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Accurate predictive biomarkers of response to immune checkpoint inhibitors (ICIs) are required for better stratifying patients with cancer to ICI treatments. Here, we present a new concept for a bioassay to predict the response to anti-PD1 therapies, which is based on measuring the binding functionality of PDL1 and PDL2 to their receptor, PD1. In detail, we developed a cell-based reporting system, called the immuno-checkpoint artificial reporter with overexpression of PD1 (IcAR-PD1) and evaluated the functionality of PDL1 and PDL2 binding in tumor cell lines, patient-derived xenografts, and fixed-tissue tumor samples obtained from patients with cancer. In a retrospective clinical study, we found that the functionality of PDL1 and PDL2 predicts response to anti-PD1 and that the functionality of PDL1 binding is a more effective predictor than PDL1 protein expression alone. Our findings suggest that assessing the functionality of ligand binding is superior to staining of protein expression for predicting response to ICIs.

Plasma cell dyscrasias are a group of entities characterized by neoplastic proliferation of a single clone of plasma cells, typically producing a monoclonal Immunoglobulin [1].

We aimed to collect and analyze available cases of intraoral acantholytic squamous cell carcinoma (aSCC), that consisted of the authors’ cases and cases derived from the existing literature, with an emphasis on the pathological staging and patient outcome. Our research question was whether aSCC is more aggressive than conventional SCC. The literature was searched for documented cases of aSCC involving the intra-oral mucosa, excluding those from the lips and tonsils, and seven new cases were added from our files. The authors compared the obtained aSCC data to existing data for conventional SCC. Fisher Exact or Pearson’s χ(2) tests were used for categorical variables. Fifty-five cases of intraoral aSCC were reviewed, of which 48 were retrieved from the literature. Analysis of the published cases was reinforced by contacting the authors of all the papers with incomplete data for further clarifications. The most common sites of aSCC were the tongue (24/55) and the maxilla/maxillary gingiva and/or palate (11/55). The overall survival rate was 36/53 (67.9%) with a mean follow-up period of 22 months against 62.5% for conventional SCC (p = 0.6). No statistically significant difference between the two variants of the tumor with respect to the oral cavity was detected. The differences in age, sex, survival rate, staging, and locations were not statistically significant. Based on the available data from 55 cases, there is no evidence to suggest that aSCC is more aggressive than conventional SCC in intraoral cases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12105-021-01368-8.

Yaseen Awad-Igbaria,1,2 Shilo Dadon,1,2 Alon Shamir,3,4 Alejandro Livoff,5 Mark Shlapobersky,5 Jacob Bornstein,1,2,* Eilam Palzur2,* 1Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel; 2The Research Institute of Galilee Medical Center, Nahariya, Israel; 3Psychobiology Research Laboratory, Mazor Mental Health Center, Akko, Israel; 4The Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel; 5Pathology Department, Barzilai University Medical Center, Ashkelon, Israel*These authors contributed equally to this workCorrespondence: Yaseen Awad-Igbaria, The Research Institute of Galilee Medical Center, PO Box 21, Nahariya, 22100, Israel, Tel +972 50-4500101, Email Yaseenawad123@gmail.comBackground: Provoked vulvodynia (PV) is the main cause of vulvar pain and dyspareunia. The etiology of PV has not yet been elucidated. However, PV is associated with a history of recurrent inflammation, and its often accompanied by increases in the numbers of mast cells (MCs) and sensory hyperinnervation in the vulva. Therefore, this study aimed to examine the role of MCs and the early inflammatory events in the development of chronic vulvar pain in a rat model of PV.Methods: Mechanical and thermal vulvar sensitivity was measured for 5 months following zymosan vulvar challenges. Vulvar changes in glutamate and nerve growth factor (NGF) were analyzed using ELISA. Immunofluorescence (IF) staining of the vulvar section after 20, 81, and 160 days of the zymosan challenge were performed to test MCs accumulation, hyperinnervation, and expression of pain channels (transient receptor potential vanilloid/ankyrin-1-TRPV1 & TRPA1) in vulvar neurons. Changes in the development of vulvar pain were evaluated following the administration of the MCs stabilizer ketotifen fumarate (KF) during zymosan vulvar challenges.Results: Zymosan-challenged rats developed significant mechanical and thermal vulvar sensitivity that persisted for over 160 days after the zymosan challenge. During inflammation, increased local concentrations of NGF and glutamate and a robust increase in MCs degranulation were observed in zymosan-challenged rats. In addition, zymosan-challenged rats displayed sensory hyperinnervation and an increase in the expression of TRPV1 and TRPA1. Treatment with KF attenuated the upregulated level of NGF during inflammation, modulated the neuronal modifications, reduced MCs accumulation, and enhanced mechanical hypersensitivity after repeated inflammation challenges.Conclusion: The present findings suggest that vulvar hypersensitivity is mediated by MCs accumulation, nerve growth, and neuromodulation of TRPV1 and TRPA1. Hence, KF treatment during the critical period of inflammation contributes to preventing chronic vulvar pain development.Keywords: provoked vulvodynia, inflammation, mast cell, nerve growth factor, glutamate, hyperinnervation

