Paths of causal influence from prenatal inflammation and preterm gestation to childhood asthma symptoms.

Introduction: Long-lasting respiratory symptoms have a huge impact on the quality of life in prematurely born children. The aim was to investigate paths of assumed causality leading from foetal inflammatory response syndrome (FIRS) to asthma symptoms in preterms. Methods: Demographic, antenatal, delivery and outcome data were collected from 262 infants with less than 32 completed weeks of gestational age over a 10-year period in a prospective cohort study. The presence of symptoms of asthma beyond the age of 5 years was the primary outcome measure. The causal effect of FIRS on childhood asthma was tested with three different logistic regression models and two structural equation models (SEM). Results: FIRS (OR = 4.7) and subsequent chronic lung disease of prematurity (OR = 7.7) and early childhood wheezing (OR = 9.5) are the most important risk factors for development of asthma symptoms in children born with less than 32 weeks of gestational age. The path analysis showed that FIRS has a large direct (0.59), medium indirect (0.11) and large overall (0.70) effect on CLD; large negative direct effect on ECW (-0.34) and a large positive indirect effect (0.74), mediated by CLD. On the occurrence of asthma symptoms, FIRS has a medium negative direct effect (-0.18) and a medium positive indirect effect (0.26), mediated by CLD and ECW. Conclusion: Prenatal inflammation plays an important role in the development of chronic respiratory disturbances in preterm infants. This influence is mainly related to structural and developmental lung abnormalities initiated in utero as consequences of FIRS, resulting in CLD of prematurity, and overcoming the protective mechanisms of chorioamnionitis.

[CLINICAL GUIDELINES FOR DIAGNOSIS, TREATMENT AND MONITORING OF PATIENTS WITH INVASIVE BREAST CANCER--CROATIAN ONCOLOGY SOCIETY]. / KLINICKE UPUTE HRVATSKOGA ONKOLOSKOG DRUSTVA ZA DIJAGNOZU, LIJECENJE I PRACENJE BOLESNICA/KA OBOLJELIH OD INVAZIVNOG RAKA DOJKE.

Breast cancer is the most common cancer in women. It can be diagnosed in early stage through screening, early detection and educational programs, and when diagnosed early it can be efficiently treated. Treatment modalities include surgery, chemotherapy, radiotherapy, hormonal therapy and targeted biologic therapy, according to the stage of the disease and patient condition. Treatment decisions should be made after multidisciplinary team discussion. Due to the significance of this disease it is important to define and implement standardized approach for diagnostic, treatment and monitoring algorithm as well. The following text presents the clinical guidelines in order to standardize the procedures and criteria for diagnosis, management, treatment and monitoring of patients with breast cancer in the Republic of Croatia.

[Analysis of sentinel lymph node in early breast cancer patient - Clinical Hospital Center Rijeka]. / Analiza limfnog cvora cuvara u bolesnica s ranim invazivnim rakom dojke - Klinicki bolnicki centar Rijeka.

Sentinel lymph node (SLN) biopsy is an accurate method for the detection of axillary metastases in early breast cancer patients and is of value as a replacement for axillary dissection. However, variations in the methods and protocols used for the pathological evaluation of SLN exist in everyday practice. Therefore, standardization how to detect, dissect, process, stain, assess and report SNL is required in order to stratify patients into adequate prognostic groups. The aim of this study was to present our experience in SLN analysis in patients with early breast cancer and clinical stage T1-2 and N0. In the period between 2003 and 2011, 1071 consecutive patients or 1915 SLN were analyzed. The protocol included intraoperative analysis of histological frozen sections and cytological imprint, followed by analysis of paraffin sections according to the protocol that included sections of whole SLN with the interval of 250 prm. According to the accepted protocol 75% of SLN were negative. The obtained results were correlated with literature data.

Breast abscess in a man due to Salmonella enterica serotype Enteritidis.

Nontyphoidal salmonellae can cause breast infection only exceptionally. A case of breast abscess in a 70-year-old man due to Salmonella enterica serotype Enteritidis (Salmonella Enteritidis) is reported. The infection was successfully treated with a combination of surgical and antibiotic treatment.

Chorioamnionitis and chronic lung disease of prematurity: a path analysis of causality.

