Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe.

Genomic patterns of nasopharyngeal carcinomas (NPCs) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemoradiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating-lymphocyte-rich (TILs) samples were available in 19 and paired tumor-germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n = 27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n = 21); and of intermediate stability (1-7 singly mutated genes, n = 78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients (p < 0.001). No pathogenic germline mutations were identified. NPC exhibited APOBEC3A/B and nucleotide-excision-repair-related mutational signatures. As compared to TC, TILs demonstrated few shared and a higher number of low frequency private mutations (p < 0.001). In multivariate analysis models for progression-free survival, EBV positivity was a favorable prognosticator in stable tumors; BRCA1 mutations were unfavorable only in tumors of intermediate stability. In conclusion, other than described for SEA NPC, somatic BRCA1 mutations were common in SEE NPC; these were shared between TC and TILs, and appeared to affect patient outcome according to tumor genomic stability status. Along with the identified mutational signatures, these novel data may be helpful for designing new treatments for locally advanced NPC.

Unselective Measurement of Tumor-to-Stroma Proportion in Colon Cancer at the Invasion Front-An Elusive Prognostic Factor: Original Patient Data and Review of the Literature.

The tumor-to-stroma ratio is a highly debated prognostic factor in the management of several solid tumors and there is no universal agreement on its practicality. In our study, we proposed confirming or dismissing the hypothesis that a simple measurement of stroma quantity is an easy-to-use and strong prognostic tool. We have included 74 consecutive patients with colorectal cancer who underwent primary curative abdominal surgery. The tumors have been grouped into stroma-poor (stroma < 10%), medium-stroma (between 10 and 50%) and stroma-rich (over 50%). The proportion of tumor stroma ranged from 5% to 70% with a median of 25%. Very few, only 6.8% of patients, had stroma-rich tumors, 4% had stroma-poor tumors and 89.2% had tumors with a medium quantity of stroma. The proportion of stroma, at any cut-off, had no statistically significant influence on the disease-specific survival. This can be explained by the low proportion of stroma-rich tumors in our patient group and the inverse correlation between stroma proportion and tumor grade. The real-life proportion of stroma-rich tumors and the complex nature of the stroma-tumor interaction has to be further elucidated.

Expression profiling of 21 biomolecules in locally advanced nasopharyngeal carcinomas of Caucasian patients.

BACKGROUND: Since scarce data exist on the pathogenesis of nasopharyngeal carcinoma in Caucasian patients, we attempted to elucidate the responsible molecular pathways in this patient population. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples from 107 patients, diagnosed with locally-advanced nasopharyngeal carcinoma and treated with chemotherapy or chemo-radiotherapy, were analyzed by immunohistochemistry for the expression of the following proteins: E-cadherin, P-cadherin, Fascin-1, Cyclin D1, COX-2, EGFR, VEGF-A, VEGF-C, VEGFR-2, VEGFR-3, ERCC1, p53, p63, Ki67, MAPT, phospho-p44/42MAPK, PTEN, phospho-AKT, phospho-mTOR, and phospho-GSK-3ß. EBER status was assessed by in situ hybridization. The majority of the cases were included in tissue microarray. All stains were performed and assessed centrally by two pathologists. The median follow-up time was 76.8 (42.3 - 99.2) months. RESULTS: Biomolecules expressed in >90% of cases were: p53, COX-2, P-cadherin, EBER, phospho-GSK-3ß, and Fascin-1. WHO II+III tumors were more frequently EBER & PTEN positive and VEGF-A negative. Advanced age was significantly associated with positive phospho-GSK-3ß and ERCC1 expression; male gender with positive phospho-AKT and phospho-p44/42MAPK; and worse performance status (1 or 2) with negative Ki67, ERCC1, PTEN, and phospho-mTOR expression. Earlier disease stage was closely associated with p63, MAPT, PTEN, and Cyclin D1 positivity. Univariate Cox regression analysis highlighted Cyclin D1 as a negative prognostic factor for disease-free survival (p=0.034) and EBER as a positive one for overall survival (p=0.048). In multivariate analysis, advanced age and stage, poor performance status, and positive ERCC1 emerged as predictors of worse disease-free and overall survival, as opposed to positive phospho-mTOR. Clustering analysis defined two protein-expression groups being predictive of better overall survival (p=0.043). CONCLUSIONS: Our study is the first to examine the activation and interaction of established biomolecules and signaling pathways in Caucasian NPC patients in an effort to reveal new therapeutic targets.

Preoperative MRI accuracy after neoadjuvant chemoradiation for locally advanced rectal cancer.

