Informing the Recommended Phase III Dose of Alnuctamab, a CD3 × BCMA T-Cell Engager, Using Population Pharmacokinetics and Exposure-Response Analysis.

Alnuctamab, a B-cell maturation antigen (BCMA)-targeting T-cell engager, has demonstrated encouraging antitumor activity in the phase I study CC-93269-MM-001 treating patients with relapsed or refractory multiple myeloma. Identification of a recommended Phase III dose (RP3D) was a key objective, as such population pharmacokinetic (PopPK) and exposure-response analysis was critical. Intravenous (IV) alnuctamab was administered in fixed doses (0.15-10 mg) or in step-up doses to a maximum 10-mg target dose. Subcutaneous (SC) step-up doses of 3 and 6 mg were followed by a target dose range of 10-60 mg. Concentration data from IV and SC alnuctamab administration was pooled and was well described by a two-compartment PopPK model with first-order absorption and elimination. Covariate analysis determined that the inclusion of baseline soluble BCMA (sBCMA) on clearance significantly improved model fitting. Individual exposure parameters were estimated from the final model to characterize exposure-response relationships. Switching from IV to SC administration improved the safety profile of alnuctamab by limiting the frequency of grade ≥2 CRS events. A significant exposure-CRS relationship was observed after the first SC dose, but not subsequent dose administrations. Exposure-safety analysis did not find a statistically significant relationship between increasing exposure and the probability of key safety events of interest. Logistic regression analysis for patients administered SC alnuctamab identified that increased exposure significantly increased the probability of response, although the additional benefit was minimal at exposures above 30 mg target dose. Considering the totality of exposure-response data, the clinical pharmacology assessment supported a SC RP3D of 3/6/30 mg.

Synthetic 18F labeled biomolecules that are selective and promising for PET imaging: major advances and applications.

The concept of positron emission tomography (PET) based imaging was developed more than 40 years ago. It has been a widely adopted technique for detecting and staging numerous diseases in clinical settings, particularly cancer, neuro- and cardio-diseases. Here, we reviewed the evolution of PET and its advantages over other imaging modalities in clinical settings. Primarily, this review discusses recent advances in the synthesis of 18F radiolabeled biomolecules in light of the widely accepted performance for effective PET. The discussion particularly emphasizes the 18F-labeling chemistry of carbohydrates, lipids, amino acids, oligonucleotides, peptides, and protein molecules, which have shown promise for PET imaging in recent decades. In addition, we have deliberated on how 18F-labeled biomolecules enable the detection of metabolic changes at the cellular level and the selective imaging of gross anatomical localization via PET imaging. In the end, the review discusses the future perspective of PET imaging to control disease in clinical settings. We firmly believe that collaborative multidisciplinary research will further widen the comprehensive applications of PET approaches in the clinical management of cancer and other pathological outcomes.

Model based assessment of food and acid reducing agent effects on oral absorption of mezigdomide (CC-92480), a novel cereblon E3 ligase modulator.

Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) agent with enhanced autonomous cell-killing activity in multiple myeloma (MM) cells, and promising immunomodulatory and antitumor activity in patients with MM. We developed a population pharmacokinetics (PKs) model for mezigdomide in healthy subjects (HSs), and quantified effects of high-fat meal and proton pump inhibitor (PPI) on human disposition parameters. Plasma concentrations from 64 HS in two phase I clinical studies (NCT03803644 and NCT04211545) were used to develop a population PK model. The HSs received single oral doses of 0.4-3.2 mg mezigdomide with full PK profiles collected. A two-compartment linear PK model with first-order absorption and lag time best described mezigdomide PK profiles in HSs. The population PK parameters of absorption rate constant, lag time, central volume of distribution, clearance, peripheral volume of distribution, and intercompartmental clearance were estimated to be 1.18 h-1 (interoccasion variability [IOV]: 65%), 0.423 h (IOV: 31%), 440 L (interindividual variability [IIV]: 63%), 35.1 L/h (IIV: 40%), 243 L (IIV: 26%), and 36.8 L/h (IIV: 26%), respectively. High-fat meal increased oral bioavailability by ~30% and PPI co-administration decreased oral bioavailability by ~64%. Mezigdomide demonstrated a linear dose-exposure relationship in HSs. The PK model suggests a modest effect of high-fat meal, and a substantial effect of PPIs on mezigdomide oral bioavailability. This population PK model enables data integration across studies to identify important covariate effects and is being used to guide dose selection in clinical study designs for mezigdomide in patients with MM.

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

Bioanalytical Methods for Characterization of CAR-T Cellular Kinetics: Comparison of PCR Assays and Matrices.

