Visceral Spread Research Articles

Through thick and thin: confronting the aggressive cutaneous T-cell lymphomas.

The cutaneous T-cell lymphomas (CTCLs) comprise a diverse set of diseases with equally diverse presentations ranging from asymptomatic solitary lesions to highly aggressive diseases with propensity for visceral spread. The more aggressive CTCLs, which herein we consider as certain cases of advanced-stage mycosis fungoides/Sézary syndrome (MF/SS), primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAETCL), and primary cutaneous gamma delta T-cell lymphoma (PCGDTCL), require systemic therapy. Over the last 5 years, treatment options for MF/SS have expanded with biological insights leading to new therapeutic options and increasingly unique management strategies. An enhanced appreciation of the compartmental efficacy of these agents (skin, blood, lymph nodes, visceral organs) is incorporated in current management strategies in MF/SS. In addition, approaches that combine modalities in attempts to increase depth and durability of responses across multiple compartments are being trialed. In contrast to MF/SS, PCAETCL and PCGDTCL remain diseases with few prospective studies to guide treatment. However, recent genomic insights on these diseases, such as the presence of JAK2 fusions in PCAETCL and cell of origin findings in PCGDTCL, have created options for new biomarker-driven strategies.

First detection of Leishmania major in dogs living in an endemic area of zoonotic cutaneous leishmaniasis in Tunisia

BackgroundDogs are considered the main domestic animals that may be a reservoir for Leishmania infantum, the agent of zoonotic visceral leishmaniasis (ZVL) in several countries of the world. The dog may host other Leishmania species, but its epidemiological role in the maintenance and spreading of these parasites is not completely elucidated. Zoonotic cutaneous leishmaniasis (ZCL), caused by Leishmania major, affects thousands of people every year and is particularly diffused in many countries of North Africa and Middle East Asia. In ZCL endemic countries, few reports of L. major-positive dogs have been reported, probably because most human cases occur in poor rural areas where the social role of the dog and its medical management is not well considered. The aim of the present study is to better understand the possible involvement of domestic dogs in the epidemiology of ZCL.MethodsOur research focused on a well-established endemic focus of ZCL, in the area of Echrarda, Kairouan Governorate, central Tunisia. A total of 51 dogs with no or mild clinical signs of vector borne diseases were selected in small villages where human cases of ZCL are yearly present. All dogs were sampled for the Leishmania spp. diagnosis, by using the following procedures: blood sample for serology and buffy coat quantitative polymerase chain reaction (qPCR), popliteal fine needle aspiration, and cutaneous biopsy punch for lymph node and skin qPCR.ResultsThe results demonstrated a high percentage (21.6%) of dogs positive at least at one or more test; the most sensitive technique was the lymph node qPCR that detected 8/11 positive dogs. Nine, out of the eleven positive dogs, resulted as infected by Leishmania infantum; ITS1-PCR-sequencing allowed Leishmania major identification in the remaining two cases, both from the popliteal lymph node samples, which can suggest a possible visceral spread of a cutaneous Leishmania species in the dog. Interestingly, one of the two L. major-positive dogs was living in the same house where 6-year-old children showed cutaneous lesions referred to as ZCL.ConclusionsTo our knowledge, this is the first report of L. major-positive dogs in Tunisia, the epidemiological role of which remains under investigation.Graphical

Abstract PO3-06-01: Factors associated with first- and second- line attrition among metastatic breast cancer patients