Current evidence suggests that additional pathogenetic factors could play a role in the development of chronic lung disease of prematurity, other than mechanical ventilation and free radical injury. The introduction of the concept of "fetal inflammatory response syndrome" offers a new perspective on the pathogenesis of chronic lung disease of prematurity. New statistical approaches could be useful tools in evaluating causal relationships in the development of chronic morbidity in preterm infants. The aim of this study was to test a new statistical framework incorporating path analysis to evaluate causality between exposure to chorioamnionitis and fetal inflammatory response syndrome and the development of chronic lung disease of prematurity. We designed a prospective cohort study that included consecutively born premature infants less than 32 weeks of gestation whose placentas were collected for histological analysis. Histological chorioamnionitis, clinical data, and neonatal outcomes were related to chronic lung disease. Along with standard statistical methods, a path analysis was performed to test the relationship between histological chorioamnionitis, gestational age, mechanical ventilation, and development of chronic lung disease of prematurity. Among the newborns enrolled in the study, 69/189 (36%) had histological chorioamnionitis. Of those with histological chorioamnionitis, 28/69 (37%) were classified as having fetal inflammatory response syndrome, according to the presence of severe chorioamnionitis and funisitis. Histological chorioamnionitis was associated with a lower birth weight, shorter gestation, higher frequency of patent ductus arteriosus, greater use of surfactant, and higher frequency of chronic lung disease of prematurity. Severe chorioamnionitis and funisitis were significantly associated with lower birth weight, lower gestational age, lower Apgar score at 5 minutes, more frequent use of mechanical ventilatory support and surfactant, as well as higher frequency of patent ductus arteriosus and chronic lung disease. The results of the path analysis showed that fetal inflammatory response syndrome has a significant direct (0.66), indirect (0.11), and overall (0.77) effect on chronic lung disease. This study demonstrated a strong positive correlation between exposure of the fetus to a severe inflammatory response and the development of chronic lung disease of prematurity.

The carcinoid tumour in Meckel's diverticulum: how to treat young adults with appendicitis?--Case report.

This case reports the concomitant and unexpected finding of carcinoid tumour within a Meckel's diverticulum presenting as an acute abdomen due to gangrenous appendicitis in a young adult male. Both Meckel's diverticula and carcinoid tumour are rare clinical entities, and carcinoid tumours occurring within a Meckel's diverticulum are even more uncommon. The initial clinical presentation of carcinoid tumours occurring in a Meckel's diverticulum is usually similar to that of appendicle carcinoids.Carcinoid tumours are the most common primary tumour of the small bowel. They resemble appendicle carcinoids to the extent that they are usually small, single, and asymptomatic. Surgical treatment of Meckel's diverticula is recommended procedure. By presenting this case we wished to stress the value of systematic identification and removal of the diverticulum during laparotomy and to underline the importance of exploration the Meckel's diverticulum particularly in case of young adult subjects.

[Clinical recommendations for diagnosis, treatment and monitoring of patients with invasive breast cancer]. / Klinicke upute za dijagnozu, lijecenje i pracenje bolesnika oboljelih od invazivnog raka dojke.

Breast cancer is the most common malignancy in women. Preventive measures, early diagnosis and development of all treatment modalities (surgery, radiotherapy, chemotherapy, hormonal and targeted biologic therapy) led to improvement in survival and quality of life of the patient. In order to standardize and optimize the approach, following good clinical practice standards, we bring consensus guidelines for diagnosis, treatment and monitoring of breast cancer patients as a result of consensus of a multidisciplinary team of experts for breast cancer.

HSP70 In triple negative breast cancer: Prognostic value and clinical significance.