Sufficient tumor tissues are often not available for large HLA peptidome analysis. We demonstrate here that using patient derived xenograft (PDX) tumors are a useful source of large tumors for obtaining detailed and authentic HLA peptidomes that enable identification of many tumor antigens and even neoantigens of potential usefulness for personalized cancer immunotherapy., Graphical Abstract Highlights • Sufficient tumor tissues are often unavailable large HLA peptidome discovery. • Using patient derived xenograft (PDX) tumors can overcome this limitation. • The large PDX HLA peptidomes expand significantly those of the original biopsies. • The HLA peptidomes of the PDX tumors included many tumor antigens., Personalized cancer immunotherapy targeting patient-specific cancer/testis antigens (CTA) and neoantigens may benefit from large-scale tumor human leukocyte antigen (HLA) peptidome (immunopeptidome) analysis, which aims to accurately identify antigens presented by tumor cells. Although significant efforts have been invested in analyzing the HLA peptidomes of fresh tumors, it is often impossible to obtain sufficient volumes of tumor tissues for comprehensive HLA peptidome characterization. This work attempted to overcome some of these obstacles by using patient-derived xenograft tumors (PDX) in mice as the tissue sources for HLA peptidome analysis. PDX tumors provide a proxy for the expansion of the patient tumor by re-grafting them through several passages to immune-compromised mice. The HLA peptidomes of human biopsies were compared with those derived from PDX tumors. Larger HLA peptidomes were obtained from the significantly larger PDX tumors as compared with the patient biopsies. The HLA peptidomes of different PDX tumors derived from the same source tumor biopsy were very reproducible, even following subsequent passages to new naïve mice. Many CTA-derived HLA peptides were discovered, as well as several potential neoantigens/variant sequences. Taken together, the use of PDX tumors for HLA peptidome analysis serves as a highly expandable and stable source of reproducible and authentic peptidomes, opening up new opportunities for defining large HLA peptidomes when only small tumor biopsies are available. This approach provides a large source for tumor antigens identification, potentially useful for personalized immunotherapy.

Plasmacytoma is a malignant tumor of the plasma cells. Extra-medullary plasmacytoma is rare and with an even lower incidence appears as a primary tumor of the stomach. Initial onset of the disease in the upper gastrointestinal tract is reported in the literature as just second to primary plasmacytomas of the head and neck system. The presenting symptoms are related to the organ involved and systemic symptoms can be weight loss, pain, bleeding and even fever. As this is a rare disease, there is no standard treatment and patients undergo endoscopic resection or chemotherapy with or without additional radiation. The prognosis of the disease depends on the possible future diagnosis of multiple myeloma which can be up to 50% within only a few years. We hereby report a case of a male patient with a past locally advanced breast cancer who was on prolonged adjuvant hormonal treatment. He developed a new symptom of melena and underwent a thorough evaluation including imaging and repeated biopsies from a large gastric lesion. The results were inconclusive mainly because of the differential diagnosis between breast cancer metastases and a new second primary malignancy. In view of a clinical deterioration and lack of diagnosis, an operation of radical gastrectomy was eventually performed only to surprisingly diagnose a rare hematologic disease of the stomach - gastric plasmacytoma. This diagnosis is rare in itself, especially having his previous male breast cancer and maternal multiple myeloma. The diagnostic procedure in this case had also provided the full treatment for his illness.

Background Diabetic patients have an increased predisposition to thromboembolic events, in most cases originating from thrombi in the left atrial appendage (LAA). Remodeling of the LAA, which predisposes to thrombi formation, has been previously described in diabetic patients with atrial fibrillation, but whether remodeling of the LAA occurs in diabetics also in the absence of atrial fibrillation is unknown. To investigate the contribution of diabetes, as opposed to atrial fibrillation, to remodeling of the LAA, we went from humans to the animal model. Methods We studied by echocardiography the structure and function of the heart over multiple time points during the evolution of diabetes in the Cohen diabetic sensitive rat (CDs/y) provided diabetogenic diet over a period of 4 months; CDs/y provided regular diet and the Cohen diabetic resistant (CDr/y), which do not develop diabetes, served as controls. All animals were in sinus rhythm throughout the study period. Results Compared to controls, CDs/y developed during the evolution of diabetes a greater heart mass, larger left atrial diameter, wider LAA orifice, increased LAA depth, greater end-diastolic and end-systolic diameter, and lower E/A ratio—all indicative of remodeling of the LAA and left atrium (LA), as well as the development of left ventricular diastolic dysfunction. To investigate the pathophysiology involved, we studied the histology of the hearts at the end of the study. We found in diabetic CDs/y, but not in any of the other groups, abundance of glycogen granules in the atrial appendages , atria and ventricles, which may be of significance as glycogen granules have previously been associated with cell and organ dysfunction in the diabetic heart. Conclusions We conclude that our rodent model of diabetes, which was in sinus rhythm, reproduced structural and functional alterations previously observed in hearts of human diabetics with atrial fibrillation. Remodeling of the LAA and of the LA in our model was unrelated to atrial fibrillation and associated with accumulation of glycogen granules. We suggest that myocardial accumulation of glycogen granules is related to the development of diabetes and may play a pathophysiological role in remodeling of the LAA and LA, which predisposes to atrial fibrillation, thromboembolic events and left ventricular diastolic dysfunction in the diabetic heart.

We present a case of a 64-year-old man with a bilateral nasal obstruction. An endoscopic biopsy taken from the mass revealed a vascular clear cell tumor underneath an intact Schneiderian membrane compatible with a renal cell carcinoma. Following inquiry, it was revealed that the patient had gone through right radical nephrectomy for renal cell carcinomas 17 years prior to admission, a fact that was not known when the biopsy was taken. A following workup showed areas suspicious for metastases in lungs and maxillary sinuses. The patient started treatment with Sunitinib. On five months follow- up, the lung lesions had regressed.

Aim: Inflammatory myofibroblastic tumors (IMTs) are uncommon neoplasms of intermediate biologic behavior that typically present in the lungs of children and young adults but may occur elsewhere in the body. The head and neck is an unusual site of involvement and in the jaws these are even less common. The purpose of this study is to present a central IMT arising within the mandibular bone of a seven year old female and to analyze the available literature of intrabony/central IMTs of the jaws. Methods: Publications in the English language literature on central IMTs arising within the jawbones were located by a PubMed and googlescholar search of case reports and series. Results: 25 cases including the present one were included. The mean age of the patients was 34.8 ± 19.6 years. The mandible was affected in most cases. All cases were osteolytic, all but the present one were unilocular, and more than 50% were well defined. Bony expansion was evident in 42.8% and root resorption in 53.8% of the cases. The lesions were composed of spindle fibroblastic and myofibroblastic cells with a variable inflammatory infiltrate, most commonly lymphocytes (85%) and plasma cells (75%), but other inflammatory cells such as neutrophils, eosinophils and mast cells were also present. Immunohistochemically smooth muscle actin was positive in 100% and ALK1 was positive in 6 of 14 cases (42.8%). 2 cases were h-Caldesmon positive. The present case stained diffusely with an antibody against Paladin, implicated in mesenchymal transition process of metastatic breast carcinoma. Treatment options consisted mostly of surgery, but pharmacological therapy with glucocorticoids and combinations of these were also documented. Conclusion: Central IMT of the jawbone is a rare tumor that could have an alarming clinical presentation. The differential diagnosis of spindle cell lesions accompanied by inflammatory infiltrate in children is diverse; Paladin antibody could be used to emphasize the myofibroblastic nature of the lesion.