Abstract Background: Estimating patient attrition across lines of treatment, i.e., the probability that upon failing one treatment the patient will be able to receive a subsequent treatment, may be a valuable tool for treatment sequencing. We sought to describe first-to-second line (1to2-line) and second-to third line (2to3-line) attrition rate and factors associated with attrition. Methods: The GIM14/BIO-META is an ongoing, ambispective observational multicenter study enrolling breast cancer patients receiving first-line therapy. In progressing patients, attrition was defined as no further anticancer treatment and death within 6 months from the end of the previous line. Attrition from 1to2-line and from 2to3-line was studied by descriptive analyses, factors associated with attrition by univariate ad multivariable logistic models. Results: From January 2000 to December 2021, 3,109 patients with metastatic breast cancer were enrolled in the GIM14/BIO-META study. After the exclusion of 611 patients with ongoing first-line treatment, we included 2,498 patients in the analysis of 1to2-line attrition. Considering tumor subtype, 1,650 (66.0%) patients were diagnosed with metastatic luminal-like, 622 (24.9%) with HER2-positive and 177 (7.1%) with triple negative (TN) tumors. At the time of diagnosis of advanced disease, almost half of the patients (52.0%) had only one involved metastatic site and 45.9% of the patients were diagnosed with visceral involvement. Overall, 1to2-line attrition was 9.0% (224/2,498) with similar attrition for patients with luminal-like (8.5%) and HER2-positive (7.1%) breast cancer. Patients with TN disease experience the highest 1to2-line attrition (13.0%). Age, disease-free interval from primary tumor diagnosis, and type of metastatic spread independently predicted 1to2-line attrition. Univariate analyses of factors associated with 1to2-line attrition among patients with luminal-like breast cancer were similar to those of the entire cohort. Overall, 2to3-line attrition was 14.0% (260/1,861) with higher attrition rates among patients with TN disease (22.7%) compared to patients with luminal-like (13.4%) and HER2-positive (13.0%) breast cancer. Age, tumor subtype, pattern of visceral spread and shorter time-to treatment discontinuation during first-line therapy were independent factors associated with 2to3-line attrition. Conclusions: Pending confirmation in independent series and integration with biomarkers of treatment failure, these results, may provide a valuable support for treatment decisions and clinical research on treatment sequencing. Citation Format: Eva Blondeaux, Luca Boni, Giovanna Chilà, Arianna Dri, Roberta Caputo, Francesca Poggio, Alessandra Fabi, Grazia Arpino, Federico Pravisano, Elena Geuna, Tommaso Ruelle, Irene Giannubilo, Michelino de Laurentiis, Fabio Puglisi, Claudia Bighin, Matteo Lambertini, Filippo Montemurro, Lucia Del Mastro. Factors associated with first- and second- line attrition among metastatic breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-01.

Unusual Sites of Visceral Spread in Prostate Cancer: A Prostate-Specific Membrane Antigen-Based Theranostic Imaging Series.

Prostate cancer commonly metastasizes to lymphatic and skeletal systems with lesser frequency to visceral organs; however, uncommon visceral sites have also been found and reported as case reports. We present a series of uncommon metastatic visceral spread in prostate cancer on prostate-specific membrane antigen-based diagnostic and posttherapeutic imaging modalities.

A case of fatal monkeypox infection: necropsy and molecular findings, with some considerations related to clinical management

ObjectiveHuman monkeypox (mpox) is usually self-limited infection; however, rising data show a worse outcome in patients with impaired immune status, particularly those co-infected with HIV [Mitjà O, Alemany A, Marks M, Lezama Mora JI, Rodríguez-Aldama JC, Torres Silva MS et al. Mpox in people with advanced HIV infection: A global case series. Lancet. 2023; 401:939–49. DOI:https://doi.org/10.1016/S0140-6736(23)00273-8] [Govind A, Lazarte SM, Kitchell E, Chow JY, Estelle CD, Fixsen E et al. Severe mpox infections in people with uncontrolled human immunodeficiency virus (HIV). Clin Infect Dis. 2023; 76:1843–6. DOI:https://doi.org/10.1093/cid/ciad052]. MethodsWe report the clinical, pathological, and molecular study of a patient with mpox infection and a late HIV diagnosis, with fatal outcome. ResultsNecropsy revealed visceral spread of mpox. Mpox virus was sequenced twice during the admission, uncovering an emerging mutation near a genomic region where mutations associated with tecovirimat resistance have been documented. DiscussionMonkeypox can manifest as an opportunistic infection in individuals with advanced HIV-associated immunosuppression.