BACKGROUND: Triple-negative breast cancer (TNBC) has the worst prognosis and the highest immunogenic potential of all breast cancer subtypes. It is characterized by a lack of estrogen and progesterone receptors as well as HER2. A major component of the tumor microenvironment (TME) of TNBC is tumor-infiltrating lymphocytes (TILs). A chaperone heat shock protein 70 (HSP70) is involved in several pathways that enable tumour growth and progression, as well as in immune modulation. METHODS: Immunohistochemical analysis of HSP70 expression in immune cells, as well as expression of immunosuppressive markers CTLA4 and PD-L1 and major TILs components: CD8, CD4 and Tregs were analyzed in the superficial and deep tumor layer of primary TNBC and compared with established clinicopathological parameters. Clinical data and surgical tissue samples from 68 TNBC patients who underwent initial surgery were included in the analysis and 36 control samples from benign breast tissue biopsies. RESULTS: A higher expression of TILs, CD4, CD8 and PD-L1 was found in the invasive tumor front (ITF), as compared to the tumor center (TC) (p < 0001). HSP70 positive immune cells (HSP70(+) IC) in TC were associated with adverse clinical and pathological markers: higher stage of disease (P = 0.013), higher grade (P = 0.05) and a higher pN status (P < 0.001). In addition, higher expression of HSP70(+) IC from TC was correlated with the higher expression of FOXP3(+)T cells both in ITF (N = 61, rho=0.42, p < 0.001) and in metastatic tissue from the draining lymph nodes (N = 13, rho=0.61, P = 0.026). CONCLUSION: Correlations between HSP70 immune cells expression and individual TILs components support the hypothesis of its active role in inducing immunosuppression and tumor progression. Routine determination of HSP70 expression, in immune cells of TC, may be of added value in the clinical decision-making process concerning axillary surgery.

The "round block" surgical technique in the management of multicentric fibroadenomas.

The "round block" surgical technique in the treatment of a female patient with multiple, multicentric fibroadenomas in both breasts is presented. The advantages of this technique for patients with multicentric benign breast lesions are minimal postoperative scar and a favourable aesthetic result. Breast dimensions and the areolar diameter were measured in 203 subjects of Primorsko-Goranska county during examination in the Out-Patient Hospital for Breast Diseases, including the operated patient. Smaller breast dimensions and a larger areolar diameter provide an easier access to any part of the breast due to a smaller distance between the incision and a fibroadenoma and a larger circumference of circular periareolar incision, thus facilitating the surgery. The analysis of average, maximum and minimum values measured shows that the "round block" technique can be performed in all cases of multiple and multicentric fibroadenomas regardless of breast size, areolar diameter and the location of fibroadenoma in the breast.

The relationship between histologic chorioamnionitis and decidual macrophage polarization and their influence on outcomes of neonates born before the 32nd gestational week.

PURPOSE: To explore the relationship between histologic chorioamnionitis (HCA) and decidual macrophage (DM) polarization and their influence on outcomes of neonates born before the 32nd gestational week. MATERIALS AND METHODS: Eighty-four neonates and their placentas were included in this retrospective case-control study and divided into two groups: with and without HCA present (HCA + and HCA-). Neonatal, maternal, and placental risk factors were explored and their influence on neonatal outcomes was examined. We used CD68 and iNOS as markers for polarized DMs type 1 (M1) and CD163, CD206 and arginase (Arg-1) for polarized DMs type 2 (M2). RESULTS: HCA was present in 47 (56%) cases, and 37 (44%) cases were without the present HCA. There was no statistically significant difference in neonatal risk factors between the two groups (HCA + and HCA-). Higher rates of HCA (p = .042) were observed in mothers who received antepartum corticosteroid therapy. The frequency of vaginal deliveries in HCA + pregnancies was significantly higher than in HCA- pregnancies where deliveries by cesarean section were more frequently observed (p < .001). M2 DM were more abundant in the HCA + group (p = .035). Multiple regression model assessed the association between the presence of HCA, M1, and M2 DM with ROP stages. It has been observed that HCA is a risk factor for ROP stages (ß coefficient = 0.34, rpartial = 0.246, p = .024). With the logistic regression model, the association between the presence of HCA, M1, and M2 DM with neonatal nCPAP respiratory support and necrotizing enterocolitis (NEC) was assessed. The presence of M2 macrophages in decidua is an independent risk factor for neonatal nCPAP respiratory support (coefficient -0.07, OR = 0.928, 95% CI 0.87-0.99, p = .024) and the presence of M1 macrophages in decidua increases the risk for NEC (coefficient 0.010, OR = 1.0108, 95% CI 1.00-1.02, p = .032). CONCLUSIONS: The significantly more abundant presence of M2 DM was detected in HCA + placentas and their association with the increased risk for neonatal nCPAP respiratory support was observed. On the contrary, the presence of M1 DM increases the risk for NEC. The presence of HCA is a risk factor for ROP stages.

