Whole breast radiotherapy in cN0 early breast cancer patients with pathological sentinel lymph nodes (pN1mic, pN1a) without axillary dissection: preliminary results of the observational LISEN trial.

PURPOSE: Axillary management remains unclear when sentinel lymph node (SLN) results are positive in cN0 patients with breast cancer (BC). The trial ACOSOG Z0011 represented a revolution with axillary lymph node dissection (ALND) omission in SLN+ patients, despite critiques regarding non-uniformity of radiation fields. We conducted an observational study (LISEN) where whole breast radiotherapy (WBRT) was planned with tangential fields without nodal irradiation in patients eligible for the Z0011 trial. METHODS: Inclusion criteria were female patients with histologically proven BC, cT1-2cN0, planned conservative surgery, no neoadjuvant therapy. Patients were stratified into two groups: micrometastatic (pN1mic, group 1) and macrometastatic (pN1a, group 2) lymph nodes. Tangential field WBRT was mandatory. Clinical outcomes were analysed, measured from surgery until the first event. RESULTS: In all, 199 patients underwent conservative surgery and SLN biopsy; 133 patients meeting criteria were analysed: 41 patients (30.8%) pN1mic and 92 (69.2%) pN1a. The 5­year disease-free survival (DFS) was 95.0% (85.9-100%) in group 1 and 93.0% (86.3-100.0%) in group 2 (p = 0.78). Overall survival (OS) was 100% (100-100%) in group 1 and 97.4% (92.4-100%) in group 2 (p = 0.74). For the whole cohort DFS and OS were 93.6% (88.2-99.4%) and 96.9% (91.5-100.0%), respectively. For groups 1 and 2, the 5­year outcomes were 5.0% (0.0-14.4%) and 2.3% (0.0-6.1%) for local recurrence (p = 0.51), and 6.2% (0.0-17.4%) and 7.0% (0.0-13.7%) for distant metastasis (p = 0.61), respectively. In group 1, regional recurrence (RR) and local regional recurrence (LRR) were 5.0% (0.0-14.1%; p = 0.13). In group 2, RR and LRR were 0.0% (0.0-0.0%). CONCLUSION: Our results showed good regional control in patients who met the Z0011 trial criteria. WBRT, without nodal surgery or RT, avoiding axillary morbidity, seems to be a good choice.

Long-term outcome of neoadjuvant endocrine therapy with aromatase inhibitors in elderly women with hormone receptor-positive breast cancer.

BACKGROUND: Aromatase inhibitors (AIs) are more effective than tamoxifen as neoadjuvant endocrine therapy (NET) for hormone receptor (HR)-positive breast cancer. Here we report the surgical and long-term outcome of elderly postmenopausal patients with locally advanced, HR-positive breast cancer treated with preoperative AIs. METHODS: Between January 2003 and December 2012, 144 postmenopausal patients inoperable with breast conservative surgery (BCS) received letrozole, anastrozole, or exemestane as NET. Patients underwent breast surgery and received adjuvant AIs. Adjuvant systemic therapy, chemotherapy and/or trastuzumab, and adjuvant radiotherapy were administered as appropriate, but limited to high-risk patients with few or no comorbidities. RESULTS: After a median follow-up of 49 months, 4 (3.0 %) patients had local relapse, 18 (12.5 %) had distant metastases, and 24 (17.0 %) died. BCS was performed in 121 (84.0 %) patients. A tumor size <3 cm and human epidermal growth factor receptor 2 (HER2) negativity were predictors of BCS. The achievement of BCS and grade G1 were significantly associated with longer disease-free survival (DFS) (p = 0.009 and p = 0.01, respectively) and overall survival (p = 0.002 and p = 0.005, respectively). Residual tumor ≤2 cm (yT0-yT1) in the longest diameter after NET was also statistically associated with longer DFS (p = 0.005). CONCLUSIONS: The results of this retrospective study indicate that elderly breast cancer patients with a tumor size <3 cm at diagnosis and HER2 negativity have a higher probability of achieving BCS after NET. Moreover, patients treated with BCS and with grade G1 tumor have a reduced risk of recurrence and death in the long-term follow-up.

Diffuse large B-cell lymphoma of the colon with synchronous liver metastasis: a rare case report mimicking metastatic colorectal adenocarcinoma.