S2598 Gastric Kaposi Sarcoma Presenting as Acute Upper Gastrointestinal Hemorrhage in a Heart Transplant Patient

Introduction: Kaposi sarcoma (KS), a multifocal neoplasm of lymphatic cells, occurs more often in organ transplant patients, and its pathogenesis is related to use of immunosuppressive (IS) medications. Acute gastrointestinal hemorrhage due to KS is exceedingly rare and has never been reported in a heart transplant patient. We report a case of KS presenting as gastrointestinal hemorrhage in a heart transplant patient whose bleeding resolved with supportive care and treatment of his underlying KS. Case Description/Methods: A 63-year-old man originally from Sudan with a history of non-ischemic cardiomyopathy requiring heart transplant on IS presented with melena and acute anemia. Medical history included cutaneous KS of the right leg diagnosed 1 year following transplant previously treated with paclitaxel and in clinical remission. He was treated with intravenous proton-pump inhibitor and blood transfusions. EGD showed a patch of nodular mucosa on the lesser curvature of the stomach. Pathology of the nodule showed dilated capillaries with spindle cells in the lamina propria, and staining for human herpesvirus-8 (HHV-8) was positive in the spindled cells, supporting a diagnosis of recurrent KS. He had no further bleeding, hemoglobin stabilized, and he was discharged. He was resumed on paclitaxel for recurrent KS after discharge and had no further bleeding (Figure 1). Discussion: We report a case of KS presenting with GI bleeding in a patient on chronic IS following heart transplant. While GI bleeding from KS has been reported in renal transplant recipients, this is the first such report we are aware of in a heart transplant patient. The GI tract is a common site of visceral involvement in KS, and presentation can include vomiting, diarrhea, and occult blood loss. Overt GI bleeding in KS is rare. Endoscopic appearance varies from flat lesions to polypoid or nodular growths, and histopathology shows spindle cells positive for HHV-8. Management of GI bleeding in KS depends on severity, and in less severe cases, the role of endoscopy is to confirm the visceral spread of KS with biopsy. Thereafter, management includes IS reduction and chemotherapy for refractory disease. Though KS is a rare cause of overt GI bleeding, it should be considered in patients with immunodeficiency or on chronic IS, and biopsy for suspicious lesions should be performed to confirm diagnosis.Figure 1.: Lesser curvature gastric nodule.

Identification of Leishmania tropica from Pediatric Visceral Leishmaniasis in Southern Mediterranean Region of Turkey.

Background and ObjectiveProtozoa of the genus Leishmania are obligate intracellular parasites, and Leishmania species cause a spectrum of species-specific clinical symptoms known as cutaneous, mucocutaneous, and visceral leishmaniasis. For example, Leishmania major and Leishmania tropica cause cutaneous leishmaniasis, while Leishmania infantum and Leishmania donovani cause visceral leishmaniasis (VL). However, molecular studies in recent years have shown that Leishmania species cause different clinical symptoms.ObjectivesOur aim was to evaluate the relationship between the clinical and molecular characterization of leishmania isolates in children with VL defined in Turkey, an intercontinental transitional region.MethodsThe clinical diagnosis of VL was confirmed by detecting amastigotes in the bone marrow aspirate and/or the rK39 test and/or molecular methods (genus-specific PCR, Real-Time PCR, ITS1 PCR-RFLP, DNA sequencing).ResultsMost of the VL patients were referred from the districts of Adana (53.3%) and others from neighboring provinces; Hatay (16.6%), Osmaniye (3%), Gaziantep (3%), Adıyaman (3%), and 20% case were Syrian immigrants A clinical diagnosis of VL was confirmed in 30 patients with different diagnostic methods. 93% was found positive with microscopic examination, 79.1% with rK39 dipstick test, and 60% with genus-specific PCR assay in clinical samples. The Leishmania isolates were identified as L. infantum (40%), L. donovani (26.7%), and L. tropica (23.3%) using Real-Time PCR, ITS1 PCR-RFLP, and DNA sequencing. There was no cutaneous finding in any case in clinical examination.The most common clinical findings were fever (93.3%) and splenomegaly (90%), followed by hepatomegaly (76.6%). The most common laboratory finding was thrombocytopenia (86.6%), followed by anemia (70%). In addition, hemophagocytic lymphohistiocytosis was detected in bone marrow aspiration in two of our patients. Since pentavalent antimony salts treatment initially failed in four patients, it was necessary to switch to Liposomal-Amphotericin B with treatment success.ConclusionsThe presence of L. tropica in VL patients, despite the absence of cutaneous findings in any of the cases, shows that this strain can cause VL, contrary to conventional knowledge. In the Adana province, where this study was carried out, L. infantum from CL cases in previous studies should be taken into account, and visceral spread in CL cases and accompanying cutaneous lesions in VL cases should be investigated in detail.

Visualisation of tumour cells in bone in vivo at single-cell resolution.

