Visceral Lymph Nodes Research Articles

Sarcoidosis of mediastinal and abdominal (visceral) lymph nodes, lungs, liver, goldbladder, spleen, complicated by phlegmonous cholecystitis

The article contains a description of generalized sarcoidosis diagnosed morphologically after cholecystectomy for phlegmonous cholecystitis.

Long-term prognostic characteristics of patients with clinical stage IA part-solid lung adenocarcinoma: a conditional survival analysis.

Despite excellent 5-year survival, there are limited data on the long-term prognostic characteristics of clinical stage IA part-solid lung adenocarcinoma. The objective was to elucidate the dynamics of prognostic characteristics through conditional survival analysis. Consecutive patients who underwent complete resection for clinical stage IA part-solid lung adenocarcinoma between 2011 and 2015 were retrospectively reviewed. Conditional survival is defined as the probability of surviving further y years, conditional on the patient has already survived x years. The conditional recurrence-free survival (CRFS) and conditional overall survival (COS) were analysed to evaluate prognosis over time, with conditional Cox regression analysis performed to identify time-dependent prognostic factors. A total of 1539 patients were included with a median follow-up duration of 98.4 months, and 80 (5.2%) patients experienced recurrence. Among them, 20 (1.3%) recurrence cases occurred after 5 years of follow-up with 100% intrathoracic recurrence. The 5-year CRFS increased from 95.8% to 97.4%, while the 5-year COS maintained stable. Multivariable Cox analysis revealed that histologic subtype was always an independent prognostic factor for CRFS even after 5 years of follow-up, while the independent prognostic value of consolidation-to-tumour ratio, visceral pleural invasion and lymph node metastasis was observed only within 5 years. Besides, age, pathologic size and lymph node metastasis maintained independent predictive value for COS during long-term follow-up, while consolidation-to-tumour ratio was predictive for COS only within 5 years of follow-up. The independent prognostic factors for clinical stage IA part-solid lung adenocarcinoma changed over time, along with gradually increasing 5-year CRFS and stable 5-year COS.

Survival Patterns Based on First-site–specific Visceral Metastatic Prostate Cancer: Are Outcomes of Visceral Metastases the Same?

Background and objectiveVisceral metastatic disease in prostate cancer patients conveys a poor prognosis. Using advanced imaging techniques, studies have demonstrated increasing detection rates of visceral metastasis. Visceral metastases are now seen in up to 30–60% of prostate cancer patients. Survival patterns of site-specific visceral metastasis are described poorly in the literature. Here, we sought to investigate survival patterns in prostate cancer patients according to their first detected site of visceral metastasis. MethodsRetrospectively, we identified 203 prostate cancer patients with visceral metastases from the Mayo Clinic Advanced Prostate Cancer Registry. Patients were divided into three groups according to the first site of visceral metastases detected: lung, brain, or liver. Visceral metastases were detected primarily on either metabolic imaging (C-11 choline) or prostate-specific membrane antigen positron emission tomography computed tomography (CT) scan. Confirmation of visceral metastasis diagnosis was established with either biopsy when feasible or focused conventional imaging, including focused CT or magnetic resonance imaging. Overall survival and cancer-specific survival were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression model was conducted to assess different variables that affect overall and cancer-specific survival. Key findings and limitationsOver a median (interquartile range) follow-up duration of 16.2 (3.9–49.8) mo, the overall and cancer-specific survival of the entire cohort suggests better survival patterns in patients with first-site lung metastases than in patients with first-site brain or liver metastases (p < 0.0001). In univariate and multivariate analyses of factors impacting patients’ overall and cancer-specific survival, a high prostate-specific antigen level at diagnosis of visceral metastasis, concomitant bone and lymph node disease, and more than four visceral metastases were associated with poor overall and cancer-specific survival (p < 0.05). On the contrary, first-site lung metastasis was associated with improved overall and cancer-specific survival, compared with first-site liver and brain metastases (p < 0.001). Conclusions and clinical implicationsThese data suggest that prostate cancer patients with visceral metastatic disease have varying survival patterns according to first-site detected visceral metastasis. In our cohort, patients with first-site lung metastasis demonstrated better survival outcomes than patients with first-site brain or liver metastasis. Patient summaryOur study explored the survival outcomes among patients with visceral metastatic prostate cancer employing cutting-edge imaging methods. Prostate cancer patients with metastases to different organs have different survival rates. Patients with cancer spreading to the lungs first showed better survival than those with cancer spreading to the brain or liver first.

