Slow and steady wins the race: Fractionated near-infrared treatment empowered by graphene-enhanced 3D scaffolds for precision oncology.

Surgically addressing tumors poses a challenge, requiring a tailored, multidisciplinary approach for each patient based on the unique aspects of their case. Innovative therapeutic regimens combined to reliable reconstructive methods can contribute to an extended patient's life expectancy. This study presents a detailed comparative investigation of near-infrared therapy protocols, examining the impact of non-fractionated and fractionated irradiation regimens on cancer treatment. The therapy is based on the implantation of graphene oxide/poly(lactic-co-glycolic acid) three-dimensional printed scaffolds, exploring their versatile applications in oncology by the examination of pro-inflammatory cytokine secretion, immune response, and in vitro and in vivo tumor therapy. The investigation into cell death patterns (apoptosis vs necrosis) underlines the pivotal role of protocol selection underscores the critical influence of treatment duration on cell fate, establishing a crucial parameter in therapeutic decision-making. In vivo experiments corroborated the profound impact of protocol selection on tumor response. The fractionated regimen emerged as the standout performer, achieving a substantial reduction in tumor size over time, surpassing the efficacy of the non-fractionated approach. Additionally, the fractionated regimen exhibited efficacy also in targeting tumors in proximity but not in direct contact to the scaffolds. Our results address a critical gap in current research, highlighting the absence of a standardized protocol for optimizing the outcome of photodynamic therapy. The findings underscore the importance of personalized treatment strategies in achieving optimal therapeutic efficacy for precision cancer therapy.

Multidisciplinary ocular and periocular cancers meetings: implementation in a tertiary referral center and analysis over a 12-months period.

PURPOSE: The complexity of multimodal approaches in cancer management has lately led to the establishment of multidisciplinary tumor boards (MDTBs) to define targeted, patient-centered treatment strategies. However, few data are available regarding the application of this approach in Ocular Oncology. Hereby, the Authors analyze the implementation and outcomes of a trained MDTB in a tertiary ocular oncology referral center. METHODS: A retrospective descriptive analysis of MDTB meetings discussing patients with ocular and periocular cancers, over a 12-months period, was carried out. Data were grouped by main site involved, topics discussed and final clinical decisions therefore taken. Meetings were held by a constant 'Core team' or - when required - by a broader 'Extended team'. RESULTS: During the observational period 86 cases were discussed. In 27 patients ocular surface tissues were involved (31%), in 25 patients orbital tissues (29%), in 22 patients eyelids (26%), and in 12 patients intraocular tissues (14%). In 13 cases (15%) naïve or referred new patients, in 34 cases (40%) imaging or histopathologic reports and in 39 cases (45%) treatment plans were discussed. Regarding final decisions, a treatment plan was scheduled in 47 cases (55%) and a diagnostic ascertainment was required in 27 patients (31%); locally advanced and/or systemic diseases were referred or teamed up with other specialists in 12 cases (14%). CONCLUSIONS: Ocular Oncology multidisciplinary team, by sharing expertise of different specialists, ensures a comprehensive evaluation of patients improving the accuracy of diagnosis and staging upon which planning a proper treatment. Further studies are needed to assess if this approach may also improve the outcomes and prognosis of patients.

DOG1 as an Immunohistochemical Marker of Acinic Cell Carcinoma: A Systematic Review and Meta-Analysis.

DOG1 is a transmembrane protein originally discovered on gastrointestinal stromal tumors and works as a calcium-activated chloride channel protein. There are a limited number of articles on the potential utility of this antibody in the diagnosis of salivary gland tumors in routine practice. In this study, we aimed to investigate the role of DOG1 as an immunohistochemical marker in patients with salivary acinic cell carcinoma (ACC) through meta-analysis. A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2010 to September 2021. The literature search revealed 148 articles, of which 20 were included in the study. The overall rate of DOG1 expression in salivary acinic cell carcinoma was 55% (95% CI = 0.43-0.58). Although ACC is a challenging diagnosis, paying careful attention to the cytomorphological features in conjunction with DOG1 immunostaining can help to reach an accurate diagnosis.

Clinical Evaluation of the Optical Filter for Autofluorescence Glasses for Oral Cancer Curing Light Exposed (GOCCLES®) in the Management of Potentially Premalignant Disorders: A Retrospective Study.

BACKGROUND: Any oral potentially malignant disorders (OPMDs) must be regularly monitored through clinical examination to detect any possible malignant transformation. Conventional intraoral exams, however, can be difficult because these conditions may resemble benign lesions. For this reason, several non-invasive diagnostic technologies have been developed to help the clinician in detecting and distinguishing between cancerous and benign lesions. Epithelial dysplasia can be considered the most important predictor of malignant evolution. Therefore, in this study we aim to evaluate the ability of an optical filter for autofluorescence Glasses for Oral Cancer Curing Light Exposed (GOCCLES®) and of toluidine blue staining in identifying dysplastic areas in patients with OPMDs. METHODS: In this retrospective study, medical records, photographs and videos of 25 patients with oral lesions were analyzed. Forty-two biopsy samples in 25 patients with OPMDs and at least one suspicious oral mucosa lesion that were evaluated in white light, autofluorescence with optical filter GOCCLES®, toluidine blue staining and then biopsied with histopathological analysis were analyzed. RESULTS: The sensitivity and specificity for the autofluorescence evaluation with GOCCLES® for identifying dysplasia or carcinoma were 66% and 48%, respectively. The positive and negative predictive values were 34% and 77%, respectively, and the accuracy was 53%. The sensitivity and specificity for toluidine blue staining were 91% and 68%, respectively. The positive and negative predictive values were 55% and 95%, respectively, and the accuracy was 75%. CONCLUSIONS: The optical filter for autofluorescence (GOCCLES®) and toluidine blue staining are simple, inexpensive, rapid and non-invasive procedures that can assist the clinician in distinguishing OPMDs from healthy mucosa but they are not able to distinguish benign and malignant lesions.

Adenocarcinoma NOS arising from accessory lacrimal glands: A case report and a review of the literature.

Primary malignant epithelial tumours arising from accessory lacrimal glands (ALGs) are extremely rare, with only few cases reported in literature. They generally appear as gradually increasing masses of the upper or the lower eyelid. Only one case of primary adenocarcinoma or adenocarcinoma not otherwise specified (ACNOS) from ALGs has been reported in literature. Herein, we describe a case of ACNOS arising from ALGs with an atypical clinical presentation and review prior cases of ALGs epithelial malignancies reported in the literature. A 78-year-old man referred to our Ocular Oncology Unit for adjuvant therapy after the excision of a conjunctival tumour of the left eye with a histological diagnosis of squamous cell carcinoma. He underwent topical chemotherapy with MMC and during follow up he presented a multinodular iris mass in his left eye. The MRI of the orbit showed an ocular mass infiltrating orbital soft tissues of the inferior palpebral region with an involvement of the corresponding zygomatic cutis. We performed orbital exenteration and histological studies revealed an epithelial neoplasm with a solido-glandular growth pattern with lumens containing an eosinophilic material positive for PAS and PAS-D. The immunohistochemical findings confirmed the diagnosis of adenocarcinoma NOS from ALGs. Although ALGs epithelial malignancies are extremely uncommon, they should be considered in the differential diagnosis of ocular tumours. A vigilant approach towards these entities is required, since they can be clinically insidious and locally aggressive.

The Role of Cytology in the Diagnosis of Subcentimeter Thyroid Lesions.

Thyroid nodules are common and typically detected by palpation and/or ultrasound (US). Guidelines have defined the management of large nodules, but controversy exists regarding nodules ≤ 1 cm. We evaluated a cohort of patients with subcentimeter nodules to determine their rate of malignancy (ROM). A total of 475 thyroid FNAs of lesions ≤ 1 cm with available follow-up were identified from January 2015-December 2019. For comparative analysis, we added a control series of 606 thyroid lesions larger than 1 cm from the same reference period. All aspirates were processed with liquid-based cytology and classified according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Subcentimeter nodules were stratified as 35 category I-non-diagnostic cases (ND; 7.3%), 144 category II-benign lesions (BL; 30.3%), 12 category III-atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS; 2.5%), 12 category IV-follicular neoplasm/suspicious for follicular neoplasm (FN/SFN; 2.5%), 124 category V-suspicious for malignancy (SM; 26.1%), and 148 category VI-positive for malignancy (PM; 31.1%). A total of 307 cases (64.6%) underwent subsequent surgery. Only one ND and three BLs had a malignant outcome. ROM for indeterminate lesions (III + IV) was 3.2%; with 1.6% for category III and 3.2% for category IV. ROM for the malignant categories (V + VI) was 88.2%. The control cohort of lesions demonstrated a higher number of benign histological diagnoses (67.3%). We documented that 57.2% of suspected subcentimeter lesions were malignant, with a minor proportion that belonged in indeterminate categories. There were very few ND samples, suggesting that aspirates of subcentimeter lesions yield satisfactory results. Suspected US features in subcentimeter lesions should be evaluated and followed by an interdisciplinary team for appropriate patient management.

Pathological features, immunoprofile and mismatch repair protein expression status in uterine endometrioid carcinoma: focus on MELF pattern of myoinvasion.

AIMS: Microcystic, elongated, and fragmented (MELF) pattern of myoinvasion has been related with increased risk of lympho-vascular space invasion (LVSI) and lymph node metastasis. We analysed a cohort of endometrioid endometrial carcinomas (EECs) to examine the relationships between the MELF pattern of invasion and the clinico-pathological and immunohistochemical features of EEC. METHODS AND RESULTS: 129 EECs were evaluated for the presence of MELF pattern and immunohistochemically tested for Mismatch repair (MMR) proteins, p16, p53 and beta-catenin. We observed 28 MELF + EECs and 101 MELF- EECs. LVSI was observed in 20 MELF + cases and in MELF- tumors. Lymph-node metastases were observed in 7 MELF + cases (2 macrometastases, 3 micrometastases and 2 ITCs). None of the MELF- cases showed micrometastases or ITCs, 18 cases had macrometastatic lymph-nodes. Statistical analysis showed that MELF + tumors carry an increased risk of developing nodal metastasis independent of tumor dimension and LVSI. Loss of MMR proteins expression was observed in 11 MELF + cases and 45 MELF- cases, respectively. Our data showed a higher frequency of immunohistochemical MLH1-PMS2 loss in MELF- pattern of invasion (32.67% of MELF- cases vs 21.43% of MELF + cases) but a higher prevalence of MSH2-MSH6 loss in MELF + pattern (7.14% in MELF + population vs 3.96% of MELF- population) CONCLUSIONS: The morphological recognition of MELF pattern is more reliable than immunohistochemical and molecular signatures of EEC in predicting the risk of nodal involvement. The observed higher prevalence of MSH2-MSH6 loss in MELF + group and MLH1-PMS2 loss in MELF- group may suggest a different molecular signature.

Histopathological Ratios to Predict Gleason Score Agreement between Biopsy and Radical Prostatectomy.

Biopsy proven Gleason score is essential to decide treatment modalities for prostate cancer, either surgical (radical prostatectomy) or non-surgical (active surveillance, watchful waiting, radiation therapy and hormone therapy). Several studies indicated that biopsy proven Gleason score may underestimate Gleason score at radical prostatectomy, hence we aimed to calculate the minimum length of biopsy cores needed to have Gleason score agreement. We evaluated 115 prostate cancer patients who underwent multiparametric magnetic resonance/transperineal ultrasonography fusion biopsy and subsequently, radical prostatectomy. Biopsy proven Gleason score was consistent with Gleason score at subsequent radical prostatectomy in 82.6% of patients, while in 17.4% of patients, Gleason score was higher at radical prostatectomy. Gleason score agreement showed a strong direct association with a ratio > 0.05 between the total volume of biopsies performed in tumor area and the volume of the corresponding tumor at radical prostatectomy. A significant association was also found with a ratio ≥ 0.0034 between the tumor volume in the biopsy and the volume of the corresponding tumor at radical prostatectomy and with a ratio ≥ 0.086 between the tumor volume in the biopsy and the total volume of biopsies performed in the tumor area. These results could be exploited to calculate the minimum length of biopsy cores needed to have a correct Gleason score estimation and therefore be used in fusion targeted biopsies with volume adjustments.