Background and aims: To evaluate the performance of magnetic resonance imaging (MRI) in restaging locally advanced rectal cancers (LARC) after neoadjuvant chemoradiotherapy (nCRT), with pathologic correlation. Methods: 80 patients with LARC treated with neoadjuvant therapy, with restaging MRI and surgery, were enrolled and prospectively reviewed. The diagnostic accuracy of the restaging MRI was assessed for tumor (ymrT), nodal status (ymrN), circumferential resection margin (ymrCRM), extramural vascular invasion (ymrEMVI) and tumoral deposits (ymrN1c) by calculating the sensitivity (Se), specificity (Sp), negative predictive values (NPV) and positive predictive values (PPV). Response to treatment was classified as good response (complete/near complete) vs. poor response (poor/partial response). The agreement between the tumor regression grade at MRI (mrTRG) and pathology (pTRG) was reported, as well the performance of mrTRG to identify good responders. The correlation between restaging MRI and histopathology was assessed by Spearman correlation coefficient. Results: The MRI accuracy ranged between 63.8% and 92.5% for T stage and was 81.3% for N stage. All MRI parameters evaluated at restaging were statistically significant correlated with histopathology evaluation, but EMVI. There was moderate correlation for N and N1c and a positive strong correlation for T, CRM and TRG (Spearman correlation coefficient of 0.390 for mrN1c-pN1c, 0.428 for mrN-pN, 0.522 for mrCRM-pCRM, 0.550 for mrT-pT and 0.731 for mrTRG-pTRG). Diagnostic accuracy of anal sphincter invasion was 91.3%, with a negative predictive value (NPV) of 100%. Accuracy rate varied between 70% for partial response to 93.75% for complete response after nCRT. Conclusions: MR imaging had good accuracy in restaging LARCs after nCRT. Our results showed high MRI accuracy in detecting anal sphincter involvement for low rectal tumors, with high NPV to exclude tumoral invasion. Restaging MRI predicted well the tumor regression grade, with good diagnostic performance in differentiating good responders from poor/partial responders. The accuracy was high for detecting complete response.

MRI Evaluation of Complete and Near-Complete Response after Neoadjuvant Therapy in Patients with Locally Advanced Rectal Cancer.

Purpose To evaluate MRI performance in restaging locally advanced rectal cancers (LARC) after neoadjuvant chemoradiotherapy (nCRT) and interobserver agreement in identifying complete response (CR) and near-complete response (nCR). Methods 40 patients with CR and nCR on restaging MRI, surgery and/or endoscopy were enrolled. Two radiologists independently scored the restaging MRI and reported the presence of split scar sign (SSS) and MRI tumor regression grade (mrTRG). Diagnostic accuracy and ROC curves were calculated for single and combined sequences, with inter-reader agreement. Results Diagnostic performance was good for detecting CR and weaker for nCR. T2WI had the highest AUCs among individual sequences. There was a significant positive correlation between SSS and CR, with high Sp (89.5%/73.7%) and PPV (90%/79.2%) for both Readers. Similar accuracy rates were observed for the combination of sequences, with AUCs of 0.828-0.847 for CR and 0.690-0.762 for nCR. Interobserver agreement was strong for SSS, moderate for T2WI, weak for the combination of sequences. Conclusions Restaging MRI had good diagnostic performance in identifying CR and nCR. SSS had high Sp and PPV in diagnosing CR, with a strong level of interobserver agreement. T2WI with DWI was the optimal combination of sequences for selecting good responders.

What to do when nothing else is left to be done - metastatic non-HPV vulvar squamous cell carcinoma with multiple lines of chemotherapy.

Recurrent vulvar squamous cell carcinoma with multiple site metastases is a rare entity - (up to 14.2% of the total number of recurrences), with a poor prognosis (only 15% of the patients alive at 5 years). Due to its "hard to find" character, there are no standardized guidelines available and the treatment is extrapolated from advanced cervical carcinoma, anal carcinoma and other squamous cell carcinomas. Immunotherapy has shown some positive results in vulvar carcinoma with PD-L1 positive, high TMB, high MSI or with MMR deficiency. An alternative for selected cases without therapeutic resources could be the HPV vaccine. We present the case of a 64-year-old woman diagnosed in 2014 with vulvar squamous cell carcinoma stage II for which she underwent radical vulvectomy with bilateral inguinal lymphadenectomy followed by external radiotherapy. In 2019 she developed local recurrence associated with lung, pleural, lymph nodes and subcutaneous metastasis, treated with three lines of chemotherapy: paclitaxel/carboplatin followed by cisplatin/5-fluorouracil and carboplatin/gemcitabine. The patient's general health status altered progressively, and she died after the 4th cycle of carboplatin/gemcitabine. This case's management could be a starting point for the vulvar carcinoma cases where the standard therapeutical options do not represent a choice anymore, providing the necessary example on how to approach it.