Novel presentation of a feline patient with visceral and cervical lymph node hemangiosarcoma.

To report a novel presentation of feline hemangiosarcoma. A 14-year-old spayed female feline patient diagnosed with hemangiosarcoma of the spleen and a cervical lymph node. The patient presented to the emergency service following a 1-week history of lethargy and hiding. Abdominal ultrasound revealed splenomegaly with multiple nodules and peritoneal fluid that was consistent with hemorrhagic effusion. The patient underwent a routine splenectomy and was started on doxorubicin. Histopathologic evaluation of the spleen confirmed visceral hemangiosarcoma. When the disease showed signs of progression, combination chemotherapy with cyclophosphamide and vincristine was initiated. Four months following presentation, a submandibular lymph node was removed and found to have metastatic hemangiosarcoma. From presentation to euthanasia, the patient survived 205 days. Hemangiosarcoma is a rare cancer in feline patients, with a lack of veterinary literature on its presentation and chemotherapy protocols. The subject of this case report had a novel presentation of hemangiosarcoma and responded favorably to a chemotherapy protocol not previously described for this disease.

Activity of biogenic silver nanoparticles in planktonic and biofilm-associated Corynebacterium pseudotuberculosis.

Corynebacterium pseudotuberculosis is a gram-positive bacterium and is the etiologic agent of caseous lymphadenitis (CL) in small ruminants. This disease is characterized by the development of encapsulated granulomas in visceral and superficial lymph nodes, and its clinical treatment is refractory to antibiotic therapy. An important virulence factor of the Corynebacterium genus is the ability to produce biofilm; however, little is known about the characteristics of the biofilm produced by C. pseudotuberculosis and its resistance to antimicrobials. Silver nanoparticles (AgNPs) are considered as promising antimicrobial agents, and are known to have several advantages, such as a broad-spectrum activity, low resistance induction potential, and antibiofilm activity. Therefore, we evaluate herein the activity of AgNPs in C. pseudotuberculosis, through the determination of minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), antibiofilm activity, and visualization of AgNP-treated and AgNP-untreated biofilm through scanning electron microscopy. The AgNPs were able to completely inhibit bacterial growth and inactivate C. pseudotuberculosis at concentrations ranging from 0.08 to 0.312 mg/mL. The AgNPs reduced the formation of biofilm in reference strains and clinical isolates of C. pseudotuberculosis, with interference values greater than 80% at a concentration of 4 mg/mL, controlling the change between the planktonic and biofilm-associated forms, and preventing fixation and colonization. Scanning electron microscopy images showed a significant disruptive activity of AgNP on the consolidated biofilms. The results of this study demonstrate the potential of AgNPs as an effective therapeutic agent against CL.

A phase II study evaluating the efficacy of enzalutamide and the role of liquid biopsy for evaluation of ARv7 in mCRPC patients with measurable metastases including visceral disease (Excalibur study).

Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) develop visceral metastases, which are associated with a poor prognosis. Efficacy of enzalutamide in mCRPC patients with measurable metastases, including visceral and/or extra-regional lymph nodes. In this phase II multicenter study, patients with mCRPC and measurable metastases received enzalutamide as the first line. Primary endpoint: 3-month (mo) disease control rate (DCR) defined as the proportion of patients with complete (CR) or partial response (PR) or stable disease (SD) as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoint: safety. Exploratory endpoint: the association between ARv7 splicing variants in basal circulating tumor cell (CTC)-enriched blood samples and treatment response/resistance using the AdnaTest ProstateCancerSelect kit and the AdnaTest ProstateCancer Panel AR-V7. From March 2017 to January 2021, 68 patients were enrolled. One patient never started treatment. Median age: 72 years. A total of 52 patients (78%) received enzalutamide as a first line for mCRPC. The median follow-up was 32 months. At the 3-month assessment, 24 patients presented an SD, 1 patient achieved a CR, and 23 patients had a PR (3-mo-DCR of 72%). Discontinuations due to adverse events (AEs), disease-related death, or disease progression occurred in 9%, 6%, and 48% of patients. All patients reported at least one grade (G) 1-2 AE: the most common were fatigue (49%) and hypertension (33%). Six G3 AEs were reported: two hypertension, one seizure, one fatigue, one diarrhea, and one headache. Basal detection of ARv7 was significantly associated with poor treatment response (p = 0.034) and a nonsignificant association (p = 0.15) was observed between ARv7 detection and response assessments. At month 3, ARv7 was detected in 57%, 25%, and 15% of patients undergoing progressive disease, SD, and PR, respectively. The study met its primary endpoint, showing the efficacy of enzalutamide in men with mCRPC and measurable metastatic lesions in visceral and/or lymph node sites. ClinicalTrials.gov Identifier: NCT03103724. First Posted: 6 April 2017. First patient enrollment: 19 April 2017.

Phytomodification Effects of Visceral Lymph Node Aging

Lymph nodes are prioritized in protecting and ensuring endoecological safety at different periods of life, especially in retirement age. It destabilizes the structure and function of the lymphatic system and organs when aging increases the risk of comorbid conditions. This is a sign of age-related pathology. Improving lymph node function is an essential task in integrating gerontology and lymphology. The solution to this problem is possible with the help of a phytotherapeutic agent, which involves the evaluation of efficacy with effect on intranodular functional systems - compartments, hydration, and trace elements. Phytotherapy weakens (slows) the intensity of the old lymph node changes. Phytotherapy has a modifying effect on structures with increased hydration and trace element concentration. Phytotherapy prevents age-dependent changes in the lymph node and increases the reliability of lymph node operation in old age.

Locoregional Treatment in Patients With Metastatic Cervical Cancer: Benefit of Dose Escalation Strategies

The objective of this work was to examine the benefit of an intensive locoregional treatment including an image guided adaptive brachytherapy (IGABT) among patients with cervical cancer and extrapelvic extension. Medical records of consecutive patients with a metastatic cervical cancer and receiving external beam radiation therapy and IGABT boost in Gustave Roussy Institute as part of their first line of treatment were examined. Depending on tumor sites, patients received pelvic ± para-aortic external beam radiation therapy. For those with visceral or supradiaphragmatic lymph node metastases, chemoradiation was delivered after usually 3 cycles of chemotherapy. All patients received a brachytherapy boost, guided by magnetic resonance imaging and aimed at increasing the dose to the high-risk clinical target volume (CTVHR). Local control (LC), patient overall survival (OS), progression-free survival, and radiation therapy-related side effects were examined, and prognostic factors were searched. One hundred sixty-four patients were included; 76.2% had para-aortic lymph node extension without distant metastasis (N2) and 23.8% had distant metastatic sites (M1). There was not a statistically significant difference in survival between both groups. With a median follow-up of 36 months, OS, progression-free survival, and LC at 3 years were 55.5% (95% CI, 48%-64%), 40.6% (95% CI, 38%-54%), and 90% (95% CI, 85%-96%), respectively. In multivariate analysis, a D90CTVHR dose ≥80 Gy was significant for better OS (hazard ratio, 0.96; 95% CI, 0.94-0.98; P < .001). Most toxicities were mild to moderate, with 2% grade 3 late urinary toxicity, 7% late grade 2 vaginal sequelae, and 1 grade 3 proctitis. During follow-up, rectovaginal fistula occurred in 2 patients without local relapse. IGABT permits dose escalation and high LC rates for patients with cervical cancer and extrapelvic extension. Dose/effect relationships for survival were shown. Because of high frequency of distant events, systemic intensification should be tested more specifically among these patients.

