Results from the UNITED study: a multicenter study validating the prognostic effect of the tumor-stroma ratio in colon cancer.

BACKGROUND: The TNM (tumor-node-metastasis) Evaluation Committee of Union for International Cancer Control (UICC) and College of American Pathologists (CAP) recommended to prospectively validate the cost-effective and robust tumor-stroma ratio (TSR) as an independent prognostic parameter, since high intratumor stromal percentages have previously predicted poor patient-related outcomes. PATIENTS AND METHODS: The 'Uniform Noting for International application of Tumor-stroma ratio as Easy Diagnostic tool' (UNITED) study enrolled patients in 27 participating centers in 12 countries worldwide. The TSR, categorized as stroma-high (>50%) or stroma-low (≤50%), was scored through standardized microscopic assessment by certified pathologists, and effect on disease-free survival (DFS) was evaluated with 3-year median follow-up. Secondary endpoints were benefit assessment of adjuvant chemotherapy (ACT) and overall survival (OS). RESULTS: A total of 1537 patients were included, with 1388 eligible stage II/III patients curatively operated between 2015 and 2021. DFS was significantly shorter in stroma-high (n = 428) than in stroma-low patients (n = 960) (3-year rates 70% versus 83%; P < 0.001). In multivariate analysis, TSR remained an independent prognosticator for DFS (P < 0.001, hazard ratio 1.49, 95% confidence interval 1.17-1.90). As secondary outcome, DFS was also worse in stage II and III stroma-high patients despite adjuvant treatment (3-year rates stage II 73% versus 92% and stage III 66% versus 80%; P = 0.008 and P = 0.011, respectively). In stage II patients not receiving ACT (n = 322), the TSR outperformed the American Society of Clinical Oncology (ASCO) criteria in identifying patients at risk of events (event rate 21% versus 9%), with a higher discriminatory 3-year DFS rate (stroma-high 80% versus ASCO high risk 91%). A trend toward worse 5-year OS in stroma-high was noticeable (74% versus 83% stroma-low; P = 0.102). CONCLUSION: The multicenter UNITED study unequivocally validates the TSR as an independent prognosticator, confirming worse outcomes in stroma-high patients. The TSR improved current selection criteria for patients at risk of events, and stroma-high patients potentially experienced chemotherapy resistance. TSR implementation in pathology diagnostics and international guidelines is highly recommended as aid in personalized treatment.

Expression of p53 protein product in triple negative breast cancers and relation with clinical and histopathological parameters.

INTRODUCTION: "Triple" negative breast cancer is a subgroup of so-called basal-like breast cancer. They are represented with 15% of all breast cancers, characterized with lack of hormone receptor as well as with negative expression of HER2 test. These tumors are more frequent in Afro-Americans and Latin-Americans, in patients with BRCA1 mutations and in patients with recent delivery. The aim of this study is to present the immunohistochemical and clinico-pathological characteristics of the triple negative breast cancer and their correlation with expression of the protein product of the tumor suppressor gene p53. METHODS: A retrospective analyses of 24 patients with triple negative breast cancer was performed. All of the patients were evaluated in the Histopathological Laboratory of the Clinical Hospital Sistina, during the period from June 2009, until June 2011. The standard immunohistochemical procedures, including the hormone receptor status, HER2 status, proliferative index - Ki67 and p53 gene protein product were performed, as well as additional immunohistochemical staining for so-called basal keratins (Cytokeratin 5/6 and high molecular weight cytokeratin 34BE12). RESULTS: The age of the patients ranged from 29-77 years. Positive lymph nodes were found in 14 (59%) patients. The tumor was poorly differentiated in 19 patients (79%). Overexpression of the p53 protein product was evaluated in 19 (79%) of the cases. All p53 negative patients (5/5) had poorly differentiated tumors (G3), associated with positive regional lymph nodes. The p53 positive group expressed quite opposite correlation, only 9/19 (47%) were with positive lymph nodes (p = 0.03). The expression of p53 protein product was also associated with the nuclear grade (p = 0.005), the mitotic index (p = 0.001), lymph-vascular invasion (p = 0.005) and with the proliferation index Ki67 (p = 0.003). There was a trend for association with the tumor size - pT (p = 0.05). CONCLUSION: According to the results, the triple negative breast cancers are subgroup of the poorly differentiated neoplasms frequently associated in the younger age groups. The majority of these have overexpression of the p53 protein product, which in other hand, are inversely correlated with lymph nodes metastases. Hence, the necessity of enriching the immunohistochemical protocol of these patients with new antibodies, in order to evaluate their expression, which would be helpful for prediction the outcome of different therapeutical modalities.