Relevance of rosette patterns in variants of papillary thyroid carcinoma.

INTRODUCTION: The detection of rosette-like clusters (RLC) of follicular cells in thyroid carcinoma has been reported mostly in the columnar cell variant of papillary thyroid carcinoma (PTC). Despite the fact that diagnosing variants of PTC is no longer encouraged by The Bethesda System for Reporting Thyroid Cytopathology, the identification of cytomorphological features such as RLC linked with these tumours might help reduce possible misinterpretation in thyroid fine needle aspiration (FNA) cytology. We accordingly investigated the potential correlation of architectural patterns including RLC with PTC variants. METHODS: We analysed 225 thyroid FNA cytology cases diagnosed as suspicious for malignancy (SFM) and positive for malignancy (M) over a 1-year time where all samples had corresponding histology. We also included 150 benign lesions from the same period. The presence of RLC vs similar appearing solid clusters, papillary structures and microfollicles were evaluated. We also performed immunocytochemistry and molecular testing for BRAFV600E. RESULTS: We included 100 (44.4%) SFM favouring PTC and 125 (55.6%) M cases with cyto-histological correlation. On histology, all SFM and M cases showed malignancy including 140 (62.2%) classic PTC and 85 (37.8%) PTC variants. The cytomorphological patterns in all FNA samples included solid (74%), papillary (89%), microfollicular (70%), and pseudo-RLC morphology (25.7%). We identified only pseudo-RLC in 33 FNA specimens from PTC variant cases that included tall cell variant (42.4%), hobnail variant (21.2%) and miscellaneous variants (36.3%) of PTC. No definitive RLC were detected in our series. Immunocytochemistry and BRAFV600E were not specifically linked with an RLC pattern. CONCLUSIONS: These findings demonstrate that in our dataset the architectural pattern of RLC was not recognised within PTC variants. However, we did identify a pseudo-RLC pattern that was observed in association with tall cell variant and hobnail variant cases of PTC.

Insulinoma-associated protein 1 (INSM-1) expression in medullary thyroid carcinoma FNA: a multi-institutional study.

INTRODUCTION: Insulinoma-associated protein 1 (INSM-1) is expressed in both normal tissues and neoplasms with neuroendocrine differentiation such as small cell lung carcinoma and pancreatic neuroendocrine tumors. The aim of this study was to evaluate the INSM-1 expression in medullary thyroid carcinoma (MTC) in the aspirated material and its preoperative diagnostic value. MATERIALS AND METHODS: MTC cases with available cytological material from 5 institutions were retrospectively identified. INSM-1 expression was analyzed in 48 cell blocks prepared from fine-needle aspiration samples from histologically confirmed cases of MTC. Twenty-nine samples were aspirates from primary thyroid lesions and 19 from secondary lesions lymph node or liver lesions. INSM-1 immunostain was done using the Ventana Automatic System (Ventana Medical Systems, Tucson, AZ). The control group consisted of 20 samples from histologically confirmed cases of papillary, follicular, and anaplastic thyroid carcinomas and secondary thyroid malignancies (squamous cell carcinoma, malignant melanoma). RESULTS: The male to female (M:F) ratio in MTC group was 1:1.5 and the average age was 55.6 years (range: 24-84 years). INSM-1 nuclear staining in at least 5% of cells was considered positive. Forty-five (93.75%) MTC samples were positive including all primary tumor aspirates. All control samples were negative. CONCLUSIONS: INSM-1 nuclear positivity is a reliable marker of MTC neuroendocrine differentiation on cytology material from both primary tumor and metastases. INSM-1 can also discriminate MTC from other primary and secondary thyroid carcinomas when there are cytomorphologic overlaps.