Recently, multiple chimeric antigen receptor T-cell (CAR-T)-based therapies have been approved for treating hematological malignancies, targeting CD19 and B-cell maturation antigen. Unlike protein or antibody therapies, CAR-T therapies are "living cell" therapies whose pharmacokinetics are characterized by expansion, distribution, contraction, and persistence. Therefore, this unique modality requires a different approach for quantitation compared with conventional ligand binding assays implemented for most biologics. Cellular (flow cytometry) or molecular assays (polymerase chain reaction (PCR)) can be deployed with each having unique advantages and disadvantages. In this article, we describe the molecular assays utilized: quantitative PCR (qPCR), which was the initial platform used to estimate transgene copy numbers and more recently droplet digital PCR (ddPCR) which quantitates the absolute copy numbers of CAR transgene. The comparability of the two methods in patient samples and of each method across different matrices (isolated CD3+ T-cells or whole blood) was also performed. The results show a good correlation between qPCR and ddPCR for the amplification of same gene in clinical samples from a CAR-T therapy trial. In addition, our studies show that the qPCR-based amplification of transgene levels was well-correlated, independent of DNA sources (either CD3+ T-cells or whole blood). Our results also highlight that ddPCR can be a better platform for monitoring samples at the early phase of CAR-T dosing prior to expansion and during long-term monitoring as they can detect samples with very low copy numbers with high sensitivity, in addition to easier implementation and sample logistics.

Characterizing the exposure-response relationship of idecabtagene vicleucel in patients with relapsed/refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel; bb2121) is a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T cell therapy approved for treatment of patients with heavily pretreated relapsed and refractory multiple myeloma. This analysis evaluated exposure-response (ER) relationships of ide-cel with key efficacy end points and safety events. Ide-cel exposure data were available from 127 patients treated at target doses of 150, 300, or 450 × 106 CAR+ T cells from the phase II KarMMa study (NCT03361748). Key exposure metrics, including area under the curve of the transgene level from 0 to 28 days and maximum transgene level, were calculated using noncompartmental methods. Logistic regression models, using both linear and maximum response function of exposure on the logit scale, were evaluated to quantify observed ER trends, and modified by including statistically significant individual covariates in a stepwise regression analysis. There was wide overlap of exposures across the target doses. ER relationships were observed for the overall and complete response rates, with higher response rates associated with higher exposures. Model-based evaluations identified female sex and baseline serum monoclonal protein less than or equal to 10 g/L as predictive of a higher objective response rate and a higher complete response rate, respectively. ER relationships were observed for safety events of cytokine release syndrome requiring tocilizumab or corticosteroids. The established ER models were used to quantify the ide-cel dose-response, which showed a positive benefit-risk assessment for the range of ide-cel exposures associated with the target dose range of 150-450 × 106 CAR+ T cells.

Clinical activity of CC-90011, an oral, potent, and reversible LSD1 inhibitor, in advanced malignancies.

BACKGROUND: CC-90011 is an oral, potent, selective, reversible inhibitor of lysine-specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long-term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first-in-human study of CC-90011. METHODS: CC-90011-ST-001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015-005243-13) is a phase 1, multicenter study in which patients received CC-90011 once per week in 28-day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). RESULTS: Sixty-nine patients were enrolled, including 50 in the dose-escalation arm and 19 in the dose-expansion arm. Thrombocytopenia was the most common treatment-related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose-escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose-expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC-90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin-releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte-to-macrophage differentiation-associated. CONCLUSIONS: The safety profile of CC-90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once-per-week dosing support further exploration of CC-90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies.

A periodic development of BPA and BSH based derivatives in boron neutron capture therapy (BNCT).

Boron neutron capture therapy (BNCT) is a particular type of radiotherapy that requires a selective and high concentration of boron accumulation in neoplastic cells. To distinguish the distribution of boron compounds between tumour and normal cells, multiple research groups have been involved and successively innovated a wide variety of boron-based compounds. Despite the development of numerous boron compounds, only boronophenylalanine (BPA) and sodium mercaptoundecahydro-closo-dodecaborate (BSH) have emerged as effective in clinical trials. Here, we highlight the detailed progress in the molecular design of BPA and BSH derivatives from the historical perspective to the latest advances in light of the widely accepted performance required for effective BNCT. In this report, we have provided an overview of a variety of derivatives of BPA and BSH, including amino acids, peptides, polymers, monoclonal antibodies and chelated complexes, and it is observed that such derivatives of BPA and BSH are judicious choices for BNCT. Finally, we have summarised the critical issues for BPA and BSH that must be addressed if BNCT is to become a more widely accepted clinical modality.

Phase I Study of Lysine-Specific Demethylase 1 Inhibitor, CC-90011, in Patients with Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma.