Background Thoracic and abdominal aortic aneurysms and dissection often develop in hypertensive elderly patients. At higher risk are smokers and those who have a family history of aortic aneurysms. In most affected families, the aortic aneurysms and dissection is inherited in an autosomal dominant manner with decreased penetrance and variable expressivity. Mutations at two chromosomal loci, TAA1 at 11q23 and the TAA2 at 5q13–14, and eight genes, MYLK, MYH11, TGFBR2, TGFBR1, ACTA2, SMAD3, TGFB2, and MAT2A, have been identified as being responsible for the disease in 23% of affected families. Results Herein, we inform on the clinical, genetic and pathological characteristics of nine living and deceased members of a large consanguineous Arab family with thoracic aortic aneurysm and dissection who carry a missense mutation c.4471G > T (Ala1491Ser), in exon 27 of MYLK gene. We show a reduced kinase activity of the Ala1491Ser protein compared to wildtype protein. This mutation is expressed as aortic aneurysm and dissection in one of two distinct phenotypes. A severe fatal and early onset symptom in homozygous or mild late onset in heterozygous genotypes. Conclusions We found that MYLK gene Ala1491Ser mutation affect the kinase activity and clinically, it presents with vascular aneurysms and dissection. We describe a distinct genotype phenotype correlation where; heterozygous patients have mild late onset and incomplete penetrance disease compared with the early onset severe and generally fatal outcome in homozygous patients.

Acantholytic squamous cell carcinoma (ASCC) is an uncommon variant of squamous cell carcinoma (SCC). It is characterized by a combination of typical SCC and pseudoglandular structures, dyskeratotic cells and prominent acantholysis. The purpose of this study was to analyze the histochemical and immunohistochemical characteristics of the intraoral variant of ASCC. Cases of intraoral ASCC were retrieved from the English language literature. Four new cases from our files were added. In total, 35 cases were included and analyzed in this study. The mean age of the patients was 61.5 + 13 years (age range 38–92 years), with a male-to-female ratio of 1.7:1. According to the available data, histochemical and immunohistochemical stains for mucins were found to be consistently negative. E- cadherin, a marker of adherens junctions, was usually reported to be expressed in areas of “typical” (non acantholytic) SCC, but reduced in the acantholytic areas. We examined for the first time the expression of claudin 1, a marker of tight junctions, and found it to be reduced in the acantholytic areas, similar to E-cadherin. Several cases of oral ASCC also expressed vimentin and cytokeratin (CK) 19, markers associated with epithelial-mesenchymal transition. A wide range of non-epithelial markers yielded negative immunoreactions. In conclusion, ASCC is an uncommon variant of squamous cell carcinoma. The acantholytic process appears to involve reduced expression of molecular components of both adherens junctions and tight junctions. These findings could suggest a relation to the epithelial mesenchymal transition process and therefore further studies are needed in order to establish such a link and the subsequent possible impact on the clinical outcome of the patients.

We aimed to immunohistochemically characterize the pattern of expression of epithelial markers in rare head and neck squamous cell carcinoma (HNSCC) variants: carcinoma cuniculatum (CC) and adenosquamous carcinoma (ASC). We also present an additional variant of HNSCC with concomitant basaloid and squamous components that has overlapping morphological features with odontogenic and non-odontogenic tumors, which we termed basalo-squamous carcinoma (BSC). The selected markers included CK5/6, p40, CK19, BerEP4, p16 and SOX10. All tumors were CK5/6 and p40 positive. CK19 and BerEP4 were positive in BSC and focally in ASC but negative in CC. p16 was positive in 3 (60%) of the CCs, focally positive in ASC and negative in BSC. SOX10 was negative in all three variants. Our results highlight the plasticity of the lining epithelium revealing differential profiles of immuno-expression of the selected molecular markers, possibly reflecting their diverse histopathogenesis.

