Real-world use of multigene signatures in early breast cancer: differences to clinical trials.

PURPOSE: In Italy, Lombardy was the first region to reimburse multigene assays (MGAs) for patients otherwise candidates for chemotherapy. This is a real-world experience of MGAs usage in six referral cancer centers in Lombardy. METHODS: Among MGAs, Oncotype DX (RS) was used in 97% of cases. Consecutive patients tested with Oncotype DX from July 2020 to July 2022 were selected. The distribution of clinicopathologic features by RS groups (low RS: 0-25, high RS: 26-100) was assessed using chi-square and compared with those of the TAILORx and RxPONDER trials. RESULTS: Out of 1,098 patients identified, 73% had low RS. Grade and Ki67 were associated with RS (p < 0.001). In patients with both G3 and Ki67 > 30%, 39% had low RS, while in patients with both G1 and Ki67 < 20%, 7% had high RS. The proportion of low RS in node-positive patients was similar to that in RxPONDER (82% vs 83%), while node-negative patients with low RS were significantly less than in TAILORx (66% vs 86%, p < 0.001). The distribution of Grade was different from registration trials, with more G3 and fewer G1 (38% and 3%) than in TAILORx (18% and 27%) and RxPONDER (10% and 24%) (p < 0.001). Patients ≤ 50 years were overrepresented in this series (41%) than in TAILORx and RxPONDER (31% and 24%, respectively) (p < 0.001) and, among them, 42% were node positive. CONCLUSIONS: In this real-world series, Oncotype DX was the test almost exclusively used. Despite reimbursement being linked to pre-test chemotherapy recommendation, almost 3/4 patients resulted in the low-RS group. The significant proportion of node-positive patients ≤ 50 years tested indicates that oncologists considered Oncotype DX informative also in this population.

Advancing the PD-L1 CPS test in metastatic TNBC: Insights from pathologists and findings from a nationwide survey.

Pembrolizumab has received approval as a first-line treatment for unresectable/metastatic triple-negative breast cancer (mTNBC) with a PD-L1 combined positive score (CPS) of ≥ 10. However, assessing CPS in mTNBC poses challenges. Firstly, it represents a novel analysis for breast pathologists. Secondly, the heterogeneity of PD-L1 expression in mTNBC further complicates the assessment. Lastly, the lack of standardized assays and staining platforms adds to the complexity. In KEYNOTE trials, PD-L1 expression was evaluated using the IHC 22C3 pharmDx kit as a companion diagnostic test. However, both the 22C3 pharmDx and VENTANA PD-L1 (SP263) assays are validated for CPS assessment. Consequently, assay-platform choice, staining conditions, and scoring methods can significantly impact the testing outcomes. This consensus paper aims to discuss the intricacies of PD-L1 CPS testing in mTNBC and provide practical recommendations for pathologists. Additionally, we present findings from a nationwide Italian survey elucidating the state-of-the-art in PD-L1 CPS testing in mTNBC.

The role of line-field confocal optical coherence tomography (LC-OCT) in the diagnosis of eccrine poroma: A case report.

Poroma is skin cancer that arises from the sweat gland cells. Its diagnosis could be difficult. Line-field optical coherence tomography (LC-OCT) is a novel imaging technique that has shown promise in the diagnosis and monitoring of various skin conditions. We report a case of poroma diagnosed by LC-OCT.

A Rare Complex BRAF Mutation Involving Codon V600 and K601 in Primary Cutaneous Melanoma: Case Report.

BRAF is one of the most common mutated kinases detected in human cancer, particularly in cases of primary cutaneous melanomas (PCM). Mutations of the BRAF proto-oncogene, at the p.V600 codon, has been detected in more than 50% of primary and metastatic melanoma cells in clinical samples. In addition to the most frequent BRAF p.V600E mutation, corresponding to the single base pair substitution c.1799T>A, rarer mutations, within and outside the V600 codon, have been described. Expectedly, BRAF and MEK inhibitors (or their combination) have been poorly explored as potential therapeutic strategies in metastatic melanomas harboring this rare mutation. By using a set of sequencing techniques and immunohistochemistry, this work reports the genomic and clinical features of two melanoma patients showing a rare complex mutation affecting codon V600 and K601 of the BRAF gene, leading to a V600E2; K601I change. Specifically, these two patients show a distinct clinical behavior and significantly differ in their responses to BRAF and MEK inhibitors. Indeed, although this treatment has proven to be effective and safe in both cases, the observed variability between the two patients resulted as a direct consequence of the baseline extent of brain involvement, intracranial treatment failure as well as on the PTEN status.