PURPOSE: Lysine-specific demethylase 1 (LSD1) is implicated in multiple tumor types, and its expression in cancer stem cells is associated with chemoresistance. CC-90011 is a potent, selective, and reversible oral LSD1 inhibitor. We examined CC-90011 in advanced solid tumors and relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: CC-90011-ST-001 (NCT02875223; 2015-005243-13) is a phase I, multicenter, first-in-human dose-escalation study. Nine dose levels of CC-90011 (1.25-120 mg) given once per week were explored. Primary objectives were to determine safety, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to evaluate preliminary efficacy and pharmacokinetics. RESULTS: Fifty patients were enrolled, 49 with solid tumors (27 neuroendocrine tumors/carcinomas) and 1 with R/R NHL. Median age was 61 years (range, 22-75). Patients received a median of three (range, 1-9) prior anticancer regimens. The RP2D was 60 mg once per week; the nontolerated dose (NTD) and MTD were 120 mg once per week and 80 mg once per week, respectively. Grade 3/4 treatment-related toxicities were thrombocytopenia (20%; an on-target effect unassociated with clinically significant bleeding), neutropenia (8%; in the context of thrombocytopenia at the highest doses), and fatigue (2%). The patient with R/R NHL had a complete response, currently ongoing in cycle 34, and 8 patients with neuroendocrine tumors/carcinomas had stable disease ≥6 months, including bronchial neuroendocrine tumors, kidney tumor, and paraganglioma. CONCLUSIONS: CC-90011 is well tolerated, with the RP2D established as 60 mg once per week. The MTD and NTD were determined to be 80 mg once per week and 120 mg once per week, respectively. Further evaluation of CC-90011 is warranted.

Orbital giant cell angiofibroma: immuno-histochemistry and differential diagnosis.

CASE REPORT: A 57-year-old woman presented with a 16-month history of a slowly growing mass in the medial aspect of her right lower eyelid. On radiologic examination, the mass was seen to extend into the anterior orbit. Initial attempt at excision was complicated by problems with hemostasis and only a portion was removed. Histopathologic examination revealed a giant cell angiofibroma, which was subsequently excised. COMMENTS: Giant cell angiofibroma is a benign spindle cell neoplasm characterized by multinucleated giant cells and pseudovascular spaces with a propensity to occur in the anterior soft tissues of the orbit of middle-aged adults. It is part of a wide differential diagnosis of tumours that can be separated by various histologic and immunohistochemical features, which are discussed in the report. It is important to consider it preoperatively because the vascular nature of this tumour may create problems with hemostasis during excision.

Characterization of lymphoproliferative lesions of the conjunctiva: immunohistochemical and molecular genetic studies.

BACKGROUND: Conjunctival lymphoproliferative lesions have not been selected for independent analysis with newer immunohistochemical and molecular genetic techniques to highlight their unique profile. METHODS: Retrospective case series examined biopsies from 16 consecutive patients with conjunctival lymphoproliferative lesions. The histopathologic, immunohistochemical, and molecular genetic features were characterized, as well as the frequency of tumour type, prognostic implications, clinical features, and treatments offered. RESULTS: The diagnosis was lymphoma in 12 cases, atypical lymphoid hyperplasia (ALH) in 1 case, and reactive lymphoid hyperplasia (RLH) in 3 cases. The primary lymphomas consisted of 4 mucosa-associated lymphoid tissue lymphomas (MALTL), 1 follicular lymphoma (FL), 2 diffuse large B-cell lymphomas (DLBCLs), 1 lymphoplasmacytic lymphoma, and 1 T-cell lymphoma. Primary lymphomas were treated with radiation (n = 7), surgery (n = 1), and topical chemotherapy (n = 1). Complete remission was achieved in 8 of 9 primary lymphomas. Two cases of recurrence to the other conjunctiva were treated with radiation and both remained disease free. Secondary lymphomas included 2 DLBCL and 1 MALTL. Complete remission was seen in 2 patients after radiation plus chemotherapy, while the patient treated with chemotherapy alone was lost to follow-up. The 1 case of ALH presented bilaterally and achieved complete remission after topical chemotherapy treatments. The 3 RLH cases were surgically managed and 2 of the 3 recurred and were subsequently excised. Eleven lymphomas were of B-cell lineage by immunophenotyping. Molecular genetic studies of immunoglobulin heavy chain (IgH) gene rearrangement by polymerase chain reaction (PCR) showed clonal bands in 6 of 12 lymphomas, 1 of 3 RLH (polyclonal by immunophenotyping) and 1 ALH. BCL2-IgH [t(14;18)] rearrangement was seen in 8 of 12 cases (1 FL, 3 DLBCLs, 4 MALTLs) by real-time quantitative PCR. INTERPRETATION: Conjunctival lymphomas are predominantly B-cell type with a high prevalence of MALTL. An unexpected finding was the BCL2-IgH rearrangement seen in 4 of 5 MALTL cases in our series. The significance of this remains unclear.

Chronic lymphocytic leukemia involving the coronary arteries with accompanying acute myocardial infarction.

An 83-year-old man with chronic lymphocytic leukemia (CLL) for 10 years presented with dyspnea and hypotension. Blood investigations and electrocardiogram were consistent with acute myocardial infarction. The patient deteriorated quickly and died shortly thereafter. At autopsy, there was severe atherosclerosis of the coronary arteries and an inferolateral left ventricular wall myocardial infarct. