Solid Carcinoma Research Articles

Primary cutaneous endocrine mucin-producing sweat gland carcinoma: a rare case report

Background: Endocrine mucin-producing carcinoma is a rare adnexal tumour of the skin with low-grade cytological features and neuroendocrine differentiation. It has a predilection for skin of the eyelid, but has also been reported in the face and rarely extra-facial locations. The tumour is seen more frequently in women affecting the elderly. It is histologically and immunohistochemically analogous to solid papillary carcinoma of breast/ductal carcinoma in situ with nodular, solid, papillary, and /or cribriform architecture, neuroendocrine differentiation and mucin production with preserved myoepithelial cell layer.

A large-scale clinicopathological and long-term follow-up study of solid papillary carcinoma of the breast.

Solid papillary carcinoma of the breast (SPC) is a rare tumor of the breast with the unique histology and frequent neuroendocrine differentiation. However, a real nature and diagnostic importance of the neuroendocrine differentiation have not been properly handled. And relationship between SPC and the other types of invasive breast carcinoma, especially neuroendocrine tumor of the breast (NETb), has not been fully explained. We conducted a clinicopathological study of SPC to tackle these problems.In the study, we included 127 cases of SPC with long-term follow-ups of up to 30years. The incidence in the breast carcinoma was 2.0%. The patients with SPC had a significantly better prognosis and no patients died of the tumor. The 35 cases had only SPC in situ (SPC-IS), while the 92 cases had both SPC-IS and SPC with invasion (SPC-INV). Immunohistochemically, 123 of the 127 cases exhibited diffuse expression of one or more neuroendocrine markers. Fifty of the 92 cases had exclusively invasive SPC (iSPC) as the invasive component. Twenty-two cases of iSPC were combined with NETb and the 18 cases with MUC. Six of 8 cases with metastatic SPC-INV disclosed iSPC in the axillary lymph node.This study suggests that SPC is immunohistochemically compatible with NET of the systemic organs (NETs). And the unique morphology of SPC may represent a traditional histology of NETs. The study also indicates that SPC has close relationship between NETb and type B MUC. And SPC and NETb may represent a spectrum of the same disease.

Apoptotic Responses Mediated by Nostoc-Synthesized Silver Nanoparticles against Ehrlich Ascites Carcinoma Tumor-Bearing Mice

Among the metallic nanoparticles (NPs), silver NPs are the leading anticancer nanoagents due to their physicochemical properties and inhibitory activities against different cancers. Many reports exhibited the cytotoxic effect of silver-NPs fabricated by cyanobacteria against various cancer cell lines. However, their lethal mechanisms have not been elucidated. The antiproliferative and cytotoxic effects of silver-NPs synthesized previously using Nostoc Bahar M (N-SNPs), and their associated mechanisms were evaluated in the solid Ehrlich ascites carcinoma (EAC) tumor-bearing mice model. Blood parameters, liver enzymes (alanine transaminase, aspartate aminotransferase, and alkaline phosphatase), lactate dehydrogenase, adenosine triphosphate, and oxidative stress markers, including glutathione, glutathione peroxidase, catalase, and malondialdehyde, were analyzed. In addition, the expression of pro- and antiapoptotic genes and proteins was screened utilizing quantitative real-time polymerase chain reaction and western blotting. N-SNPs significantly reduced tumor size in mice without affecting body weight and did not compromise liver function or alter blood parameters. Besides, N-SNPs negatively impact membrane integrity and metabolic activity and significantly enhance oxidative stress by causing an imbalance in antioxidant activity in tumor tissues. Intriguingly, N-SNPs-stimulated apoptosis signaling pathways via a combination of enhanced and suppressed responses of pro- and antiapoptotic genes and proteins. The cytotoxic activity and apoptosis effect of N-SNPs in tumor tissue could be attributed to the surge in reactive oxygen species production and depletion of antioxidant activity. Certainly, N-SNPs could provide robust antitumor agents against solid tumors.

Mutations and polymorphisms in mitochondrial genome of dogs with solid mammary carcinoma – a preliminary study

In recent years, the association between mitochondrial DNA (mtDNA) changes and tumorigenesis has been discussed. In contrast to human medicine, there are still few studies on the molecular basis of canine tumors. One of the most commonly diagnosed, solid mammary carcinoma, is characterized by its aggressiveness, difficult treatment, and generally poor prognosis. The aim of the study was to reveal mutations and polymorphisms in mtDNA in dogs with solid mammary carcinoma and to determine the relationship of these changes with the process of neoplastic transformation. Blood, healthy tissue, and neoplastic tissue samples were collected from two crossbreed dogs diagnosed with G3 and G2 solid mammary carcinoma. Subsequently, for the first time, Next Generation Sequencing (NGS) was used to analyze the whole genome mtDNA of dogs with solid mammary carcinoma. Thus, bioinformatic analyses included all 37 mitochondrial genes. As a result, 10 polymorphisms and 20 mutations were identified. Most polymorphisms/mutations were found in the dog with the more advanced stage of the disease (G3). Twelve of the thirty changes identified have not been described in the literature so far. These include eleven mutations in COX2 (m.7308A>G), ATP6 (m.8536C>T), ND4L (ins.9913_9914AG, ins.9913_9914TG, m.10165C>T), ND4 (m.10204C>T), CYTB (m.16248A>G, m.16268A>G), D-loop (m.16378G>A, m.16408G>A, m.16507T>A) which may be related to canine tumorigenesis.

Histopathological evaluation of canine mammary gland tumours: a study of 92 cases

Neoplasms of the mammary glands are the most common tumours in female dogs, albeit rare cases in male dogs are reported as well. Canine mammary tumours (CMT) are a naturally occurring heterogeneous group of cancers with a high incidence rate of up to 25-50% among females. Despite many years of research, the aetiology and high incidence of these tumours are still poorly understood. There is a need to present epidemiological data on mammary tumour occurrence in different breeds of dogs in different countries to select prognostic risk factors and identify breeds with higher susceptibility to tumour development. The aim of this study was to describe histopathological findings for 92 animals, including 87 female and five male dogs, diagnosed with mammary gland tumours (MGTs) in Poland and to determine such epidemiological characteristics as age, breed and size as well as their relationship with tumour incidence and malignancy. Histopathological analyses showed that 82 (89.1%) of the 92 dogs had malignant tumours, seven dogs (7.6%) had benign tumours, and three dogs (3.3%) had non-neoplastic changes in the form of dysplasias. Thirty (33.7%) of the 89 dogs with mammary gland tumours had more than one neoplasia. The highest number of cases were epithelial tumours (79.8%), followed by mesenchymal (14.6%) and mixed (5.6%) tumours. The vast majority of malignant tumours were tubulopapillary carcinomas (33.7%), complex carcinomas (24.7%) and solid carcinomas (11.2%). It is worth noting a large variation in the degree of tumour malignancy among the tubulopapillary carcinoma cases. The present study showed a higher incidence of mammary gland tumours in female dogs aged 8-13 years. The vast majority of female cases were diagnosed at the age of 12 years. The average year of surgical intervention in the male dogs was 9 years. Among 25 breeds of dogs in which MGTs were noted, the highest number of affected animals were crossbreeds (30.3%), German Shepherds (23.6%) and English Cocker Spaniels (9.0%). The large size of the tumour (≥ 5 cm) was strongly associated with its malignancy.

Expression of receptor-type tumour endothelial marker 8 in carcinoma cells showing luminal progenitor-like phenotypes in canine mammary gland carcinomas