The skeleton is a common site for the establishment of distant metastases. Once cancers occupy bone, the prognosis is poor as disease recurrence and visceral spread is imminent. Understanding the pathways and cellular interactions, which regulate tumour cell seeding, dormancy and growth in bone, is pertinent to improving outcomes for patients with advanced cancers. Advances in imaging techniques have facilitated the development of the concept that the behavior of bone marrow resident cells dictates the fate of tumour cells upon arrival in bone. This review summarises recent findings achieved through intravital imaging. It highlights the importance of developing both longitudinal static and acute dynamic data to develop our understanding of tumour cell engraftment, dormancy, activation and the subsequent establishment of metastases. We also describe how imaging techniques have developed our knowledge of the elements that make up the complex bone microenvironment which tumour cells interact with to survive and grow. We also discuss how through combining these imaging insights with single cell RNA sequencing data, we are entering a new era of research which has the power to define the cell-cell interactions which control tumour cell growth in bone.

Survival time in urban center breast cancer patients with CNS metastasis with or without visceral metastasis.

1088 Background: There is limited data about the role of isolated central nervous system (CNS) metastasis (mets) in patients with breast cancer (BC), since prior studies evaluated BC patients with CNS plus visceral mets. Furthermore, though Black race is associated with worse BC outcomes, there are few studies on CNS mets that predominantly included racial and ethnic minorities in their cohorts. Our study compares overall survival (OS) in BC patients with CNS involvement with and without visceral mets in an underrepresented patient population. Methods: This is a retrospective case series study. We used Montefiore’s Clinical Looking Glass software to identify patients. Inclusion criteria were females age ≥18 years at our institution with the diagnosis of BC and CNS mets between 3/31/1997 to 3/31/2019. Chart review was conducted to obtain clinical-pathological features, including date of diagnosis, treatment, clinical course, and survival status. Patients with BC and CNS mets were divided into two cohorts, those with additional mets limited to bone and lymph nodes but without further visceral spread (CNS-NV), and those with CNS mets plus visceral mets (CNS-V). Kaplan-Meier methods were used to analyze the median OS. Results: Our study included a high proportion of underrepresented minorities (n=177); 46.3% were Black, 10.7% were White, and 34.5% were Other Race; besides, 28% were Hispanic. Mean age at diagnosis of CNS mets was 58 years (SD = 12.9). 62.1% were estrogen receptor (ER) and/or progesterone receptor (PR) positive, 27.1% were HER2 positive; and 19.8% were ER, PR and HER2 negative. Mean number of chemotherapy and endocrine therapy lines before CNS mets were 2 (IQR = 1-2) and 1 (IQR = 1-2), respectively. CNS-NV and CNS-V cohorts included 35 and 142 patients, respectively. Patients with CNS-NV had longer OS than CNS-V (2118 vs. 1120 days, p=0.02). Further subgroup analysis for group CNS-NV was performed based on treatment modality. In this cohort, OS was not significantly different between patients who did and did not receive chemotherapy (n =35, mean OS 1509 vs. 960 days, p = 0.49). In addition, OS was not significantly different between patients who received and did not receive endocrine therapy (n = 24, mean OS 857 vs. 1394 days, p = 0.4). Finally, OS did not significantly differ between patients who did and did not receive anti HER2 treatment (n = 11, 1753 vs. 849 days, p = 0.15). Conclusions: Minimal research has been conducted on breast cancer patients with CNS mets and distal involvement limited to the bones or lymph nodes. In a heterogenous racial and ethnic population, patients with BC and CNS mets have prolonged OS if the extent of distal involvement is limited to the bones or lymph nodes, compared to those with visceral mets. More research with larger sample sizes is needed to confirm our findings, which may help to de-escalate and tailor treatment for patients with CNS mets.

Is skipped nodal metastasis a phenomenon of cutaneous melanoma?