Prevalence and risk factors of bovine tuberculosis in slaughtered cattle, Malawi

Bovine tuberculosis (bTB) is an infectious disease with significant socioeconomic, animal, and public health impacts. However, the prevalence of bTB remains largely unclear in Malawi due to a paucity of information. Additionally, the existence of multiple risk factors is postulated to enhance bTB transmission in animals. A cross-sectional survey to estimate the prevalence of bTB, animal characteristics and identify associated risk factors was conducted from slaughtered cattle at three major regional abattoirs (southern, central and northern regions) in Malawi. Out of a total of 1547 cattle examined, 154 (9.95%) had bTB-like lesions in various visceral organs and lymph nodes; one sample per animal was collected, processed, and cultured in the in the BACTEC Mycobacterial growth indicator tube (MGIT) 960 system. From the 154 cattle that showed tuberculous like lesions, only 112 were positive on MGIT and 87 were confirmed to have M. bovis based on multiplex PCR. Cattle from the southern region (odds ratio (OR) = 1.96, 95% CI: 1.03–3.85) and central region (OR = 2.00, 95% CI: 1.16–3.56) were more likely presented with bTB-like lesions at slaughter than from the northern region. The risk of having bTB-like lesions was higher in females (OR = 1.51, CI: 1.00–2.29), older cattle (OR = 2.17, CI: 1.34–3.37), and crossbreeds (OR = 1.67, 95% CI: 1.12–2.47) than in males, younger animals, and Malawi Zebu breed, respectively. The high prevalence of bTB is of critical concern and necessitates active surveillance and strengthening of the current control strategies under a One Health (OH) approach at the animal-human interface.

Microscopic changes in some organs of cats at the infectious peritonitis

The study's relevance is that pathomorphological changes in the infectious peritonitis of cats have been studied by a few authors and still need to be fully described. This paper describes the microscopic changes in the brain and spinal cord, liver, and somatic and visceral lymph nodes in cats with infectious peritonitis. The leading research method is a histological examination of sections obtained from the listed organs of cats of various ages that died from mixed (26 animals) and dry (7 animals) forms of infectious peritonitis. Sections were stained with hematoxylin and eosin according to the generally accepted method. It was found that microscopic changes in the brain and spinal cord do not depend on the form and duration of the disease. Gray and white matter are swollen, blood vessels are spasmodic, and nerve cells are in basophilia. A particularly significant swelling was found in the white matter of the spinal cord, which at the same time underwent lysis. In the liver, microscopic changes do not depend on the disease's form but are somewhat different depending on the duration of its course. In cats that were ill for less than three weeks before death, fibrinous-necrotic overlays are found on the surface of the capsule in places. Areas where mesotheliocytes of the capsule undergo metaplasia, are also seen – they acquire a cubic or columnar shape. In some places, the liver capsule is destroyed. The portal tracts are swollen and infiltrated with a small number of lymphocytes and monocytes, and the walls of the arteries of the hepatic triad are necrotized. Foci of tissue necrosis of the portal tract are also detected. Veins and bile ducts are not differentiated. Liver lobules are infiltrated with lymphocytes and monocytes. Cell swelling and destruction of hepatocytes were established. In animals that were ill for more than three weeks before death, in addition to the changes typical for infectious peritonitis, portal hepatitis, edema, and disorganization of liver lobules, hydropic dystrophy, destruction, and necrosis of hepatocytes were found. Changes in the lymph nodes are individual and do not depend on the form and duration of the course of the disease. However, in all cases of the registry, there were foci of necrosis in the central part of lymphoid nodules and the paracortical zone.

Vector Analysis of Multicentric Lymphoma in a Severe Hemophilia Α Dog after AAV Gene Therapy

Background Adeno-associated viral (AAV) vector gene therapy for severe hemophilia A (HA) is approaching a clinical reality with multiple successful clinical trials. Despite this success, questions remain about the long-term safety of AAV vectors, especially regarding genomic integration and resulting oncogenesis. Studies of neonatal mice have demonstrated AAV integrations that drive hepatocellular carcinoma formation (Donsante et al. Science, 2007). Studies in HA canine models have also demonstrated AAV integrations and clonal expansion of hepatocytes with integrated vector genomes, but no evidence of tumor formation (Nguyen et al. Nat Biotechnol, 2021). Additionally, three tumors have been reported in AAV gene therapy recipients with HA or hemophilia B in clinical trials, without evidence of vector integrations driving oncogenesis. Though overall reassuring, these data highlight that the field needs to remain vigilant about the possibility of AAV integrations driving cancer development. Thus, the assessment of tumors in gene therapy recipients remains important for the AAV field. Aims To determine the role of AAV vector in the development of multicentric lymphoma in a severe HA dog that received liver-directed gene therapy. Methods Vector genome copy numbers in relevant tissues were determined by real-time PCR with primers situated in the 3'-end of the promoter and the 5'- end of the transgene. The vector copy number was calculated by comparing the analyte amplification signal against a standard curve of the plasmid DNA. Results A privately owned mixed-breed dog (PC9) with a history of recurrent spontaneous bleeding events presented with canine factor VIII (cFVIII) levels <1% normal, consistent with severe HA. At 9-months of age, he received liver-directed AAV8 gene therapy with a high-expressing canine factor FVIII (cFVIII-ΔF/V3) variant transgene at a dose of 6 x 1012 vg/kg via intravenous administration. Following gene therapy, his cFVIII levels increased to 2-3% normal and remained stable through duration of follow-up. His annualized bleeding rate decreased from 8 pre-gene therapy to 0 post-gene therapy. At 3.5 years after vector administration, PC9 was diagnosed with a widely disseminated cancer and euthanized due to complications of the disease. At autopsy, he was diagnosed with multicentric lymphoma involving peripheral and visceral lymph nodes, spleen, liver, and lungs. The average age of lymphoma diagnosis in dogs is between 6-9 years of age (Edwards et al. Vet Comp Oncol, 2003), so the development of cancer at an early age in a gene therapy recipient warranted additional study. Vector copy number analysis showed that the liver had the highest levels of AAV vector genomes, as expected. Liver samples showed a heterogenous distribution of vector genomes, consistent with previous studies of AAV8 transduction (Bell et al. Hum Gene Ther, 2011). Splenic samples also had a high level of AAV vector genomes, which again is consistent with known targeting of AAV8. Importantly, the lymph nodes had no detectable AAV vector genomes present, suggesting that vector integration could not contribute to lymphoma development. cFVIII levels remained stable before and after diagnosis of lymphoma, supporting lack of vector integration in the malignant cells. Conclusions AAV gene therapy resulted in a 100% reduction in the annualized bleeding rate in this pet dog with severe HA. Furthermore, the multicentric lymphoma that developed 3.5 years after liver-directed gene therapy is unlikely related to the AAV vector. We are unable to rule out other factors that may have contributed, including environmental influences or genetic predispositions for lymphoma. These results support the ongoing efforts to treat HA with AAV-based gene therapy and reinforce the safety profile of AAV vectors outside of a laboratory environment.

A Case Report of a Prevertebral Mass in an Elderly Male Post Hodgkin's Lymphoma

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory autoimmune disease characterized by tissue infiltration by dense lymphoplasmacytic infiltrate composed of T cells, activated B-cells, and plasma cells expressing IgG4 and has varied presentations with similar histopathology. It can involve visceral organs, glands, aorta, lymph nodes, and retroperitoneal tissue. In our case, a 68-year-old male with a past history of Hodgkin's lymphoma and in remission presented for investigation of polyclonal gammopathy. Serum electrophoresis showed increased free kappa light chains, free lambda light chains, and kappa lambda ratio; immunoglobulin G (IgG) levels were also increased. A positron emission tomography (PET) scan and magnetic resonance imaging (MRI) thoracic spine suggested a hypermetabolic prevertebral soft tissue density. Biopsy of the mass suggested IgG4-related disease (IgG4-RD). He also had a compression fracture of the T7 vertebra. He was started on intravenous methylprednisolone and rituximab, following which he had a significant decrease in the size of the mass along with a decline in the levels of IgG, kappa, and lambda chains.

Significance of the Number and the Location of Metastatic Lymph Nodes in Locally Recurrent or Persistent Cervical Cancer Patients Treated with Salvage Hysterectomy plus Lymphadenectomy.