BACKGROUND: Primary colorectal lymphoma represents a rare minority among the colonic neoplasms. Early diagnosis is often difficult because of unspecific symptoms, with subsequent delays in diagnosis and management. We describe a rare case of colonic lymphoma presenting with synchronous liver metastasis. CASE PRESENTATION: A 70-year-old male with a 6-mo history of vague abdominal pain, constipation and melena was referred to our hospital. Computed tomography scan of abdomen revealed the presence of a mass along the proximal ascending colon. Colonoscopy biopsy showed external compression of the cecum with two ulcerations of mucosa, but it was not consistent for a definitive diagnosis. Because the difficulties in the preoperative pathological diagnosis, the high risk of bowel obstruction and the correlated hemorrhagic risk, the patient underwent a right hemicolectomy associated with locoregional lymphadenectomy and liver resection.The surgically resected right colon and liver tumors were all immunohistochemically diagnosed as diffuse large B-cell lymphomas (DLBCL). The patient refused any other antineoplastic treatment; he is alive and free of disease at 3 years after initial diagnosis. CONCLUSIONS: Primary colonic lymphomas represent a rare minority among the colonic neoplasms. Their correct pre-operative identification is crucial for the design of treatment. This case highlights the difficulty in diagnosing of primary colonic lymphoma. To our knowledge, this is the first report of a colonic lymphoma presenting with a colonic mass and a synchronous liver metastasis.

Struma ovarii with follicular thyroid-type carcinoma and neuroendocrine component: case report.

Struma ovarii (SO) is a slow-growing ovarian neoplasm with thyroid tissue as its predominant component. It is an uncommon neoplasm, usually asymptomatic with an unknown risk of malignant transformation. Due to difficulties in assessing the rare biological nature and the discrepancies in the reported cases, a consensus on the appropriate treatment has not been definitively reached. A 50-year-old female was subjected to upper gut endoscopy which showed a 30-mm mass located in the gastric antrum, suggestive of mesenchimal tumor. Incidentally, a pelvic CT scan also documented a solid mass in the right adnexa, with morphological characteristics of ovarian neoplasm. The patient underwent gastrectomy, total hysterectomy, bilateral salpingo-oophorectomy with lymph node dissection, and omentectomy. Histology documented the presence of gastric cavernous angioma, and, in the right adnexa, foci of follicular thyroid-type carcinoma arising in SO with a well-differentiated neuroendocrine component.Here we report and discuss the clinical and morphological presentation of follicular thyroid-type carcinoma arising in SO. The neoplasm was discovered incidentally and had a favorable clinical outcome at 1-year follow-up.

Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis.

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.

Malignant PEComa: a case report with emphasis on clinical and morphological criteria.

BACKGROUND: Malignant perivascular epitheliod cell tumor (PEComa) is a very rare entity composed of distinctive perivascular epitheliod cells with variable immunoreactivity for melanocytic and muscle markers. At present this neoplasm does not have a known normal cellular counterpart and the natural history is often unpredictable. Up to now, few cases of PEComa have been described and treatment modalities are still controversial, particularly in advanced conditions. CASE PRESENTATION: We handled the case of a 42-year-old man with unresectable PEComa of the abdomen. A 7 cm hepatic hypodense lesion between segment V and VIII of the liver and diffuse intraperitoneal nodules of 0,3-3,5 cm along the right subcapsular hepatic region, were documented by a CT scan. Radiological images showed abnormal lymph nodes of the right internal mammary chain and anterior mediastinum. The patient underwent an explorative laparotomy for uncontrolled intraabdominal hemorrhage without a well-defined preoperative tumor diagnosis. At surgery, multiple lobulated nodules containing hemorrhagic fluid on the liver surface, peritoneum and omentum were confirmed. The procedure had a palliative intent and consisted of hemostasis, hematomas evacuation and omentectomy. The diagnosis of PEComa was made after surgery on the basis of morphological and immunohistochemical criteria. Radiological and intra operative findings suggest that the mass has an hepatic origin with diffuse involvement of hepatic capsule and suspensory ligaments. The patient received medical support care with blood and plasma transfusions. In our experience, PEComa was clinically malignant, leading to a fatal outcome 25 days after hospital admission of patient. CONCLUSIONS: Here we report and discuss the peculiar clinical, radiological and morphological presentation of unresectable PEComa. Although in the majority of the reported series, PEComas show a more better prognosis, our case presents with a particular aggressive biological behaviour. The importance of a correct preoperative diagnosis, the need for more effective targeted therapies based on tumor molecular knowledge and evidence-based clinical studies are emphasized together with a revision of the concerning scientific literature.

Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer.

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from ß-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of ß-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/ß-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2-centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.

PONDx: real-life utilization and decision impact of the 21-gene assay on clinical practice in Italy.

Clinicopathological prognostic features have limited value to identify with precision newly diagnosed patients with hormone receptor (HR)-positive, HER2-negative breast cancer (BC), who would benefit from chemotherapy (CT) in addition to adjuvant hormonal therapy (HT). The 21-gene Oncotype DX Breast Recurrence Score® (RS) assay has been demonstrated to predict CT benefit, hence supporting personalized decisions on adjuvant CT. The multicenter, prospective, observational study PONDx investigated the real-life use of RS® results in Italy and its impact on treatment decisions. Physicians' treatment recommendations (HT ± CT) were documented before and after availability of RS results, and changes in recommendations were determined. In the HR+ HER2- early BC population studied (N = 1738), physicians recommended CT + HT in 49% of patients pre-RS. RS-guided treatment decisions resulted in 36% reduction of CT recommendations. PONDx confirms that RS results provide clinically relevant information for CT recommendation in early-stage BC, resulting in a reduction of more than a third of CT use.

Speed rate (SR) as a new dynamic index of melanoma behavior.

Melanomas are skin tumors that show a variety of biological behavior. Some develop very fast and some other grow extremely slow, with metastasis appearing, eventually, many years after the diagnosis. The number of mitoses in primary melanoma has been related to a more aggressive tumor and may have a potential as predictive factor for cutaneous melanoma survival. However, tumor mitotic rate is a static measure and in multivariate analysis on tumor survival, it has scored less than other tumor characteristics. We tried to evolve tumor mitotic rate from a static parameter to a time-dependent one. Similar to the already described growth rate (GR), we propose the speed rate (SR). SR is defined as the ratio of tumor mitotic rate to time to melanoma development. A prospective series of 345 patients with melanoma was investigated for the role of SR as predictive factor for sentinel lymph node (SLN) positivity and tumor progression. We calculated the best threshold for SR and GR to predict the risk of recurrence. Melanoma clinical and histological characteristics as well as GR were correlated in a multivariated analysis with SR. SR values >0.2 mitoses/month were associated with negative prognostic factors such as ulceration (82.8%), SLN positivity (80%), progression (82.8%), and death (85.7%). The association of GR > 0.3 mm/months and SR > 0.2 mitoses/month had a significant predictive value in terms of SLN positivity, progression, and recurrence-free survival. We propose SR as a new "dynamic" predictor of histological SLN positivity and melanoma recurrence risk. We think that he association with this new feature with GR may be helpful in improving the accuracy of predicted clinical outcome of patient especially with thin melanomas.

Treatment Intensification for Locally Advanced Rectal Cancer: Impact on Pathological Complete Response and Outcomes.

AIM: Pathological complete response (pCR) and clinical outcomes [overall survival (OS), disease-free survival (DFS), locoregional control (LC)] were evaluated in a single-institution experience of different schedules of neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Data for 322 patients with LARC were retrospectively analyzed. pCR was evaluated according to Mandard tumor regression grade (TRG). The Kaplan-Meier method was used to estimate OS, DFS and LC. RESULTS: Three hundred and three (94.1%) patients underwent surgery. pCR was observed in 81 patients (26.7%), with TRG1-2 rate of 41.8%. The 5- and 10-year OS, DFS and LC rates were 82.5%±2.5% and 65.5%±3.8%, 81.2%±2.4% and 79.3%±2.9%, 93.1%±1.7% and 90.5%±2.1%, respectively. CONCLUSION: Neoadjuvant CRT in LARC patients resulted in favorable long-term oncological outcomes, with a high pCR rate and acceptable toxicity.

Prognostic relevance of DNA damage and repair biomarkers in elderly patients with hormone-receptor-positive breast cancer treated with neoadjuvant hormone therapy: evidence from the real-world setting.