This study aimed to investigate the expression of receptor-type tumour endothelial marker 8 (TEM8RT) in canine mammary gland carcinomas (CMGCs) using immunohistochemistry and to evaluate the association between carcinoma cell TEM8RT expression and tumour histological features, histological grades and the differentiation status of neoplastic epithelial cells. TEM8RT expression was more frequently detected in simple carcinomas (tubular and tubulopapillary) than in solid carcinomas, and it was significantly correlated with histological grade Ⅰ tumours and a low mitotic index. Additionally, TEM8RT+ carcinoma cells were more frequently found in CMGCs showing luminal progenitor-like phenotypes, such as Notch1+, CK19+/CK5+/CD49f+ and CK19+/CK5-/CD49f+. Double-labelling immunofluorescence detection techniques confirmed that most TEM8RT+ carcinoma cells expressed CD49f, Notch1 and CK19. However, TEM8RT immunoreactivity was not found in carcinoma cells expressing GATA3, which upregulates mature luminal cell differentiation. Furthermore, TEM8RT+ carcinoma cells were detected in a few CMGCs showing basal/stem cell-like phenotypes such as CK19-/CK5+/CD49f+ and CK19-/CK5+/CD49f−. These findings indicate that TEM8RT is expressed in luminal progenitor-like carcinoma cells in CMGCs. Since TEM8 enhances self-renewal in human mammary stem/progenitor cells, it also may be involved in maintenance of luminal progenitor-like carcinoma cells, resulting in prevention of their transition to basal/stem cell-like carcinoma cells and development of less malignant CMGCs. Therefore, TEM8RT may be useful for indicating prognostic outcomes and identifying the possible ontogeny of carcinoma cells in mammary gland tumours.

Evaluation of tumour associated macrophages in different histopathological types and grades of canine mammary tumours

Canine mammary tumours (CMTs) are the second highest reported tumours in female dogs, following skin tumours. Human breast cancers (HBCs) and CMTs share common clinical and molecular features and hence, CMTs are considered as ideal models to study the different aspects of HBC. The study utilised samples from 25 CMT suspected cases presented to University Veterinary Hospitals in Thrissur district from December 2020 to October 2021. The tumour samples were analysed histopathologically and the lesions were classified. Among the 25 cases, one was identified as ductal hyperplasia, one as a benign myxoma and all the others were found to be malignant neoplasms. Malignant tumours were further categorised into different histotypes.Histological Malignancy Grading (HMG) was also done in 23 malignant CMTs and 21.74 percent were found to be of grade I, 47.83 per cent were grade II and 30.43 per cent were grade III. Majority of the malignant tumours were simple carcinomas which comprised tubulopapillary, ductal, cribriform, solid and comedocarcinomas. Highly aggressive tumours like cribriform, solid, comedo and inflammatory carcinomas belonged to higher grades, either II or III. Infiltration of tumour associated macrophages (TAMs) was studied in different histotypes and grades of CMTs. It was identified that malignant high grade CMTs had greater TAM infiltration and hence, with further validation TAMs could be effectively used in predicting prognosis and also as a therapeutic target.

What's new in the WHO 2022 classification of kidney tumours?

The World Health Organization (WHO) 2022 classification of urinary and male genital tumours (5th edition) has significantly improved our understanding of the morphologic, immunohistochemical, and molecular characteristics of renal tumours. The aim of this review is to outline the most important changes and diagnostic updates in the WHO 2022 classification of kidney tumours. A major change in this edition is the grouping of renal tumours into broader categories that include "clear cell renal tumours", "papillary renal tumours", "oncocytic and chromophobe renal tumours", "collecting duct tumours" as well as adding two categories of "other renal tumours" and "molecularly defined renal carcinomas". Novel entities included in the WHO 2022 classification are eosinophilic solid and cystic renal cell carcinoma (ESC RCC), anaplastic lymphoma kinase (ALK)-rearranged RCC and ELOC (formerly TCEB1)-mutated RCC. The category of "other renal tumours" includes a group of diverse, unrelated renal tumours that do not fit into other categories. The group of "molecularly defined renal carcinomas" reflects recent discoveries in the renal tumour genomics. These molecularly-defined renal entities demonstrate a set of morphologic features reflecting genotype-phenotype relationships. Final diagnosis of such entities rests on phenotypic and immunohistochemical (IHC) correlation, usually associated with IHC surrogate makers that reflect specific genetic abnormalities.

The Compact Bleb-Eosinophilic Solid and Cystic Renal Cell Carcinoma

The contemporary, indolent, Eosinophilic solid and cystic renal cell carcinoma configures as a predominantly solitary neoplasm delineating solid and cystic pattern of tumour evolution. Neoplastic cells are incorporated with abundant Eosinophilic cytoplasm and intracytoplasmic inclusions or basophilic stippling. Tumour cells display frequent somatic loss of function genetic mutations confined to TSC1 (9q34.13) gene or TSC2 (16p13) gene. Eosinophilic tumour cell clusters appear admixed with macroscopic cysts or microscopic tubules and cystic structures coated with singular layer of hobnail cells. Neoplastic cells are permeated with abundant, granular, eosinophilic cytoplasm. Tumour cells appear immune reactive to PAX8, CK20, AMACR, CD10, SDHB, fumarate hydratase, vimentin, cathepsin K and Melan A.

Chemotherapy Timing During Visceral Crisis in Patients with Liver Metastatic Solid Carcinoma

Chemotherapy Timing During Visceral Crisis in Patients with Liver Metastatic Solid Carcinoma

Vulvar Adenoid Cystic Carcinoma with Squamous Cell Carcinoma Component.

Adenoid cystic carcinoma (ACC) is a major histological type of salivary gland cancer but an uncommon form of vulvar cancer. Salivary gland ACC occasionally dedifferentiates into high-grade carcinoma, resulting in poor prognoses. The dedifferentiated component is usually a poorly differentiated cribriform or solid carcinoma, whereas squamous cell carcinoma (SCC) is exceptional. Herein, we report the case of a 78-year-old woman with vulvar ACC, including an SCC component. She presented with a vulvar nodule that had been present for 30 years and increased in size over the past few years. Magnetic resonance imaging showed a ball-like mass with high intensity on T1-weighted images and high intensity with non-uniformity on T2-weighted images. Considering the systemic and social conditions, the tumor was maximally resected without lymphadenectomy. Histologically, the tumor was composed of a marginal ACC component with a central SCC component. Stage IB vulvar cancer, which was assumed to originate from the Bartholin's gland, was diagnosed. She has survived over 2 years without additional treatments after the surgery. In this case, we assumed that slowly progressive indolent ACC could be dedifferentiated to high- grade SCC. According to our review of available literature, dedifferentiation of vulvar ACC with a high-grade SCC component has not been specifically documented. Although the nature of dedifferentiated vulvar cancer is unclear, it should be noted that high-grade dedifferentiation can occur in long-lasting vulvar masses.

Neuroendocrine Tumors of the Breast: Single-Center Experience.

Breast carcinomas with neuroendocrine (NE) differentiation are extremely rare. The aim was to discuss breast cancer cases with NE differentiation in the light of World Health Organization 2019 classification and literature information. The pathology records of 56 cases diagnosed as neuroendocrine tumor (NET) and/or breast cancers with NE differentiation presenting to a single center between January 2010 and June 2020 were evaluated. The patients were evaluated in terms of age, tumor size, location, histological grade, hormone profiles (ER, PR, HER2), guideline American Joint Committee on Cancer, lymph node status, stage, metastases, progression, survival, radiological features, surgery type and therapy modality. The age of the patients ranged from 34 to 81 years. Average tumor size was 2.3 cm. Median (range) follow up time was 31.5 (1-73 month). Metastatic lymph nodes were found in 20 cases. In our series, NE differentiation mostly accompanied invasive carcinoma of no special type, less frequently solid papillary carcinoma, and mucinous carcinoma.Four patients had a history of neoadjuvant chemotherapy. Response to treatment was very poor in all four cases. Synaptophysin and chromogranin were positive in 38 cases. No correlation was found among tumor size, grade, age, lymph node status, and presence of distant metastasis in our series. Clinical features and morphology may not help to distinguish NET from other subtypes of breast cancer. Therefore, the morphologic findings of a nested or trabecular architecture, nuclear or cytoplasmic features of NE differentiation, mucin production, or solid papillary growth pattern should prompt a pathologist to order NE markers.

The Spectrum of Mucinous Lesions of the Breast.

Mucinous lesions of the breast encompass many entities ranging from benign to malignant and nonneoplastic to neoplastic. Lesions discussed under this category are mucocele-like lesion, mucinous carcinoma, mucinous micropapillary carcinoma, solid papillary carcinoma, mucinous cystadenocarcinoma, mucoepidermoid carcinoma, invasive lobular carcinoma with extracellular mucin, mucinous ductal carcinoma in situ, and metastasis. To review clinical, pathologic, and molecular features of mucinous lesions of the breast, their differential diagnoses, and challenging features on core needle biopsies. The existing scientific and clinical literature as of December 2021. The category of mucinous lesions of the breast is vast and the differential diagnosis can be challenging, especially on core needle biopsies. In all cases, clinical, radiologic, and pathologic correlation is necessary to reach a comprehensive diagnosis. Given that the prognosis and management of each entity is different, being aware of these entities and their nuances is critical for a pathologist to guide accurate management.

EGFR-targeted bacteriophage lambda penetrates model stromal and colorectal carcinoma tissues, is taken up into carcinoma cells, and interferes with 3-dimensional tumor formation.

Colorectal cancer and other adult solid cancers pose a significant challenge for successful treatment because the tumor microenvironment both hinders the action of conventional therapeutics and suppresses the immune activities of infiltrating leukocytes. The immune suppression is largely the effect of enhanced local mediators such as purine nucleosides and eicosanoids. Genetic approaches have the promise of interfering with these mechanisms of local immunosuppression to allow both intrinsic and therapeutic immunological anticancer processes. Bacterial phages offer a novel means of enabling access into tissues for therapeutic genetic manipulations. We generated spheroids of fibroblastic and CRC cancer cells to model the 3-dimensional stromal and parenchymal components of colorectal tumours. We used these to examine the access and effects of both wildtype (WT) and epidermal growth factor (EGF)-presenting bacteriophage λ (WT- λ and EGF-λ) as a means of delivery of targeted genetic interventions in solid cancers. We used both confocal microscopy of spheroids exposed to AF488-tagged phages, and the recovery of viable phages as measured by plaque-forming assays to evaluate access; and measures of mitochondrial enzyme activity and cellular ATP to evaluate the outcome on the constituent cells. Using flourescence-tagged derivatives of these bacteriophages (AF488-WT-λ and AF488-EGF-λ) we showed that phage entry into these tumour microenvironments was possible and that the EGF ligand enabled efficient and persistent uptake into the cancer cell mass. EGF-λ became localized in the intracellular portion of cancer cells and was subjected to subsequent cellular processing. The targeted λ phage had no independent effect upon mature tumour spheroids, but interfered with the early formation and growth of cancer tissues without the need for addition of a toxic payload, suggesting that it might have beneficial effects by itself in addition to any genetic intervention delivered to the tumour. Interference with spheroid formation persisted over the duration of culture. We conclude that targeted phage technology is a feasible strategy to facilitate delivery into colorectal cancer tumour tissue (and by extension other solid carcinomas) and provides an appropriate delivery vehicle for a gene therapeutic that can reduce local immunosuppression and/or deliver an additional direct anticancer activity.

Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations.

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 is a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising telomerase inhibitors. Therefore, two novel series of pyridazine-linked to cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized to investigate the telomerase inhibitory activity of candidates. Notably, 8e and 9e exhibited the best inhibition profiles. Moreover, 8e showed strong antitumor effects against both MCF-7 and A549 cancer cell lines. The effects of 8e on the cell cycle and apoptosis were measured. Besides, 8e was evaluated for its in vivo antitumor activity using solid Ehrlich carcinoma. The reduction in both the tumor weight and volume was greater than doxorubicin. Also, molecular docking and ADME studies were performed. Finally, a SAR study was conducted to gain further insights into the different telomerase inhibition potentials upon variable structural modifications.

Solid Papillary Carcinoma: A Clinicopathological Evaluation of a Rare Variant of Carcinoma Breast

Background: Solid papillary carcinoma (SPC) of the breast is considered a low grade carcinoma with a favorable prognosis. We aimed to describe clinicopathologic features including immunohistochemistry expression profile and to delineate adverse prognostic features, if any.
 Methods: Patients diagnosed with SPC between the years 2016–2022 were retrospectively identified from the archives at Kailash Cancer Hospital and Research Centre, Goraj. Microscopic slides and clinical history were reviewed. Immunohistochemical stains were performed.
 Results: Of 12 SPCs cases retrieved, 11 (92%) were associated with ductal carcinoma in situ (DCIS). The median tumour size was 1.6cm (range 1.3-7.0cm). All tumors were positive for hormone receptor expression and negative for HER-2Neu. 6 cases (50%) show neuroendocrine differentiation. Lymph node involvement was identified in 4/12 (33.3%) patients. Of 12 patients with outcome data (median follow-up 30 months, range 7-72 months), none (0%) developed local recurrence. No distant metastasis or deaths were observed.
 Conclusions: SPCs has excellent prognosis with no local recurrence or distant metastasis in this study. Axillary node metastasis is found to be associated with larger tumor size, however it appears to have no impact on disease free or overall survival.