PD-L1 and thyroid cytology: A possible diagnostic and prognostic marker.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is emerging as an important predictive biomarker in anti-PD-L1 cancer immunotherapy. Its role has been clearly defined in various human cancers and is linked to a poor prognosis and resistance to anticancer therapies. The role of PD-L1 in thyroid cancers has not been well defined in fine-needle aspiration cytology (FNAC). The authors examined the performance of PD-L1 immunostaining in liquid-based cytology (LBC) to determine whether it could be a biomarker of malignancy or aggressive disease. METHODS: From January 2018 to March 2019, 236 thyroid lesions, which had been diagnosed by FNAC as indeterminate lesions, suspicious for malignancy (SFM), and malignant, were enrolled. PD-L1 immunostaining was performed on both LBC and corresponding histology samples. RESULTS: The FNAC cohort included 50 benign negative controls, 42 samples of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 33 samples of follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 53 samples that were suspicious for malignancy (SFM), and 58 malignant samples. AUS/FLUS samples included 3 goiters, 32 follicular adenomas (FAs), 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), 5 invasive follicular variants of papillary thyroid carcinoma (I-FVPTCs), and 1 follicular carcinoma; whereas FN/SFN samples included 24 FAs and 9 malignancies (4 I-FVPTCs, 1 NIFTP, 3 papillary thyroid carcinomas [PTCs], and 1 oncocytic follicular carcinoma). The 53 SFM samples were diagnosed on histopathology as 2 FAs, 5 NIFTPs, 15 I-FVPTCs, and 31 PTCs; whereas the 58 malignant specimens included 5 NIFTPs, 5 I-FVPTCs, and 48 PTCs. Increased plasma membrane and cytoplasmic PD-L1 expression was found in 79 cases (38.5%), including 61 PTCs (conventional and variants). Negative PD-L1 expression was found in NIFTPs and FAs. A BRAF V600E mutation was identified in 15% of PD-L1-positive malignancies. CONCLUSIONS: The current data suggest that PD-L1 expression in the thyroid gland might represent a marker of malignancy that correlates with PTC, but not with NIFTP. Thyroid neoplasms with PD-L1 expression also ae enriched with BRAF V600E mutations, suggesting that they are associated with more aggressive behavior.

A new entity in the pathological spectrum of vulvar neoplasms: The first report of a primary endometrioid adenocarcinoma.

We report the first evidence of primary endometrioid adenocarcinoma arising in the vulva, expanding the morphological spectrum of the glandular neoplasms in this anatomic region.

A large series of hyalinizing trabecular tumors: Cytomorphology and ancillary techniques on fine needle aspiration.

BACKGROUND: Hyalinizing trabecular tumors (HTTs) are rare, essentially benign, follicular cell-derived thyroid neoplasms characterized by a trabecular growth pattern and nuclear pseudoinclusions. Their cytological findings are misleading, because these tumors are often misinterpreted on fine needle aspirate cytology as malignant lesions, such as papillary thyroid cancer and/or medullary thyroid cancer, leading to unnecessary total thyroidectomy. The aim of this study was to analyze the cytomorphological features and application of ancillary techniques in a series of HTTs. METHODS: Of 26 histological cases of HTT collected from September 2001 to December 2018, 18 cases had concomitant cytopathology. Cytological cases were processed with liquid-based cytology (LBC). Immunocytochemistry for HBME-1 and galectine-3 as well as molecular testing for BRAFV600E mutation were performed on both LBC and histological specimens. RESULTS: The 18 lesions with fine needle aspirate cytology ranged in size from 5 to 45 mm. Cytological diagnoses included: 1 benign lesion favoring goiter (5.5%), 4 atypia of undetermined significance (22.2%), 6 follicular neoplasms (33.3%), 5 suspicious for malignancy favoring papillary thyroid cancer (28%), and 2 malignant (11%). Hence, 89% HTT had a negative concordant immunopanel, and they were 100% wild-type BRAFV600E . CONCLUSION: The majority of our HTTs (83.3%) were diagnosed in the indeterminate Bethesda categories, suggesting that their cytomorphological features pose issues for reaching a conclusive cytological diagnosis. The ancillary test results in our series support the fact that HTT is a benign neoplasm.

The immunocytochemical expression of VE-1 (BRAF V600E-related) antibody identifies the aggressive variants of papillary thyroid carcinoma on liquid-based cytology.