BACKGROUND: The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was explored in postmenopausal, hormone-receptor-positive breast cancer patients treated with neoadjuvant hormone therapy (NAHT). METHODS: Data on 55 patients were included. The phosphorylated ataxia-teleangectasia and Rad3-related protein (pATR), phosphorylated ataxia-telangiectasia mutated (ATM) kinase, and phosphorylated H2A Histone Family Member X (γ-H2AX) were evaluated by immunohistochemistry in paired tissues collected at baseline and following NAHT. Biomarkers were considered both singularly and within signatures. Ki-67 percentage change was the primary biomarker endpoint. Classical endpoints were also considered. RESULTS: The most favorable Ki-67 outcome was associated with the γ-H2AX/pATM signature (p = 0.011). In models of Ki-67 reduction, 'luminal B' subtype, higher grade of anaplasia, and the γ-H2AX/pATM signature tested as significant (p < 0.05 for all). Results were confirmed in multivariate analysis. No association was observed with pathologic response. An increase of ∆γ-H2AX in paired breast tissues was associated with longer event-free survival (p = 0.027) and overall survival (p = 0.042). In Cox models, both survival outcomes were solely affected by grade of anaplasia, with less favorable prognosis in the highest grades (p < 0.05 for both). CONCLUSIONS: We report novel evidence of the prognostic role of DDR biomarkers on important patient outcomes in postmenopausal hormone-receptor-positive breast cancer patients treated with NAHT. If confirmed in future and adequately sized trials, our results may help inform therapeutic decisions and clarify underlying biological mechanisms.

Changes of topoisomerase IIalpha expression in breast tumors after neoadjuvant chemotherapy predicts relapse-free survival.

PURPOSE: To assess the value of changes in the expression of topoisomerase IIalpha (TopoII) and the proto-oncogene erbB-2 (HER-2) as predictors of relapse-free survival in women with operable breast cancer treated with anthracycline-based neoadjuvant chemotherapy. PATIENTS AND METHODS: Seventy-seven patients with primary breast cancer who had undergone neoadjuvant anthracycline-based chemotherapy were included in the present study. TopoII and HER-2 were measured by immunohistochemistry in prechemotherapy and postchemotherapy (at the time of surgery) tumor specimens, and the value of their changes as predictors of relapse-free survival were evaluated by Kaplan-Meier and Cox proportional hazard regression analyses. RESULTS: Neoadjuvant chemotherapy resulted in a significant reduction in the percentage of cells expressing TopoII (P < 0.0001). No significant change was observed for HER-2. TopoII and HER-2 expression before chemotherapy predicted tumor response to treatment. Changes in TopoII expression after chemotherapy were strongly associated with a poor relapse-free survival (P < 0.0001) in a Cox multivariate analysis adjusted for other clinicopathologic prognostic factors. CONCLUSION: Changes in TopoII expression after anthracycline-based neoadjuvant chemotherapy is an independent predictor of a poor relapse-free survival in patients with breast cancer. Tumor cells displaying an increased TopoII expression after treatment may be responsible for relapses, and may, therefore, define a group of patients with anthracycline-resistant breast cancer.

Drug-induced cutaneous lupus erythematosus after 5 years of treatment with carbamazepine.

Drug-induced lupus is a disease, inducible by several drugs, that shares symptoms and laboratory characteristics with idiopathic lupus erythematosus. We report a case of carbamazepine-induced cutaneous lupus erythematosus which developed after 5 years of treatment in a patient who was on this medication because of an epileptic crisis after cranial trauma. Carbamazepine is a medication rarely implicated in drug-induced cutaneous lupus, moreover there are very few reports of such long periods between the start of therapy and the presentation of the clinical symptoms. We describe this case to emphasize the possibility of cutaneous lupus induction by carbamazepine even after many years of therapy.

Interleukin-30 Promotes Breast Cancer Growth and Progression.

The inflammatory tissue microenvironment that promotes the development of breast cancer is not fully understood. Here we report a role for elevated IL30 in supporting the breast cancer cell viability and invasive migration. IL30 was absent in normal mammary ducts, ductules, and acini of histologically normal breast and scanty in the few stromal infiltrating leukocytes. In contrast, IL30 was expressed frequently in breast cancer specimens where it was associated with triple-negative and HER2+ molecular subtypes. In stromal leukocytes found in primary tumors or tumor-draining lymph nodes, which included mainly CD14+ monocytes, CD68+ macrophages, and CD33+/CD11b+ myeloid cells, IL30 levels increased with disease stage and correlated with recurrence. A negative correlation was determined between IL30 expression by nodal stromal leukocytes and overall survival. In vitro studies showed that human recombinant IL30 upregulated expression of a pro-oncogenic program, including especially IL6 in both triple-negative and HER2+ breast cancer cells. In triple-negative breast cancer cells, IL30 boosted a broader program of proliferation, invasive migration, and an inflammatory milieu associated with KISS1-dependent metastasis. Silencing of STAT1/STAT3 signaling hindered the regulation of the primary growth and progression factors in breast cancer cells. IL30 administration in vivo fostered the growth of triple-negative breast cancer by promoting proliferation and vascular dissemination of cancer cells and the accumulation of intratumoral CD11b+/Gr1+ myeloid cell infiltrates. Overall, our results show how IL30 regulates breast cancer cell viability, migration, and gene expression to promote breast cancer growth and progression and its impact on patient outcome. Cancer Res; 76(21); 6218-29. ©2016 AACR.