Eosinophilic Solid and Cystic Renal Cell Carcinoma with Non-typical Immunophenotype: A Series of Two Cases

Abstract Introduction/Objective Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is an emerging entity receiving increasing attention. Initially characterized in a large series by Trpkov et al, the distinct features of this tumor are voluminous eosinophilic cytoplasm with granular cytoplasmic stippling, mixed solid and cystic architecture, and CK20 positivity/CK7 negativity. Methods/Case Report We present two cases of ESC RCC diagnosed at our institution which exhibit a non-typical immunophenotype. The patients were a 58-year-old female and a 59-year-old male, with a 5.5 cm and 3.5 cm incidental renal mass, respectively. Both underwent uncomplicated partial nephrectomies. The tumors exhibited solid, alveolar, tubular and focally cystic growth patterns and were composed of cells with voluminous granular eosinophilic cytoplasm. Tubules and cysts were lined by single hobnail layer of neoplastic cells. Characteristic cytoplasmic stippling and compact leishmaniasis-like globules were present. The tumor nuclei were enlarged, with irregular nuclear contours and scattered multinucleation. The second case was significant for a diffuse neutrophil infiltration along with foamy macrophages. Immunohistochemically, the tumor cells were positive for PAX8, AMACR, CD10 and vimentin, while being negative for pan-cytokeratin, CD117, CAIX, Melan A, and HMB45. Interestingly, CK20 was only positive in very rare single cells and CK7 was focally positive in both cases. In our differentials, we considered SDH-deficient, low-grade FH-deficient, and MiT family translocation-associated RCC. FISH studies showed that the tumor cells have retained the expression of FH and SDHB, without TFE3 and TFEB alterations. Although our cases demonstrated non- typical CK20/CK7 expressions, based on the morphology with other molecular manifestations, the diagnosis of ESC RCC was rendered. Results (if a Case Study enter NA) NA. Conclusion ESC RCC poses diagnostic difficulties as many eosinophilic/oncocytic entities are included in the differentials, and the immunoprofile of this entity is variable. It is important to appreciate the characteristic histomorphologic features to increase its recognition as inclusion into the WHO classification system is likely.

Blocking of The Prostaglandin E2 Receptor as a Therapeutic Strategy for Treatment of Breast Cancer: Promising Findings in a Mouse Model.

The study aimed to investigate the anticancer effect of E-prostanoid receptor 1 (EP1) antagonist, SC19220, alone or in combination with the COX-2 inhibitor Celecoxob(CXB)® in mice bearing solid Ehrlich carcinoma (SEC). The tumors were induced in 40 female mice, which were divided randomly into four equal groups (n= 10 in each group): Tumor control, CXB, EP1 antagonist, and co-treatment. CXB (10mg/kg) and EP1 antagonist (2mg/kg) were given intraperitoneally every three days, six times in total, then tissue was extracted and prepared for histopathology and measurement of weight, PGE2, and gene expression of EP1 and β 1 integrin. Both inhibitors, alone or in combination, showed a significant (p<0.001) antitumorigenic effect by decreasing, significantly (p<0.001), each of the tumor weights, tumor volumes, PGE2 levels, EP1 and β1-integrin gene expression along with increasing, significantly (p<0.001), the P53 tumor suppressor protein. The survival rate was improved from 80% in the control group to reach 100% in the treated groups. The co-treatment by CXB and EP1 antagonist showed a marked decrease in tumor weights and volumes as compared with the single treatment. In parallel, the histopathological findings showed enhanced apoptosis and diminished necrosis in the co-treated group. EP1 antagonist proved an antitumorigenic effect alone or combined with CXB and could play a new therapeutic strategy against breast cancer.