Synchronous occurrence of ileal stromal tumor (GIST) and colonic adenocarcinoma: a case report.

INTRODUCTION: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract. There is an increasing number of literature reports on synchronous occurrence of gastrointestinal stromal tumors and another malignancy of distinct etiology and evolution. The most reported cases include gastric synchronous occurrence of gastrointestinal stromal tumors and adenocarcinoma and gastric gastrointestinal stromal tumors and colonic adenocarcinoma. CASE REPORT: We present a case of a 77-old female, with synchronous cecal moderately differentiated adenocarcinoma in Stage IIA according to the TNM classification and ileal spindle cell type GIST with low malignant potential, positive for c-Kit, CD34, vimentin, Actin, and negative for S100. CONCLUSION: The synchronous occurrence of small bowel gastrointestinal stromal tumors and other primary gastrointestinal malignancies has been rarely reported. There is a need of further investigations to identify the relationship between gastrointestinal stromal tumors and colorectal cancers.

The occurrence of acute subdural haematoma and diffuse axonal injury as two typical acceleration injuries.

Closed head injuries have already been classified into contact injuries and acceleration-deceleration injuries. Two typical acceleration-deceleration injuries and at the same time, the two worst head injuries are acute subdural haematoma (ASDH) and diffuse axonal injury (DAI), and that is where they got their medico-legal importance. Using experiments, it has been shown that acceleration with an impact time of more than 20-25 min (which occurs in traffic accidents in real life) causes DAI, whereas an impact time of 5-10 min is more likely to produce acute subdural haematoma. The aim of this research is to show that not all, but some types of traffic accidents are more typical for the occurrence of DAI, as well as that the ASDH is not a common feature for all types of fall. The analysis conveyed covered 80 cases of closed head injuries (traffic accidents, falls and assaults) where a complete forensic medical autopsy has been undertaken, followed by a complete forensic-neuropathological examination. For the purpose of diagnosing DAI, immunohistochemistry using antibody against ß-amyloid precursor protein has been involved. Results show that ASDH is more likely to occur in cases of simple fall, assaults and cyclists and DAI is more typical for vehicular traffic accidents and cases of falling from a considerable height. The paper also comprises discussion about some open questions regarding the diagnosis of DAI in the medico-legal practice.

Morphology of renal interstitial fibroblasts.

INTRODUCTION: Renal fibrogenesis is a process common to all progressive kidney diseases. The main executive cell in this process is the fibroblast, by secreting and remodelling the extracellular matrix. The number of fibroblasts is minor in a healthy kidney interstitium, but it increases during the process of fibrosis. Their morphology and immunophenotype vary due to different intrinsic and extrinsic factors which makes their identification and visualization, as well as determination of their origin, very difficult. MATERIAL AND METHODS: We performed morphological and immunohistochemical analyses on kidney biopsies with interstitial fibrosis, using the following antibodies: Vimentin, α-SMA, S100A4, Cadherin 9 and CD34. We also did light-microscopy analyses of semithin sections of tissue embedded in epoxy resin and stained with Toluidine blue. RESULTS: Our observations show that different cells in the fibroblastic population show positivity for different markers, thus contributing to the theory that there are different subpopulations of fibroblasts, with different origins, that take part in renal fibrogenesis.