An 111In-Pentetreotide Positive Sclerosing Pneumocytoma.

A 43-year-old woman had an incidental lung mass identified on shoulder x-ray performed for pain. Contrast-enhanced CT showed a 38-mm mass in the medial segment of the right middle lobe, with features suggestive of carcinoid tumor. A In-pentetreotide scan showed intense uptake; furthermore, fine needle aspiration biopsy yielded neuroendocrine cells confirming the carcinoid hypothesis. However, definitive surgical histology showed a sclerosing pneumocytoma. This could potentially suggest that such rare tumors, with metastatic potential, could respond to somatostatin analogue treatment.

Clear cell thymic carcinoma: a case report.

Clear cell thymic carcinoma is a rare and invasive tumor of the mediastinum for which there are no uniform treatment guidelines. The combination of carboplatin plus paclitaxel seems to be the most effective regimen for this disease. We report a case of locally advanced clear cell thymic carcinoma treated with this schedule, in which we observed a relevant and rapid tumor shrinkage.

Tyrosine Kinase Inhibitors in EGFR-Mutated Large-Cell Neuroendocrine Carcinoma of the Lung? A Case Report.

Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a high-grade carcinoma belonging to the neuroendocrine tumors of the lung and is different from typical lung large-cell carcinoma. It represents about 3% of all pulmonary malignancies and is characterized by neuroendocrine cytologic features. The treatment usually is platinum-based chemotherapy, however the outcome remains poor. Therefore new therapeutic options are needed. Tyrosine kinase inhibitors have demonstrated greater efficacy and better tolerability than standard chemotherapy in non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR) mutations. EGFR gene mutations were also rarely identified in LCNEC. We report a patient with lung LCNEC activating EGFR mutations who showed an impressive response to gefitinib.

Primary osteosarcoma of the breast: a case report.

Introduction. Primary osteosarcoma of the breast is a rare soft-tissue form of osteosarcoma without involvement of the skeletal system. Due to the rarity of the disease, its clinical features and optimal treatment remain unclear. Case Presentation. This case report deals with a 62-year-old woman with pure osteosarcoma of the breast. Conclusions. The prognosis of primary osteosarcoma of the breast is poor. Recurrence is frequent, and it is often associated with haematogenous spread of the disease to the lung. Treatment follows the model of sarcomas affecting other locations and must be planned in a multidisciplinary fashion. Adjuvant chemotherapy should be considered for patients with tumors showing aggressive features.

Infective colitis associated with human intestinal spirochetosis.

AIM: Our study reports the detection and identification of intestinal spirochetosis in patients with colonic diseases in a tertiary-care hospital over a 12-year period, and includes a description of all cases we diagnosed. METHODS: Our patients (8323) underwent colonoscopy and histopathological examinations including transmission electron microscopy (TEM) and light microscopy. Specimens from patients suspected of intestinal spirochetosis at histopathology (17 patients) underwent microbiological investigation performed by culture and molecular methods (16S restriction fragment length polymorphism-polymerase chain reaction [RFLP-PCR], nox RFLP-PCR assays). RESULTS: Seventeen cases were diagnosed: seven patients were infected by B. aalborgi, one by B. pilosicoli, two by both species and four by Brachyspira spp. diagnosed both histopathology and microbiology (culture and molecular methods: 16S RFLP-PCR and nox RFLP-PCR assays). Three cases were referred to as Brachyspira spp. infections using only histopathology, including TEM. CONCLUSIONS: Our results demonstrated that intestinal spirochetosis, although rarely occurring, might play a role in chronic diarrhea and suggested a pathogenetic mechanism of intestinal spirochetosis based on the destruction of colonic microvilli and colitis histologically documented, providing additional clinical and pathological information on this entity. This study suggests that metronidazole seems to be the drug of choice for the eradication of intestinal spirochetosis.

Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease.

BACKGROUND & AIMS: The Marsh-Oberhuber classification of duodenojejunal mucosal lesions is currently used for celiac disease. A more simplified classification, which is based on 3 villous morphologies (A, non-atrophic; B1, atrophic, villous-crypt ratio <3:1; B2, atrophic, villi no longer detectable) and an intraepithelial lymphocyte count of >25/100 enterocytes, has recently been proposed. The aim of the study was to asses the interobserver agreement between different pathologists in classifying celiac disease lesions according to both Marsh-Oberhuber and the new classification system. METHODS: Sixty patients were selected for the study: 10 subjects without celiac disease, 13 celiac patients with normal villi but a pathologic increase in intraepithelial lymphocytes >25/100 and hyperplastic crypts, and 37 patients with celiac disease with villous atrophy. Sixty slides were sent to 6 pathologists, who were blinded to each other and were not given any clinical information. Each pathologist received the set of biopsy specimens on 2 separate occasions and had to evaluate them according to both grading systems in a random order. The kappa statistic was used to assess agreement between each pair of pathologists. RESULTS: Overall, mean kappa values were 0.35 (fair) for the Marsh-Oberhuber classification versus 0.55 (moderate) for the new classification system. CONCLUSIONS: The new classification for duodenal pathology in celiac disease gives better interobserver agreement compared with the more cumbersome Marsh-Oberhuber classification and contributes to the validity of diagnosis in celiac disease.