We retrospectively investigated the significance of metastatic lymph nodes in patients with locally recurrent or persistent cervical cancer in a previously irradiated field and subsequently had salvage hysterectomy. Clinical data were obtained from a chart review, and the prognostic impact of the presence, number (1–2 versus ≥3), and location (pelvic versus pelvic plus para-aortic) of lymph node metastasis was investigated by comparing recurrence and survival. In total, 50 patients were included in this study, of which 21 (42.0%) showed pathological evidence of lymph node metastasis (node-positive group). Both the univariate and multivariate analyses showed that lymph node metastasis was an independent prognostic factor for postoperative recurrence (hazard ratio (HR) 5.36; 95% CI 1.41–6.66; p = 0.0020). The predominant sites of recurrence after salvage surgery were the visceral organs and lymph nodes in the node-negative and node-positive groups, respectively. Patients with ≥3 node metastases showed similar survival to those with 1–2 node metastases. Patients with pelvic node metastasis showed similar survival to those with pelvic and para-aortic node metastases. The presence, not number or location, of lymph node metastasis was an independent poor prognostic factor for post-operative recurrence in patients who developed locally recurrent or persistent cervical cancer treated with salvage hysterectomy plus lymphadenectomy.

The clinicopathological features and survival of Castleman disease: a multicenter Turkish study.

In this study, we aimed to investigate the clinicopathological features and survival of CD, which is quite rare and has many unknowns. This study was conducted by retrospectively evaluating patients diagnosed with CD in six different centers in Turkey. The median age of 33 patients included in the study was 49 and 51.5% (n = 17) of these patients were women. 18 (54.5%) patients were in the hyaline vascular subtype and most of the patients were UCD (n = 20, 60.6%). The most common involvement region was head and neck (n = 19, 57.5%). The UCD group was younger than the MCD group (p=0.027). Visceral lymph node involvement was higher in MCD than in UCD (p=0.001). Similarly, it was observed that there was more hepatomegaly (p=0.035) and splenomegaly (p=0.013) in the MCD group. During the median 19.5 months follow-up period, there were no patients who died. It was observed that UCD and MCD are different clinical entities. Promising survival times can be achieved with surgical and systemic treatments in both subtypes of this extremely rare disease. However, this result should be supported by well-designed prospective comprehensive studies.

Activity of Ethanolic and Supercritical Propolis Extracts in Corynebacterium pseudotuberculosis and Its Associated Biofilm.

Corynebacterium pseudotuberculosis is the etiological agent of caseous lymphadenitis in small ruminants, a chronic disease characterized by the development of granulomas in superficial and visceral lymph nodes as well as in several organs. An important characteristic of the infection with this bacterium is the formation of a biofilm and the absence of effective antibiotic therapy against the disease. From this scenario, the objective of this study was to evaluate the susceptibility of C. pseudotuberculosis to conventional antibiotics and to red, green, and brown propolis extracts obtained by the supercritical and ethanolic extraction methods as well as its activity in the bacterial biofilm. The results of the sensitivity test using antibiotics indicated a sensitivity of C. pseudotuberculosis strains to the antimicrobial agents. The ethanolic extract of green propolis and the supercritical red propolis extract showed the best antibacterial activities against planktonic C. pseudotuberculosis. A lower antimicrobial activity of the brown propolis extract was identified. Propolis extracts were effective in interfering with the formation of the C. pseudotuberculosis biofilm but had little activity on the consolidated biofilm. In conclusion, propolis extracts are more effective against C. pseudotuberculosis in the planktonic stage, being able to interfere with the formation of bacterial biofilm. However, the action of propolis extracts in a sessile and structured microbial biofilm is reduced.

Metastatic malignant melanoma of unknown primary site to the brain: A case report.