Stereotactic Body Radiation Therapy Plus Anti-PD1/IL8 Therapy for Advanced Solid Tumors

<h3>Purpose/Objective(s)</h3> Anti-PD-(L)1 immunotherapy improves outcomes for patients across various cancers; however, many patients do not benefit. Previous studies combining multi-site stereotactic body radiation therapy (SBRT) with anti-PD1 have demonstrated feasibility and showed increased interferon signaling after SBRT. Elevated levels of serum IL8 (sIL8) associate with lack of response to anti-PD1 and we have observed that elevated IL8 is strongly associated with lack of response to immunotherapy and SBRT combinations. BMS-986253 is a fully human neutralizing antibody that binds to sIL8. The present study aims to evaluate safety and preliminary efficacy of combining BMS-986253 with nivolumab and SBRT in patients with advanced solid tumors, chiefly melanoma (MEL) and renal cell carcinoma (RCC). <h3>Materials/Methods</h3> This is a phase 1 open label single arm study which will include safety and efficacy cohorts. Patients will receive SBRT to 1-4 metastatic sites in 3 or 5 fractions with a total dose of 30-50 Gy depending on anatomic subsite and dose/fractionation. SBRT treatment planning parameters and organ at risk constraints are based on NRG BR-001 study results. SBRT will be followed by nivolumab (480mg q4 weeks) and IV BMS-986253 (2400mg q2 weeks) within seven days of completing SBRT. In the initial safety portion of the clinical trial, we will include 30 patients with advanced/metastatic solid tumors. The primary endpoint of dose limiting toxicity will be assessed by continual Bayesian monitoring. The toxicities will be attributed to combination of SBRT/immunotherapy as opposed to individual components. After completion of the safety phase, an efficacy phase will be launched. To detect a lower bound of 20% for response rate with a one-sided confidence interval, 20 patients are required. Translational correlatives include paired biopsies pre/post SBRT to interrogate gene expression changes using scRNAseq and bulk RNAseq, TCRseq, PBMC profiling for IL8 gene expression, serum IL8 levels before/during/after combination treatment, and T cell radiomics analyses of irradiated metastases to correlate with clinical outcomes. <h3>Results</h3> The phase I trial is active and recruiting patients. <h3>Conclusion</h3> Blocking IL8 in conjunction with anti-PD1 therapy and SBRT is a rational, biomarker-driven approach that may overcome resistance and broaden immunotherapy benefit in patients for whom anti-PD1 therapy is inadequate. This trial is registered at ClinicalTrials.gov, NCT04572451.

Neuroendocrine neoplasms of the breast: diagnostic agreement and impact on outcome

The classification of breast neuroendocrine neoplasms (Br-NENs) was modified many times over the years and is still a matter of discussion. In the present study, we aimed to evaluate the diagnostic reproducibility and impact on patient outcomes of the most recent WHO 2019 edition of breast tumor classification, namely, for neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). This multicentric observational study included 287 breast neoplasms with NE differentiation. The cases were blindly classified by three independent groups of dedicated breast and/or endocrine pathologists following the 2019 guidelines. Diagnostic concordance and clinical impact were assessed. We observed only a moderate overall diagnostic agreement across the three centers (Cohen’s kappa 0.4532) in distinguishing NET from solid papillary carcinomas (SPCs) and no special type carcinomas (NST) with NE differentiation. Br-NENs were diagnosed in 122/287 (42.5%) cases, subclassified as 11 NET G1 (3.8%), 84 NET G2 (29.3%), and 27 NEC (9.4%), the latter group consisting of 26 large-cell and 1 small-cell NECs. The remaining 165/287 (57.5%) cases were labeled as non-NEN, including SPC, mucinous, NST, and mixed NE carcinomas. While NET and non-NEN cases had a comparable outcome, the diagnosis of NECs showed negative impact on disease-free interval compared to NETs and non-NENs (p = 0.0109). In conclusion, the current diagnostic classification of Br-NENs needs further adjustments regarding morphological and immunohistochemical criteria to increase the diagnostic reproducibility among pathologists. Our data suggest that, apart from high-grade small- and large-cell NECs, Br-NENs behave like non-NEN breast carcinomas and should be managed similarly.