Acute renal failure in a patient with diffuse large B-cell lymphoma: case report.

INTRODUCTION: Renal parenchymal involvement is common in systemic lymphomas. In almost all cases, renal involvement appears to be a secondary process, either by direct extension from a retroperitoneal mass or via haematogenous spread in the setting of disseminated disease. Secondary renal involvement in systemic lymphomas is generally presented as multiple masses, but also as a solitary nodule. Acute renal failure by a lymphoma infiltration of the kidney is extremely rare. Primary renal non-Hodgkin's lymphoma is even more uncommon and it is a debated issue because of the absence of lymphoid tissue in normal kidneys. CASE PRESENTATION: We report on the case of a 62-year old woman, who had melena, abdominal pain, malaise and fever. She was hospitalized at the Nephrology Clinic due to severe anemia and signs of acute renal failure. The peripheral blood smear showed the presence of dysplastic erythroblasts and hypo-granular neutrophils. Ultra-sound was performed, which showed enlarged kidneys with signs of urinary obstruction of the first degree, with swollen, hypoechogenic parenchyma. After not responding to the conducted treatment, the patient died from heart failure. An autopsy was performed and Non-Hodgkin's, diffuse large B-cell lymphoma infiltrating multiple parenchymal organs was determined as the main cause of death. CONCLUSION: Diffuse large B-cell lymphoma with multiple organ affection and secondary renal involvement, presented as an acute renal failure is a rare case. We report on this case to update the literature concerning this topic and highlight the importance of renal biopsy in the diagnostics.

Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphanates.

Bisphosphonates are pyrophosphate analogues which inhibit osteoclastic activity. Long term use of bisphosphonates has recently been associated with osteonecrosis of the jaw (ONJ) defined as a three month non-healing defect in the jaw. ONJ is commonly precipitated by a tooth extraction or other stomatological procedure in patients treated with long-term, potent, high dose intravenous bisphosphonates for the management of myeloma, breast or prostate cancer. The aim of this study was to evaluate the incidence of ONJ in patients with MM treated with bisphosphonates during the last 8 years in our institution and to pre-sent the first two cases. We have analysed 247 myeloma patients diagnosed in our institution in the period 2002-09. Only 190/247 patients (76.9%) were treated with bisphosphonates. The incidence of ONJ in our group of patients treated with bisphosphonates was 2/190 (1%). The most commonly used bisphosponate was i.v. pamidronate (17.8%) and 46.6% were treated with two or more types of bisphosphonates. Sixty-five patients (34.2%) received oral forms of bisphosphonates; 42.1% patients were treated with i.v. forms of pamidronate, ibondronate or clodronate, and 45 patients (23.7%) received a combination of oral and i.v. forms of bisphosphonates. The mean duration of bisphosphonates therapy was 24.7±17.7 months. The low incidence of ONJ in our institution could be explained by the rare use of zolendronate, which is the most commonly referred bisphosphonate causing ONJ, and by a relatively shorter duration of bisphosphonates treatment in patients with MM. Despite the fact that ONJ is a rare complication in our institution, preventive measures must be considered.

Autoimmune thyroiditis and vitiligo in a child with minimal change nephrotic syndrome.

We report a 12-year-old child with multiple autoimmune components consisting of minimal change nephrotic syndrome (MCNS), Hashimoto's thyroiditis and vitiligo. This boy presented with MCNS, complicated by acute renal failure, and subsequently developed Hashimoto's thyroiditis and vitiligo. Conventional prednisone treatment did not induce remission, but multiple high dose infusions of methylprednisolone led to remission. The occurrence of nephrotic syndrome, Hashimoto's thyroiditis and vitiligo suggests that similar immunological mechanisms may be involved in the pathogenesis of these diseases.