Goblet cell carcinoid or carcinoma (GCC) is a rare tumor found incidentally during routine management of acute appendicitis. GCCs are more aggressive compared with conventional appendiceal tumors but less aggressive compared with adenocarcinomas, and they often present with serosal and mesoappendiceal involvement. We herein report two cases of acute appendicitis in a 45-year-old female and a 60-year-old male with varied clinical symptoms. Pathological examination of the appendix revealed the presence of adenocarcinoma with goblet cells and a Ki-67 index of 25% (grade 3) and 15% (grade 2), respectively. Subsequent right hemicolectomy was performed according to the current guidelines. No signs of disease recurrence or metastasis were detected during regular follow-up. However, the lack of a standardized classification system for GCC and the discrepancies in specific reliable markers renders their prognostic and predictive value in GCC at diagnosis insufficient. The present study also aimed to address current concerns regarding the diagnosis, treatment and prognosis of GCC, as well as the need to review and update current guidelines. To conclude, proper clinical management and the prediction of outcome for patients with GCC varies according to the classifications or staging criteria used by the clinicians; hence, a review of the current guidelines should be considered.

BACKGROUND AND AIM Our aim was to assess adequacy and diagnostic accuracy of endoscopic ultrasound-fine needle aspiration (EUS-FNA) specimens with or without rapid on-site evaluation (ROSE) from pancreatic, upper gastrointestinal tract (UGIT) and adjacent masses. METHOD A retrospective cohort study based on patients' files who underwent EUS-FNA in Galilee Medical Center in a 4 years period. Number of needle passes, repeated EUS and ROSE effect on tissue adequacy and diagnostic accuracy were reported. RESULTS One-hundred sixty-one patients were included. Ninety-three patients (57.7%) underwent EUS-FNA without ROSE (group A) compared to 68 patients (42.3%) with ROSE (group B). The most common location was in the pancreas (55% in group A vs 81% in group B). Addition of ROSE yielded a significantly higher specimen adequacy (65% in group A vs 92.6% in group B (Chi-Square

Goblet cell carcinoid or carcinoma (GCC) is a rare tumor found incidentally during routine management of acute appendicitis. GCCs are more aggressive compared with conventional appendiceal tumors but less aggressive compared with adenocarcinomas, and they often present with serosal and mesoappendiceal involvement. We herein report two cases of acute appendicitis in a 45-year-old female and a 60-year-old male with varied clinical symptoms. Pathological examination of the appendix revealed the presence of adenocarcinoma with goblet cells and a Ki-67 index of 25% (grade 3) and 15% (grade 2), respectively. Subsequent right hemicolectomy was performed according to the current guidelines. No signs of disease recurrence or metastasis were detected during regular follow-up. However, the lack of a standardized classification system for GCC and the discrepancies in specific reliable markers renders their prognostic and predictive value in GCC at diagnosis insufficient. The present study also aimed to address current concerns regarding the diagnosis, treatment and prognosis of GCC, as well as the need to review and update current guidelines. To conclude, proper clinical management and the prediction of outcome for patients with GCC varies according to the classifications or staging criteria used by the clinicians; hence, a review of the current guidelines should be considered.

Background: Radiation therapy (RT) is a longstanding treatment modality for cancer. In addition, immune checkpoint blockade has been a significant development in the field of immunotherapy, modifying key immunosuppressive pathways of cancer cells. Methods: The aim of the present work was to review current concepts of RT and immunotherapy synergism, the abscopal effect, and the molecular effects of RT in the tumour microenvironment, its influence on immune stimulation, and potential clinical outcomes that might evolve from ongoing studies. We also discuss potential predictors of clinical response. Results: Up-to-date literature concerning the mechanisms, interactions, and latest knowledge about RT and immunotherapy was reviewed and summarized, and is presented here. Conclusions: The possibility of using hyperfractionated RT to combine an abscopal effect with the enhanced effect of immune treatment using checkpoint blockade is a very promising method for future tumour treatments.

Radiation therapy (rt) is a longstanding treatment modality for cancer. In addition, immune checkpoint blockade has been a significant development in the field of immunotherapy, modifying key immunosuppressive pathways of cancer cells. The aim of the present work was to review current concepts of rt and immunotherapy synergism, the abscopal effect, and the molecular effects of rt in the tumour microenvironment, its influence on immune stimulation, and potential clinical outcomes that might evolve from ongoing studies. We also discuss potential predictors of clinical response. Up-to-date literature concerning the mechanisms, interactions, and latest knowledge about rt and immunotherapy was reviewed and summarized, and is presented here. The possibility of using hyperfractionated rt to combine an abscopal effect with the enhanced effect of immune treatment using checkpoint blockade is a very promising method for future tumour treatments.