Nuclear EGFR in ductal invasive breast cancer: correlation with cyclin-D1 and prognosis.

The epidermal growth factor receptor (EGFR)-family and cyclin-D1 have been extensively studied in breast cancer; however systematic studies that examine protein expression and gene status in the same cohort of patients are lacking. Also emerging evidences suggest existence of a direct EGFR-signaling pathway, which involves cellular transport of EGFR from cell membrane to the nucleus, and transcriptional regulation of the target genes. Thus, we examined the protein expression of membrane EGFR, nuclear EGFR, cyclin-D1 and the corresponding gene status in 113 breast carcinomas by immunohistochemistry and fluorescence in situ hybridization using tissue microarrays. Membrane EGFR overexpression and EGFR gene amplification were detected in 2% cases, while nuclear EGFR was detected in 40% of cases, with 12% having high nuclear EGFR staining. Nuclear EGFR correlated with tumor size (P=0.0005), lymph node metastasis (P=0.0288), Nottingham prognostic index (P=0.0011) and estrogen receptor (ER) expression (P=0.0258) but the letter correlation was observed only in premenopausal group of patients. Strong cyclin-D1 expression and cyclin-D1 gene (CCND1) amplification were found in 64 and 13% of the cases, respectively. Cyclin-D1 expression showed positive correlation with ER (P=0.0113) and inverse correlation with Nottingham prognostic index (P=0.0309) and membrane EGFR (P=0.0201). CCND1 amplification also showed inverse correlation with membrane EGFR (P=0.0420). A strong correlation between membrane EGFR expression and gene amplification (P=0.0035), as well as cyclin-D1 overexpression and gene amplification (P=0.0362), was demonstrated. On univariate analysis cyclin-D1 expression showed a correlation with longer overall survival in the premenopausal group and nuclear EGFR correlated with shorter overall survival in whole cohort as well in the premenopausal group of patients. Multivariate analysis revealed nuclear EGFR to be an independent prognostic factor and showed 3.4 times greater mortality risk for nuclear EGFR+++ patients as compared with nuclear EGFR negative patients (hazard ratio =3.402; P=0.0026).

The expression of calpain-1 and androgen receptor in breast cancer and their correlation with clinicopathological characteristics: An immunohistochemical retrospective study.

Breast cancer is a heterogeneous disease with different biological outcome and ability to acquire resistance to therapy. The calpain family of proteases and androgen receptor (AR) are implicated in breast cancer pathogenesis and progression and are potential targets for novel treatment regimens. The aim of this study was to investigate the expression of calpain-1 and AR in breast cancer and to correlate their expression with clinicopathological variables and prognosis of patients. In this study we enrolled 219 breast cancer patients with long term follow-up information available. Immunohistochemical methods on a tissue microarray were used to investigate expression of calpain-1 and AR in tumor cells. The expression of calpain-1 and AR both differed significantly between the tumor subtypes of patients (p = 0.002 and p = 0.042 respectively). High calpain-1 expression was associated with patient's age over 50 years (p = 0.005) and positive ER status (p = 0.009), but not with other clinicopathological variables. Women with AR negative breast cancers were more likely to be older (p = 0.016), to have bigger tumors (p = 0.032), higher stage of the disease (p = 0.026), presence of exulceration (p = 0.017), negative ER status (p = 0.007) and higher Ki-67 proliferative index (p = 0.027). Calpain-1 expression was not associated with breast cancer specific overall survival in the total cohort of patients, however low calpain-1 expression was associated with adverse survival (p = 0.018) in triple negative subgroup of patients. Low calpain-1 expression was also associated with significantly shorter 5-year disease-free survival in total cohort of patients (p = 0.03). AR status was not associated with overall and disease-free survival of patients. This study has demonstrated that the expression of calpain-1 and androgen receptors are associated with important clinicopathological variables. The expression of calpain-1 was associated with improved disease-free survival of all analyzed patients and with improved overall survival of triple negative breast cancer patients.

Breast infiltrating ductal carcinoma: analysis of hormone, HER-2 receptors and Ki-67 proliferation marker.