BACKGROUND: The recently introduced monoclonal V600E antibody (clone VE1) is likely to be an alternative strategy for detecting this mutation in thyroid lesions. Although VE1 immunostaining and molecular methods used to assess papillary thyroid carcinoma in surgical specimens are in good agreement, evaluation of VE1 in cytology and cell block samples is rarely performed, and its diagnostic value in cytology has not been well established. In this study, we sought to determine if VE1 is suitable for fine needle aspiration (FNA) and cell block methods. METHODS: A total of 86 patients who had BRAF V600E mutations were investigated with molecular and immunocytochemical (ICC) analysis in 45 FNA and 41 cell blocks. In total, 83 (96.5%) patients underwent surgical treatment. Assessment of BRAF V600E mutation status was performed in 72 (83.7%) cases. RESULTS: Among the 72 cases analysed, 54 cases agreed (ICC+/BRAF+ or ICC-/BRAF-), seven cases were false positive (ICC+/BRAF-) and 11 cases were false negative (ICC-/BRAF+). False negative cases were not detected in the cell block method. The statistical analysis showed that sensitivity and specificity of ICC for detecting the BRAF V600E mutation were 61% and 77% in FNA samples and 100% and 73% in cell block. CONCLUSION: The use of antibody VE-1 is a reliable method and a negative result of VE1 immunostaining might help to save time and money, restricting the molecular test to antibody-positive cases only. The identification of the aggressive variants of papillary carcinoma might be enabled by the expression of the antibody in neoplastic cells with tall cell features.

Hypochromatic large urothelial cells in urine cytology are indicative of high grade urothelial carcinoma.

In this study, we have examined 67 cytology specimens from patients from 2014 to 2016. The ratio man to women was 4:1 with a median age of 75 years (range: 55-87 years). Thin-Prep processed urinary cytology specimens demonstrated large urothelial cells, with cytologic features of malignancy, thus including hypochromatic nuclei with occasional peripherally accentuated chromatin rim. The cytological diagnosis of High Grade Urothelial Carcinoma (HGUC) was made in 55 patients while 12 specimens were classified as Atypical Urothelial Cells (AUC). This cases represent the 15% of the HGUC and the 4% of the AUC cases diagnosed in our department between 2016 to 2018. Of note, is the fact that in AUC cases, hypochromatic irregular urothelial cells were the only type of cells with malignant features observed in the specimen, and therefore, according to the Paris System criteria, the absence of nuclear hyperchromasia precludes a diagnosis of suspicious high grade urothelial carcinoma (SHGUC) or High Grade Urothelial Carcinoma (HGUC). Subsequent biopsy diagnosis of high grade urothelial carcinoma confirmed the cytological diagnosis of HGUC in 55 patients but also in all 12 patients with a AUC cytologic diagnosis. Our study series support the hypothesis that malignant urothelial cells with hypochromatic nuclei seen in urine cytologic specimens can be diagnostic for HGUC based on their very large nuclei, high nuclear cytoplasmatic ratio (N/C) >0.7, irregular nuclear outlines and coarse (frequently peripheral) chromatin in the absence of hyperchromasia.

Unusual focal keratin expression in plexiform angiomyxoid myofibroblastic tumor: A case report and review of the literature.

BACKGROUND: Plexiform angiomyxoid myofibroblastic tumor (PAMT), also known as plexiform fibromyxoma, is a rare distinctive benign intramural tumor, typical of gastric antrum, commonly causing mucosal ulceration with upper gastrointestinal bleeding and anemia, effectively treated by complete surgical resection usually accomplished by distal gastrectomy. METHODS AND RESULTS: We herein report a 47-year-old man presenting with a syncopal episode, regurgitation and epigastric discomfort, bearing a gastric antral myxoid plexiform tumor positive for α-smooth muscle actin, vimentin and, partially, for caldesmon, desmin, and CD10; CD117, DOG1, CD34, S100, CAM5.2, CK20, CK7, EMA, p53, CDX2, chromogranin A, synaptophysin, anaplastic lymphoma kinase, Melan-A, and HMB-45 were all negative. All these features are typical of PAMT. Of note, focal positivity for AE1/AE3 and pan-CK KL1 was also present. CONCLUSIONS: The finding of a focal keratin expression in PAMT contributes to enlarge the immunophenotypic spectrum of this tumor type and is relevant for avoiding presurgical misdiagnoses which could ultimately lead to inappropriate overtreatment of patients with PAMT.