Anorectal melanoma. Case report and review of the literature.

We report a case of primary anorectal melanoma, a very rare malignant tumor in this localization. The patient, a 57-year-old female, complained for one year of symptoms, which were attributed to hemorrhoids. An abdomino-perineal resection was performed. Pathologic examination revealed an anorectal melanoma with numerous lymph node metastases and an unusual metastatic deposit in a uterine leiomyoma. The pathogenesis, pathology, principles of treatment and prognosis of this entity are briefly discussed.

Primary chondroblastic osteosarcoma of the breast. Case report and review of the literature.

Primary osteosarcomas of the breast are rare tumors. We report a 58-year-old woman who presented with a left breast lump suggestive of phyllodes tumor. A sectorectomy was performed and histological examination revealed a chondroblastic osteosarcoma, an unusual finding. Two months later she underwent a mastectomy. A review of the literature revealed the divergency of therapeutic options.

Diagnostic reevaluation of 17 cases of pheochromocytoma - a retrospective study.

A rare neuroendocrine tumor, the pheochromocytoma (PCC) raises problems due both the limited experience of the researchers in this field and its pathogenic mechanisms, still not fully elucidated. The malignant potential of this tumor cannot be predicted based on its macro- or microscopic aspects, but on the presence of metastases. The aims of this study were: (1) the reevaluation of data for a pertinent and complete tumor diagnostic and prognostic pattern; (2) the statistical correlation of all investigated parameters with the malignant form and the survival rate in order to obtain a possible predictor of malignancy; (3) the potential identification of initially diagnosed benign tumors that become malignant in time. The retrospective study was conducted on 17 patients diagnosed with pheochromocytoma. We investigated: the personal data, the associated neuroendocrine syndromes, the clinical, the laboratory, the macro- and microscopic data [location, size, Hematoxylin-Eosin (HE) pheochromocytoma of the adrenal gland scaled score (PASS score), and immunohistochemical aspects] and the survival rate (analyzed by Kaplan-Meier method and Log-Rank test). The influence of diagnostic parameters on malignancy was calculated taking into consideration the survival rate. By reevaluation of the 17 cases, we tried to emphasize the value of a complex diagnosis pattern for PCCs, based on the correlation between clinical data, laboratory findings and microscopic features. A significant statistical difference between benign and malignant forms was not registered, but there were parameters as age, association with neuroendocrine syndromes, PASS score and specifically Ki-67 mitotic index that had a powerful impact on the survival rate and could be consider as possible predictors of malignancy. The potential of PCC malignant transformation was revealed in our study, by two cases that have metastasized in time.

Neoadjuvant conformal chemoradiation with induction chemotherapy for rectal adenocarcinoma. A prospective observational study.

BACKGROUND & AIMS: The purpose of this prospective observational study was to evaluate the rate and the prognostic factors for down-staging and complete response for rectal adenocarcinoma after induction chemotherapy and neoadjuvant chemoradiation followed by surgery, and to analyze the rate of sphincter-saving surgery. METHODS: We included from March 2011 to October 2013 a number of 88 patients hospitalized with locally advanced rectal adenocarcinoma in the Prof. Dr. Ion Chiricuta Institute of Oncology, Cluj. The treatment schedule included 2-4 cycles of Oxaliplatin plus a fluoropyrimidine followed by concomitant chemoradiation with a dose of 50 Gy in 25 fractions combined with a fluoropyrimidine monotherapy. RESULTS: The rate of T down-staging was 49.4% (40/81 evaluable patients). Independent prognostic factors for T down-staging were: age >57 years (p<0.01), cN0 (p<0.01), distance from anal verge >5 cm (p<0.01), initial CEA <6.2 ng/ml (p<0.01), higher number of chemotherapy cycles with Oxaliplatin (pROC=0.05) and protraction of radiotherapy of >35 days (p<0.01). Nine patients from 81 (11.1%) presented complete response (7 pathological and 2 clinical); the independent prognostic factors were stage cT2 versus cT3-4 (p<0.01), initial tumor size ≤3.5 cm and distance from anal verge >5 cm (p=0.03). Sixty-eight patients (79.1%) underwent radical surgery and among them 35 patients (51.5 %) had a sphincter saving procedure. CONCLUSIONS: Induction chemotherapy with neoadjuvant chemoradiation produced important down-staging in rectal adenocarcinoma. Independent prognostic factors for T down-staging were: age, cN0, distance from anal verge, initial CEA, the number of Oxaliplatin cycles and duration of radiotherapy; for complete response: cT2, initial tumor size and distance from the anal verge.