Severity of BPRS Affect symptoms domain was an independent predictor of inclination towards the psychosis spectrum. The underlying immune dysregulation may be shared by the disorders, rather than a unique characteristic of each, having significant implications for our understanding of the continuum vs. categorical approach to psychosis and mood disorders.

Mutational profile of hereditary breast and ovarian cancer - Establishing genetic testing guidelines in a developing country.

PURPOSE: Because many countries lack the capacity to follow the international guidelines for genetic testing, we suggest the specific approach for establishing local genetic testing guidelines that could be applied in developing countries. We focus on hereditary breast (BC) and ovarian cancer (OC) in Serbia. METHODS: From the cohort of 550 persons who were referred for genetic counseling at the Institute for Oncology and Radiology of Serbia, 392 were selected. Personal and family histories were collected and germline DNA was sequenced with NGS in a panel of 20 genes. RESULTS: Pathogenic (PV) and likely-pathogenic variants (LPV) were detected in 8 genes with the frequency of 23.7%. The most frequent were in BRCA1(7.6%), BRCA2(4.8%), PALB2(4.1%) and CHEK2(3.8%). They were also detected in ATM(1.8%), NBN(0.8%), TP53(0.5%) and RAD51C(0.3%). Whereas high carrier probability (CP), bilateral BC, BC and OC in the same patient and family history (FH) of BC/OC, were the strongest predictors for BRCA1/2 PV/LPV, lower CP values and early age of BC onset without FH were associated with higher frequency of PALB2 and CHEK2 PV/LPV. CONCLUSIONS: Population specific studies to identify specific mutational patterns and predictors of PV/LPV should be conducted in order to make scientifically sound and cost-effective guidelines for genetic testing in developing countries.

An aggressive extramedullary cutaneous plasmacytoma associated with extreme alterations in the innate immune system.

BACKGROUND: The role of natural killer (NK) cells in plasma cell diseases has not yet been fully characterized. CASE REPORT: We present the case of a 47-year-old man with an extremely aggressive extramedullary plasmacytoma of the lung with associated cutaneous lesions, whose disease was accompanied by a significantly decreased number of NK cells (CD56+, CD16+, CD3-) in the peripheral blood, very low NK cell activity levels, and a decreased interleukin-2 production from cultured cells in vitro. Histology and immunohistochemistry of the lung and cutaneous lesions identified that the tumor was composed of clonal plasma cells which were CD38+++, CD138+++, lambda chain+, kappa chain-, and cytokeratin-. Bone marrow histology and cytology were initially normal. The disease progressed rapidly despite local radiotherapy and systemic chemotherapy, and the patient died shortly after diagnosis. CONCLUSIONS: Cutaneous involvement in extramedullary plasmacytoma represents a clinically aggressive variant of plasma cell tumor, which runs a rapid course and has associated devastating effects on the patient's innate immune system.

Some patients with NHL possessed immunoreactivity to gliadin and to cow's milk proteins.

Non-Hodgkin lymphoma (NHL) represents heterogeneous group of diseases either B, or T cell origin. In order to assess whether food antigens contribute to the imbalance of immune response, the aim of this work was screening the sera of patients with (mostly) B cell NHL, and of people with non-malignant health disorders (NMD), as well as of healthy people for their immunoreactivity to food constituent gliadin, and to cow's milk proteins. Data obtained by ELISA tests show the existence of the enhanced immunoreactivity to food antigens in some NHL patients, as well as in some people with NMD. The high degree of coincidence in the presence of enhanced levels of immune complexes in circulation (CIC) and of immunoreactivity with gliadin in immunofixation (after the serum protein electrophoresis in agarose gel in veronal buffer, at pH 8.6) especially in NHL patients points that some antigliadin immunoreactivity unrevealed in ELISA tests could be hidden in CIC. This, only in the presence of malignant genotype, as well as the enhanced levels of CIC in some of NHL patients could both, at least partially contribute to the persistent non-specific support of disease. They call for the new research of the clinical importance of both, the elevated humoral immunity to food antigens (gluten, cow's milk proteins) for the course of this very severe hematological disease.