Background and MethodsSkipped nodal metastasis (SNM) is a recognized phenomenon of visceral cancers when metastases bypass the regional basin and skip to a distant nodal basin without evidence of distant metastases. Its occurrence is undocumented in cutaneous melanoma patients but of potential prognostic significance. We therefore assessed the frequency of SNM in a large series of patients with limb melanomas. Patients and MethodsWe studied melanoma patients attending a tertiary oncology hospital in northwest England using two approaches. First, we systematically searched medical records of an unselected patient sample treated 2002–2015, and second, we studied lymphoscintigrams of all patients with limb melanoma who underwent sentinel node biopsy 2008–2019. ResultsOf 672 melanoma patients whose clinical records were examined, 16 had regional nodal metastases without apparent visceral spread and one appeared to have SNM but further scans were uncovered that showed concurrent pulmonary metastases. Of 667 limb melanoma patients with lymphoscintigrams, 7 showed dual lymphatic drainage patterns to distal as well as regional nodal basins, but none had micro-metastases solely in the distant basin. ConclusionOccurrence of SNM in cutaneous melanoma is highly unlikely.

Experience with sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) with visceral spread from PROCEED.

174 Background: Trials of approved agents in mCRPC have reported shorter overall survival (OS) in men with visceral metastases (mets). The phase 3 IMPACT trial evaluated sipuleucel-T, an autologous cellular immunotherapy, in mCRPC but excluded visceral mets. PROCEED, a registry of mCRPC patients receiving sipuleucel-T, offers the first description of sipuleucel-T in patients with visceral mets. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T biweekly x 3. Dose adjustment for organ dysfunction was unnecessary. Men were followed until death, study withdrawal, or a minimum of 3 years. OS is reported in this post-hoc subgroup analysis. Results: 1902 men received ≥1 sipuleucel-T infusion between 2011-2014. Visceral mets (n = 90) included liver (n=21), lung (n=61), and brain (n=2) involvement. Compared to patients without visceral mets (Table), men with visceral mets had poorer performance status (PS) and higher baseline prostate-specific antigen (PSA). Median OS was 20.5 and 31.2 mo in those with and without visceral mets. Patients with liver and lung mets had a median OS of 16.3 and 21.0 mo, respectively. Activation of antigen-presenting cells, a measure of immune activation and product potency, was similar in those with and without visceral mets. Conclusions: Initial observations suggest that patients with mCRPC and visceral spread can activate their immune cells to produce sipuleucel-T, but have a shorter OS than those with bone and/or lymph node spread. (NCT01306890). Clinical trial information: NCT00065442. [Table: see text]

Abstract OT3-02-04: Selecting the optimal position of CDK4/6 inhibitors in hormone-receptor-positive advanced breast cancer: The BOOG 2017-03 SONIA study

Abstract BACKGROUND Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) is an effective strategy to improve progression-free survival (PFS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). There is a lack of comparative data to help clinicians decide whether CDK4/6 inhibitors can best be added to first- or second-line ET. The former strategy may provide longer PFS benefit, but is associated with longer use of the drug, which results in more toxicity and costs, whereas no clear benefit on overall survival (OS) or quality of life (QoL) has been proven thus far. No predictive biomarker exists to select patients who are most likely to benefit from the addition of CDK4/6 inhibition. TRIAL DESIGN AND AIMS The SONIA study is an investigator-initiated, multicenter, randomized phase III study, funded by 'ZonMw' and 'Zorgverzekeraars Nederland'. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor (NSAI) + CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with NSAI, followed on progression by fulvestrant + CDK4/6 inhibition). Each CDK4/6 inhibitor can be used according to its approved EMA label. The primary objective is to test whether strategy A is superior to strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include OS, safety, QoL, and cost-effectiveness. Additional biomarker analyses will be performed to optimize patient selection. ELIGIBILITY CRITERIA Patients with a proven diagnosis of HR+/HER2-negative advanced breast cancer without prior systemic therapy for advanced disease who are candidates to receive NSAIs as first-line treatment, are eligible for the study. Exclusion criteria include advanced visceral spread with the risk of life-threatening complications in the short term. Other conditions excluding a patient from participating are other malignancies, prolonged QTc time (>480ms) or any other medical condition that interferes with study procedures or compliance. STATISTICAL METHODS The difference in PFS2 will be estimated using the intention-to-treat population in a Cox proportional hazards model accounting for all stratification factors (visceral versus non-visceral disease, yes versus no prior ET in (neo)adjuvant setting, hospital, and type of CDK4/6 inhibitor). Five-hundred seventy-four primary outcome events yield 89% power to show that strategy A has statistically significant, clinically meaningful (according to European Society for Medical Oncology - Magnitude of Clinical Benefit Scale) superior PFS2 in a log-rank test at the two-sided 95% confidence level. ACCRUAL TARGET: with an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required. A total of 76 Dutch hospitals will participate. PRESENT: the study is open in 51 hospitals and 106 patients are included. Citation Format: van Ommen - Nijhof A, van der Voort A, Konings IR, Jager A, Sonke GS, On behalf of the SONIA Investigators (SONIA Steering Committee), And the Dutch Breast Cancer Research Group (BOOG). Selecting the optimal position of CDK4/6 inhibitors in hormone-receptor-positive advanced breast cancer: The BOOG 2017-03 SONIA study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-04.