The aim of this study was to analyse breast carcinomas with discordant receptor status, probably hormonal dependent (estrogen receptor (ER) positive, progesterone receptor (PR) negative or ER-PR + subgroup profile) infiltrating ductal breast carcinomas not otherwise specified (IDC NOS). Specimens from 90 IDC NOS were grouped into three categories according to hormonal status: dependent (D) (ER +PR +), probably dependent (PD) (ER +PR- or ER-PR +) and non-dependent (ND) (ER-PR-); they were evaluated considering some established prognostic parameters in breast carcinomas. Statistically significant difference was found between tumor receptor status distribution and menopausal status (p = 0.0235), age of the patients (p = 0.000467), histological grade (p = 0.000003), vascular invasion (p = 0.006), HER-2 status (p = 0.0039) and Ki-67 proliferation rate (p = 0.000311). D tumors were found exclusively in post-menopausal patients (average age 68.9 years), most of which had intermediate (II) grade, without vascular invasion, with HER-2 status score predominantly 0 or 1 + and lower Ki-67 proliferation rate. PD tumors were found predominantly in younger post-menopausal patients (average age 57.5 years), with vascular invasion found in 23% of the cases. ND tumors mostly had higher histological grade, showed the highest percentage of the Ki-67 positive tumor cells and vascular invasion in 30% of the cases. We conclude that the patients with PD breast carcinomas were younger post-menopausal women with the tumors moderately differentiated, HER-2 score 0 or 1+ and with lower Ki-67 proliferation rate.

Prognostic significance of vascular endothelial growth factor expression in clear cell renal cell carcinoma.

The purpose of this investigation was to analyze and correlate the immunohistochemical pattern of vascular endothelial growth factor (VEGF) expression with the average of microvessel density (MVD) and other clinicopathologic parameters in clear cell renal cell carcinoma (CCRCC) in order to determine its prognostic significance. Surgical specimens of 93 CCRCC were immunohistochemically analyzed for VEGF expression, MVD with anti-CD31, and Ki 67 proliferative index. VEGF expression was recorded as the percentage of positive tumor cells (<75% and >75%) and as diffuse or perimembranous VEGF expression according to cytoplasmic distribution. Sixty-three (68%) RCC had <75% and 30 had (32%) >75% of VEGF expression. A diffuse cytoplasmic pattern of VEGF expression was found in 61(66%) RCC and a perimembranous one in 32 (34%) RCC. Statistical analysis showed that tumors with >75% of VEGF expression were characterized by lower MVD value (p=0.034), higher nuclear grade (p=0.018), and higher Ki 67 proliferation index (p=0.023). Moreover, a higher nuclear grade of tumor cells was characterized by diffuse cytoplasmic VEGF distribution (p=0.005). This tumor model did not confirm the postulated simple relationship between VEGF overexpression and angiogenesis through high microvessel count. However, the study results indicated that overexpression of VEGF was a worse histologic prognostic parameter in CCRCC.

VEGF expression is associated with negative estrogen receptor status in patients with breast cancer.

The aim of this study was to analyze the association between vascular endothelial growth factor (VEGF) expression on tumor cells and other clinicopathologic parameters in breast cancer that could give additional information on its prognostic significance. Immunohistochemical analysis of expression of VEGF, estrogen (ER) and progesterone receptor (PR), HER-2/neu, and Ki67 was performed in 233 breast cancers. VEGF expression estimated semiquantitatively was correlated with all the above-mentioned parameters as well as with clinicopathologic characteristics of breast cancer such as menopausal status of patients, tumor size, histologic and nuclear grade, vascular invasion, and lymph node status. Most of the tumor cells and some stromal components expressed VEGF. A higher percentage of VEGF-positive tumor cells was present in premenopausal patients and in ER-negative tumors. In postmenopausal patients tumors with a higher expression of VEGF were associated not only with ER-negative but also with HER-2/neu-positive tumor cells. These ER-negative tumors were characterized by a higher proliferative activity. Angiogenic switch as well as proliferative activity of breast cancer cells probably are unfavorably dependent on estrogen activity. This negative correlation between VEGF expression and ER status may not only shed more light on tumor biology but may also have future therapeutic implications.

Predicting sentinel lymph node metastases in infiltrating breast carcinoma with vascular invasion.