Introduction and importanceThe natural history of metastatic melanoma in the absence of a known primary site has been poorly defined. The disease usually presents a significant cause of morbidity and mortality. Around 90% of melanomas have cutaneous origin, but still there are melanomas that could be found in visceral organs or lymph nodes with unknown primary site. Spontaneous regression of the primary site could be an explanation. The disease is frequently diagnosed after treatment for known extracranial metastases and has a poor outcome despite various local and systemic therapeutic approaches.Case presentationHerein, we present a case of a 43-year old female presented with history of headaches and enlarged a left inguinal lymph node. Notably, no cutaneous lesions could be identified by history or on physical examination. CT-scan of the brain revealed a space occupying lesion and the inguinal lymph node biopsy confirmed the diagnosis of metastatic malignant melanoma. The patient succumbed shortly after establishment of diagnosis.Clinical discussionMost patients with brain metastases from malignant melanoma are diagnosed after treatment for known extracranial metastases and have a poor outcome despite various local and systemic therapeutic approaches.ConclusionMetastatic melanomas of brain with unknown primary present a significant morbidity and mortality and confer a poor prognosis. Delay in diagnosis and treatment is of serious concern when it comes to improve the prognosis of patients with this disease. The optimal treatment depends on the objective situation, often surgery, radiosurgery, whole brain radiotherapy and chemotherapy can be used in combination to obtain longer remissions and optimal symptom relieve.

Current concepts of ectopic nodal inclusions with special emphasis on nodal nevi.

Nodal inclusions of ectopic tissue within lymph nodes are seen comparatively often in dermatopathology and general pathology. Glandular and nonglandular epithelium, as well as melanocytic nevi can be observed within lymph nodes and represent mostly incidental findings without any relevance. The main challenge in reporting these morphologic features is to differentiate such benign inclusions from metastatic settlements of distinct organ tumors. As sentinel node biopsy and lymph node dissection have become standard procedure in clinical oncology and have an immense clinical impact, the correct evaluation of these nodal inclusions is indispensable to avoid undertreatment or overtreatment of patients. In addition, the genesis of these inclusions has not yet been satisfactorily clarified. Two concepts have been laid out: the theory of benign metastases and the migration arrest theory. However, neither theory has so far been able to answer the following questions: Why do we find more nodal nevi in patients with melanoma who had a sentinel node biopsy than in patients without melanoma, and why do we not find nodal nevi in deep visceral lymph nodes? We present a comprehensive review of the current knowledge on nodal inclusions, proposing a concept for the pathogenesis of nodal nevi, to answer these questions.

Extracellular vesicles in the development of organ-specific metastasis.

Distant organ metastasis, often termed as organotropic metastasis or metastatic organotropism, is a fundamental feature of malignant tumours and accounts for most cancer‐related mortalities. This process is orchestrated by many complex biological interactions and processes that are mediated by a combination of anatomical, genetic, pathophysiological and biochemical factors. Recently, extracellular vesicles (EVs) are increasingly being demonstrated as critical mediators of bi‐directional tumour‐host cell interactions, controlling organ‐specific infiltration, adaptation and colonization at the secondary site. EVs govern organotropic metastasis by modulating the pre‐metastatic microenvironment through upregulation of pro‐inflammatory gene expression and immunosuppressive cytokine secretion, induction of phenotype‐specific differentiation and recruitment of specific stromal cell types. This review discusses EV‐mediated metastatic organotropism in visceral (brain, lung, liver, and lymph node) and skeletal (bone) metastasis, and discusses how the pre‐metastatic education by EVs transforms the organ into a hospitable, tumour cell–friendly milieu that supports the growth of metastatic cells. Decoding the organ‐specific traits of EVs and their functions in organotropic metastasis is essential in accelerating the clinical application of EVs in cancer management.

Atypical Case of Chronic Myeloid Leukemia (CML) in A Native Shepherd Dog in Duhok Province, Iraq

A typical case of a 7-years-old Kurdish male shepherd dog was referred with two weeks history of lethargy, restlessness, anorexia and severe emaciation. Physical examination of the dog revealed generalized lymphadenopathy, strong pale mucous membrane, systolic murmur of the heart, vomiting, bloody diarrhea and fever. Hematological abnormalities indicated moderate to marked leukocytosis characterized by 89% neutrophilia with a left shift to progranulocytes and 1.6% presumptive myeloid blasts, marked thrombocytopenia, marked non-regenerative normocytic hypochromic anemia and dysplasia in platelets and neutrophils. The histopathological examination revealed excessive infiltration with neoplastic myeloid cells that invaded all the internal organs. Bone marrow analysis revealed marked hypercellularity with a predominance of immature cells, marked myeloid 6.2%, dysplasia of neutrophils lineage and rare erythroid progenitors and numerous megakaryocytes. Enlargement of superficial and visceral lymph nodes and internal body organs, especially liver and spleen were observed in the autopsy after animal euthanasia. Our results confirmed that this dog was suffering from chronic myeloid leukemia. Statistically, there was a significant difference (P 0.05) was found between the mean values of leukocytic ratio in peripheral circulation and bone marrow. This is the first case report study that has been recorded in a native shepherd dog in a rural area around Duhok province/ Iraq.