Long-responders to anti-HER2 therapies: A case report and review of the literature.

Since the introduction of targeted therapies, prognosis in human epidermal growth factor receptor (HER) 2-positive metastatic breast cancer (MBC) has radically changed. The addition of Pertuzumab to Trastuzumab and standard chemotherapy has further increased patients' overall survival (OS). However, there is no agreement regarding the optimal duration of trastuzumab therapy in selected patients achieving long-term complete remission. In addition, no potential factors of long-term benefit have been identified yet. In the present study, we report the case of a MBC woman who was successfully treated with trastuzumab for over 10 years. At the time of diagnosis (February 2005), she revealed lung, nodal and bone metastases. Therefore, a first-line chemotherapy with Epirubicine and Docetaxel was administered for 6 cycles and then the patient started Trastuzumab plus hormonal therapy until reaching a sensible reduction of mammary lump and disappearance of distant metastases. Following a multidisciplinary evaluation, in November 2006, the patient underwent radical mastectomy and axillary dissection, achieving a complete remission. She continued Trastuzumab until September 2015 (for a total of 156 cycles) when a pleural diffusion was demonstrated. Long-term survival during anti-HER2 treatment remains a rare and optimal situation. Currently, no data exist to support trastuzumab interruption in this setting and collaborative efforts to better analyze the characteristics of long-responder patients are needed. Data regarding prognostic factors in this setting are relatively confusing. Our review reveals that hormonal receptor (HR)-positive disease is associated with a better prognosis, whereas the role of visceral spread differs by single or dual target anti HER2-inhibition. The introduction of Pertuzumab is raising concerns in terms of toxicity and its cost effectiveness. While waiting for novel molecular data and randomized trials, available evidence advocates continuous use of anti-HER2 therapies until disease progression or development of side effects.

Gene expression modules in primary breast cancers as risk factors for organotropic patterns of first metastatic spread: a case control study

BackgroundMetastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Molecular risk factors for particular patterns of metastastic spread in a clinical population are limited.MethodsA case-control design including 1357 primary breast cancers was used to study three distinct clinical patterns of metastasis, which occur within the first six months of metastatic disease: bone and visceral metasynchronous spread, bone-only, and visceral-only metastasis. Whole-genome expression profiles were obtained using whole genome (WG)-DASL assays from formalin-fixed paraffin-embedded (FFPE) samples. A systematic protocol was developed for handling FFPE samples together with stringent data quality controls to identify robust expression profiling data. A panel of published and novel gene sets were tested for association with these specific patterns of metastatic spread and odds ratios (ORs) were calculated.ResultsMetasynchronous metastasis to bone and viscera was found in all intrinsic breast cancer subtypes, while immunohistochemically (IHC)-defined receptor status and specific IntClust subgroups were risk factors for visceral-only or bone-only first metastases. Among gene modules, those related to proliferation increased the risk of metasynchronous metastasis (OR (95% CI) = 2.3 (1.1–4.8)) and visceral-only first metastasis (OR (95% CI) = 2.5 (1.2–5.1)) but not bone-only metastasis (OR (95% CI) = 0.97 (0.56–1.7)). A 21-gene module (BV) was identified in estrogen-receptor-positive breast cancers with metasynchronous metastasis to bone and viscera (area under the curve = 0.77), and its expression increased the risk of bone and visceral metasynchronous spread in this population. BV was further orthogonally validated with NanoString nCounter in primary breast cancers, and was reproducible in their matched lymph nodes metastases and an external cohort.ConclusionThis case-control study of WG-DASL global expression profiles from FFPE tumour samples, after careful quality control and RNA selection, revealed that gene modules in the primary tumour have differing risks for clinical patterns of metasynchronous first metastases. Moreover, a novel gene module was identified as a putative risk factor for metasynchronous bone and visceral first metastatic spread, with potential implications for disease monitoring and treatment planning.