Sentinel lymph node and clinically negative axillary node status was compared with well-known clinicopathological characteristics such as tumor size, histologic and nuclear grade, lymphovascular invasion, steroid receptor, and HER-2 status in patients with breast cancer (pT1 and pT2). Positive sentinel lymph nodes were found in 29 of 100 patients: 19 with metastases detected by hematoxylin and eosin staining and 10 with micrometastases confirmed by immunohistochemistry with cytokeratin. Positive sentinel lymph nodes were present in larger carcinomas (P < 0.03), more frequently in tumors with negative PR status (P < 0.037) and evident lymphovascular invasion (P < 0.002). Lymphovascular invasion was also associated with breast cancer of higher histologic (P = 0.011) and nuclear grade (P = 0.039). Tumor size and the presence of lymphovascular invasion were found to be significant predictors of pathologically positive sentinel lymph node in T1 and T2.

HPV 6-positive giant keratoacanthoma in an immunocompetent patient.

Keratoacanthoma (KA) is a clinically distinct, rapidly growing lesion that generally presents as a solitary crateriform nodule in sun-exposed areas in elderly, fair-skinned individuals. A KA larger than 20-30 mm is referred to as giant keratoacanthoma, a relatively rare lesion especially in young patients. Such lesions grow rapidly with possible destruction of underlying tissues. In addition to ultraviolet exposure, KAs have also been associated with chemical carcinogens, chemical peels, genetic factors, chronic skin conditions that produce scarring, trauma and thermal burns. Immunosuppressed patients, especially after transplantation, also develop KAs. A viral etiology has been suggested but not confirmed. We encountered a case of giant keratoacanthoma (greater than 50 mm in diameter) with induration of underlying structures on the upper lip of a 39-year-old male sailor. The patient reported sudden appearance and rapid enlargement of the lesion in only three weeks. Biopsy of the cutaneous lesion and the characteristic clinical history suggested the diagnosis of keratoacanthoma. Total excision with primary closure of the defect by a nasolabial advancement flap was performed. Histological examination of the tumor mass confirmed the diagnosis of KA with infiltrative growth and perineural invasion. Immunosuppression was excluded by blood analyses, as were HIV, syphilis and hepatitis infections. Only low-risk genital HPV type 6 was detected in the lesion, suggesting a possible cocarcinogenic effect of HPV and UV light in a chronically sun-exposed patient.

INTERLABORATORY CONCORDANCE IN HER-2 POSITIVE BREAST CANCER.

Accurate assessment of HER-2 status is essential for identifying patients who will benefit from HER-2 targeted therapy. The aim of the present study was to show results on the concordance between local and central laboratory testing results in HER-2 positive breast cancer patients. In cases with discordant findings, the immunohistochemical (IHC) and/or in situ hybridization (FISH/SISH) analysis was performed in central laboratories. A total of 104 out of 143 (72.72%) breast carcinoma cases were HER-2 positive (score 3+), while nearly 14% of tumors (20/43) showed weak (score 2+) and 12% (19/143) negative IHC staining (score 0 and 1+). After repeated IHC and ISH, 88% (126/143) were classified as HER-2 positive and 12% (17/143) as HER-2 negative cases. The results obtained are in agreement with many studies that confirmed similar discordance in HER-2 testing by IHC and/or FISH between local and central laboratory. Thus, our findings as well as those from other studies support the importance of regular quality assessment of the staining procedures performed and consistency of interpretation of HER-2 test results.

Metatarsal metastasis from transitional cell cancer of the urinary bladder.

Urinary bladder cancers can be grouped into three general categories: superficial, invasive and metastatic. Approximately 90% of malignant tumors of the urinary bladder are of epithelial origin and the majority of them are transitional cell carcinomas (TCC). Metastatic spread of urinary bladder cancers usually includes regional lymph nodes, the lung, the liver and the bones. The presence of metastasis tends to correlate with muscular wall invasion as often demonstrated at the initial diagnosis; consequently clinical bladder cancer represents a late phase of the disease. Although skeletal metastases of bladder cancers are rather common, they have been rarely described to occur in distal bones. For that reason, we report metatarsal metastasis from transitional cell cancer of the urinary bladder in a 59-year-old woman.