Influence of type 2 diabetes on functional and structural properties of coronary artery bypass conduits.

Recent studies have reported a high incidence of postoperative unfavorable cardiac-related events in patients with diabetes who underwent coronary artery bypass grafting (CABG). Structural and functional characteristics of CABG conduits, which have been shown to play an important role in patient outcome after myocardial revascularization, have not been fully investigated in diabetic subjects. Therefore, we sought to determine the influence of adult-onset diabetes on vasoreactivity and morphological profile of venous and arterial grafts. Of the 160 consecutive patients enrolled in the study, 90 were diagnosed with type 2 diabetes and 70 did not have diabetes (control group). All patients underwent evaluation of glucose control before surgery. Tissue specimens were collected from left internal thoracic artery (LITA) and saphenous vein (SV) grafts harvested during elective CABG. Functional tests were performed to assess contractile and vasodilative responses of bypass conduits. Histological evaluation was carried out to examine vessel wall structure. Univariate and multivariate analyses were performed to correlate the preoperative factors related to the control of the endocrine disorder with histological findings. Patient medical history and demographics did not differ between the groups. Diabetic patients showed significant microalbuminuria and higher plasma levels of C-peptide and GHb as compared with nondiabetic subjects. Functional tests of the LITA segments revealed no difference between groups with regard to contractile and vasodilative responses. In contrast, significant impairment in the endothelium-related vasodilation of the SV grafts was observed in diabetic subjects. Histological studies showed structural preservation of the arterial conduits in both groups. However, marked intimal abnormalities (also atherosclerotic calcified plaques) were detected in SV grafts harvested from diabetic patients. Logistic regression analysis showed that high levels of proteinuria and GHb were independent predictors of advanced structural degeneration of SV conduits. Treatment modality, duration of diabetes, and other demographic or metabolic factors were found to have no influence on the morphological characteristics of SV conduits. In conclusion, biological properties of LITA conduits for CABG were preserved in diabetic patients. However, these patients frequently showed impairment of the endothelium-dependent vasorelaxation and intimal degeneration of SV grafts. The extent of structural abnormalities of SV grafts was inversely correlated with the efficacy of the metabolic control of the endocrine disorder. Further studies are required to conclusively correlate preoperative SV graft abnormalities with postoperative conduit patency rate and the occurrence of adverse cardiac-related events in diabetic subjects.

Rapid detection and identification of Brachyspira aalborgi from rectal biopsies and faeces of a patient.

This study reports for the first time the detection of Brachyspira aalborgi in faeces and rectal biopsies of a female suffering for 3-4 months of abdominal pain with long-standing mucosal diarrhoea, rectal bleeding and suspected carcinoma of the rectum. After pre-treatment of samples (faeces and biopsies) with a liquid medium (trypticase soy broth-TSB) containing foetal calf serum (FCS, 10%) and spectinomycin and rifampicin (TSB-SR) the first detection of B. aalborgi isolate HBS1 was observed after 48 h in the primary plates of selective blood agar modified medium (BAM) containing spectinomycin and rifampicin (BAM-SR), where growth zones were signalled by a small weakly beta-haemolytic halo. Attempts to subculture spirochaetes in agar media failed. The new HBS1 isolate was only propagated in TSB broth and at electron microscopy it showed 4 endoflagella inserted at each tapered end. The phenotypic characterization of HBS1 demonstrated absence of hippurate hydrolysis, indole production, alpha-galactosidase, alpha- and beta-glucosidase activities in accordance with the B. aalborgi type strain. Rapid identification of B. aalborgi isolate HBS1 was performed directly from faeces and rectal biopsies and subsequently from pure cultures by a genetic method based on 16S DNA restriction fragment length polymorphism (RFLP)-polymerase chain reaction (PCR). The sequence of 16S DNA amplicon of the isolate HBS1 was found 99.2% corresponding to that of the B. aalborgi type strain. Our results encourage further investigations for the development of a suitable selective agar medium for the isolating and cultivating B. aalborgi from human specimens.