Reduced virulence of a pseudorabies virus isolate from wild boar origin in domestic pigs correlates with hampered visceral spread and age-dependent reduced neuroinvasive capacity

ABSTRACT Morbidity and mortality associated with pseudorabies virus (PRV) infection are dependent on the age of the pig and the virulence of the strain. PRV strains circulating in wild boar are considered to be low virulent, but no mechanistic explanation for their reduced virulence is available. Here infection of 2- and 15-week-old domestic pigs with the PRV wild boar strain BEL24043 did not induce clinical symptoms in 15-week-old pigs, but resulted in important neurological and respiratory disease in 2-week-old piglets. A detailed study of the (neuro) pathogenesis and associated cytokine mRNA expression showed that the reduced virulence of the wild boar strain, compared to what was previously reported for the virulent domestic NIA3 strain, is due to a severely hampered spread to visceral organs in pigs of both age categories and to an efficient suppression of viral replication at primary replication sites of 15-week-old pigs and to a lesser extent in those of 2-week-old piglets. The age-dependent difference in induced symptoms seems to be due to an immature development state of the immune and/or nervous system in 2-week-old pigs. An extensive viral replication associated with a robust expression of cytokine-related mRNA was found in the olfactory bulb of 2-week-old piglets, correlating with observed neurological disease. Neuroinvasion also occurred via the trigeminal route in 2-week-old pigs, but viral replication was efficiently suppressed in the trigeminal ganglion in the presence of a moderate induction of cytokine-related mRNA. Viral replication in the peripheral and central nervous system of 15-week-old pigs was limited and efficiently suppressed.

Solitary Hypothalamus Triple Negative Metastasis from Luminal: A Primary Breast Carcinoma

A 49 years old woman was diagnosed of bilateral and multicentric infiltrating ductal breast carcinoma with a luminal A phenotype (Figure 1) and blastic bone metastatic spread. She had a very good response to hormonotherapy and monthly zoledronic acid without visceral spread or bone events for three years. Then she consulted because of progressively asthenia, anorexia, nausea, dizziness, orthostatic, occasional abdominal pain, increased thirst and frequent urination and altered sleep-wake cycles. On physical examination, she appeared pallid without any other remarkable finding.

Bone Metastases in Medulloblastoma –Single Institution Experience

Background: Medulloblastoma has one of the highest rates of metastasis outside the central nervous system (CNS). Bone metastases are the most common lesions, although lymph node and visceral spread have also been reported. Objective: To present patients with bone metastasis in medulloblastoma and discuss their radiologic appearances and treatment approach. Patients and methods: From 1993 to 2008, 82 patients diagnosed with medulloblastoma were treated at the Institute for Oncology and Radiology of Serbia. Three (3.6%) developed extraneural metastasis (ENM). In primary treatment, patients were treated with surgery, craniospinal radiotherapy with local boost to tumor bed, and adjuvant chemotherapy [lomustine (CCNU) and vincristine]. Of the three patients with ENM, all developed bone metastases at the time of relapse. Relapse occurred within 17 to 42 months of initial diagnosis. Patients received secondary chemotherapy and palliative radiotherapy to the affected bone in two cases. Results: Among these three patients, case 1 had initially a solitary lytic lesion. Case 2 had diffuse blastic lesions and also bone marrow involvement. Case 3 had multiple mixed lytic-sclerotic lesions but later developed lymph node metastasis and metastases to both breasts, as well. All patients were without concurrent CNS involvement at the time of ENM. Unfortunately, after initial partial response, the three patients died at 24, 13, and 18 months after detection of metastases, respectively. Conclusion: With prolonged survival times in children with medulloblastoma, more emphasis should be placed on the possibility of systemic involvement. A greater understanding of the pathogenesis of the systemic metastases may be valuable in designing future, more aggressive multimodal therapy.