Overexpression of PY1289-HER3 in sporadic pulmonary carcinoid from patients bearing MEN1 gene variants.

The present study aimed to investigate the expression of human epidermal growth factor receptors (HERs) (HER1/HER2/HER3/HER4) and their phosphorylated forms (p-HER1/p-HER2/p-HER3/p-HER4) in pulmonary carcinoids (PCs). HER and p-HER protein expression was assessed by immunohistochemistry on tissue microarrays in 37 specimens of sporadic PCs, 29 typical carcinoids (TCs) and 8 atypical carcinoids (ACs). When compared with the ACs, the TCs did not exhibit any differences in terms of HER/p-HER expression. The tumors of this study have previously been characterized for the expression of menin and the mutational status of menin 1 (MEN1), a gene strongly implicated in the pathogenesis of PCs. In the present study, it was found that the cytoplasmic ('disarrayed'), but not nuclear ('arrayed') expression of menin was positively correlated with HER3 (P=0.004), HER4 (P=0.015), p-HER1 (P=0.005), p-HER3 (P<0.001), and p-HER4 (P=0.001) expression. Moreover, HER3 and p-HER3 were found to be significantly more expressed in PCs with MEN1 variants, than in tumors with MEN1 wild-type (P=0.000 and P=0.025, respectively). These findings suggest the potential clinical use of HER inhibitors in the treatment of patients with PCs, particularly for individuals with p-HER3-positive PCs harboring MEN1 gene variants.

Epithelioid angiosarcoma of the gallbladder: case report.

A patient with epithelioid angiosarcoma of the gallbladder is described. This is only the second case of an extremely rare but highly aggressive tumor reported in the international literature. Pathophysiological, clinical, and therapeutic aspects are discussed in relation to the available data on angiosarcomas of the gallbladder.

Left ventricular wall stress as a direct correlate of cardiomyocyte apoptosis in patients with severe dilated cardiomyopathy.

BACKGROUND: Apoptosis has been implicated as a possible mechanism in the development of heart failure (HF), but the mechanisms involved remain unclear. In patients with severe dilated cardiomyopathy, we evaluated cardiomyocyte apoptosis in relation to the transmural distribution of Bax and Bcl-2 proteins (2 molecules inhibiting or promoting apoptosis, respectively) and left ventricular wall stresses. METHODS: We studied the presence and distribution of cardiomyocyte apoptosis in 90 tissue samples obtained from 8 patients who were undergoing left ventricular reduction with the Batista (ventricular remodeling) operation. Apoptosis was assessed in tissue samples taken from the entire left ventricular thickness (subdivided in subepicardial, midmyocardial, and subendocardial sections) with the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL) technique and DNA agarose gel electrophoresis. The expression of Bcl-2 and Bax proteins were determined with both Western analysis and immunohistochemistry. RESULTS: TUNEL-positive cells (apoptotic index) were 2.3% +/- 1.4%. Apoptotic cells were predominantly distributed in the subendocardium, where higher levels of Bax protein were detected. The ratio of Bax to Bcl-2 proteins (Bax/Bcl-2) was similar in the midmyocardium or subepicardium, but increased in the subendocardium, where it was directly related to systolic wall stress (y = 0.009x - 0.629; r2 = 0.85, P <.001). The apoptotic index was also directly related to systolic and end-diastolic stresses calculated from hemodynamic and echocardiographic data (r2 = 0.77, P <.001 and r2 = 0.40, P <.01, respectively). CONCLUSIONS: In patients with dilated cardiomyopathy, in whom cardiomyocyte apoptosis is an important cause of cell loss, apoptosis is more extensively localized in the subendocardium and strictly related to ventricular wall stresses and the Bax/Bcl-2 ratio.