Randomized phase II study evaluating the addition of pembrolizumab to radium-223 in metastatic castration-resistant prostate cancer.

98 Background: Treatment (tx) options for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) to bone are limited. Radium-223 (R223) has demonstrated overall survival (OS) benefit, but objective clinical responses to R223 or the anti-PD1 checkpoint inhibitor (CPI) pembrolizumab (pem) are infrequent. As R223 may increase immunogenicity of mCRPC to bone and increase activity of CPI, we undertook a Phase 2 study to assess safety of the combination and differences in immune cell infiltrate in bone biopsies (bx) and preliminary clinical activity of R223 + pem vs. R223 alone. Methods: Eligibility required mCRPC to bone with no visceral metastases (mets) or lymph nodes &gt; 2 cm, ECOG PS 0 or 1, Hgb ≥ 9 g/dL, and no prior R223 or CPI. Pts underwent bone bx at screening and at 8 wks. Pts were stratified by alkaline phosphatase ≥220 vs. &lt; 220 U/L and high vs. low volume bony mets (CHAARTED criteria) and randomized 2:1 to receive R223 55 kBq/kg q4wks + pem 200 mg q3wks (Arm A) or R223 55 kBq/kg q4wks alone (Arm B). If restaging after 3 doses R223 showed at least stable disease, pts in Arm A continued pem alone until progressive disease (PD). Upon PD, R223 was resumed if no new visceral mets. Pts continued tx until clinical/radiologic PD, unacceptable toxicity or completion of 6 R223 doses. The primary endpoint was difference in CD4+ and CD8+ T-cell infiltrate in 8 wk vs. baseline bx; secondary endpoints were safety/tolerability, radiographic progression-free survival (rPFS) and OS. Exploratory endpoints included PSA response and rate of symptomatic skeletal events (SSEs). Results: Of 45 pts enrolled, 42 received study tx (29 Arm A, 13 Arm B) and were eligible for analysis. 21 pts in Arm A and 5 in Arm B had evaluable paired bone bx. Median fold-change of proportion of CD4+ T-cells/total cell count from baseline to 8 wks was 0.90 (range 0.0-26.6) in Arm A and 0.40 (0.0-13.0) in Arm B (P = 0.87); for CD8+ cells, median 0.67 (0.0-40.4) in Arm A and 0.40 (0.1-28.8) in Arm B (P = 0.77). Grade 3 treatment-related non-hematologic adverse events (AEs) occurred in 3 pts (10%) in Arm A (pneumonitis, diarrhea, AST increased); none in Arm B. Median rPFS was 6.7 mo (95% CI 2.7-11.0 mo) in Arm A and 5.7 mo (2.6-NR) in Arm B. Median OS was 16.9 mo (12.7-NR) in Arm A and 16.0 mo (9.0-NR) in Arm B. 3 pts (10%) in Arm A and 0 in Arm B had PSA reduction of ≥ 50%. SSE rate was 38% in Arm A and 54% in Arm B, with pathologic fractures in 0% of pts in Arm A and 23% in Arm B. Conclusions: In the 62% of treated pts with evaluable paired bx at baseline and after 8 wks, there was no evidence of increased CD4+ or CD8+ T-cell infiltration with R223 + pem. Additional biomarker analyses will be presented. This study revealed that R233 + pem did not result in unexpected AEs, but did not lead to prolonged rPFS or OS compared to R223 alone to support this two-drug combination in a biomarker-unselected population in this setting. Clinical trial information: NCT03093428.