Predictors of early distant metastasis in women with breast cancer

Breast cancer is a clinically heterogeneous disease. Approximately 10-15 % of breast cancer patients develop distant metastases within 2 years of diagnosis with a poor 5-year survival rate of 21 %. Little data have been gathered about how some breast cancer metastasizes earlier than expected. The study aimed to identify predictors of distant metastases among breast cancer patients in relation to their clinical and tumour characteristics. The results of the study may have important implications in our understanding of the disease process allowing more aggressive treatment and monitoring of certain subgroups of patients. Retrospective review of 215 patients (54 % early stage and 46 % locally advanced stage) who fulfilled the specified criteria was performed. Twelve variables were considered. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of developing distant metastasis within 24 months after surgery and adjuvant therapy. Of the 215 patients, 27.9 and 17.7 % developed bone and visceral metastasis, respectively. Bone metastasis was significantly dependent on stage, tumour size, lymph node involvement, lymphovascular invasion, estrogen receptor, progesterone receptor and Her/2-neu pattern (p < 0.05). Visceral metastasis was significantly dependent on age, menopausal status, stage, tumour size, lymph node involvement, estrogen receptor, progesterone receptor and Her-2/neu pattern (p < 0.05). Among patients with bone and visceral metastases, 67 and 43 % have triple negative pattern, respectively. Logistic regression provided an accurate model for predicting bone but not visceral metastasis. A significant fraction of breast cancer patients experienced early metastasis. Our data suggest that tumour stage, size and lymph node involvement are major predictors of metastasis. Her-2/neu over-expression alone is not a strong predictor of early metastasis but triple negative breast cancers belong to an aggressive subgroup with early metastatic capacity. Young, premenopausal patients may benefit from aggressive surveillance and treatment since they tend to present with early visceral spread.

Ocular Melanoma Metastasizing to Intra-Abdominal Lymph Nodes

Background. Visceral metastatic spread of ocular melanoma most commonly occurs via hematogenous route to the liver. Lymphatic spread of ocular melanoma into abdominal lymph nodes has not been reported previously. Case Presentation. A 47-year-old man with a history of ocular melanoma presented with a soft tissue mass on CT scan. The mass encased the portal structures of the hepaticoduodenal ligament. Image-guided biopsy revealed it to be a metastatic melanoma to lymph nodes. The patient underwent surgery with the intent to prolong disease-free survival. On final pathological examination, two lymph nodes were found harboring metastatic melanoma. Conclusion. Extrahepatic lymphatic intra-abdominal spread of ocular melanoma is not impossible. Since this mode of spread is rare, the oncologic significance of surgical resection of isolated intra-abdominal nodal with metastatic ocular melanoma is difficult to determine at the present time.

Classic Kaposi's sarcoma in Morocco: clinico-epidemiological study at the National Institute of Oncology.

BackgroundClassic Kaposi's sarcoma (CKS) is a rare disease likely associated with human herpes virus 8 (HHV-8) infection, and occurs predominantly in Jewish, Mediterranean and middle eastern men .There is a dearth of data in Moroccan patients with CKS regarding epidemiology, clinical characteristics and outcomes. This report examines a cohort of patients with CKS evaluated at the national institute of oncology over 11-year period.MethodsA retrospective analysis of patients referred to the national institute of oncology with classical Kaposi sarcoma, between January 1998 and February 2008, was performed. Reviewed information included demographics, clinical and pathological staging, death or last follow-up.ResultsDuring the study period, 56 patients with a diagnosis of CKS have been referred to our hospital. There were 11(19,7%) females and 45 (80,3%) males (male-to-female ratio: 4:1). Mean age at diagnosis was 61,7 ± 15 (range: 15- 86 years). Nodules and/or plaques were the most frequent type of lesion. The most common location was the lower limbs, particularly the distal lower extremity (90%). In addition to skin involvement, visceral spread was evident in 9 cases. The most common visceral involvement sites were lymph nodes (44%), lung (22%), and gastrointestinal tract (22%). Associated lymphoedema was seen in 24 (42%) of the patients. There were 18 stage I patients (32,14%), 8: stage II (14,28%), 21 stage III(37,5%) and 9 stage IV (16,07%). A second primary malignancy was diagnosed in 6 cases (10,7%), none of the reticuloendothelial system.With a median follow-up of 45 months, 38 (67,8) patients are alive, of whom 25 (65,78%) patients with stable disease, five with progressive disease currently under systemic chemotherapy and 8(21,05%) are alive and free of disease, over a mean interval of 5 years.ConclusionThis is the largest reported series in our context. In Morocco, CKS exhibits some special characteristics including a disseminated skin disease at diagnosis especially in men, a more common visceral or lymph node involvement and a less frequent association with second malignancies.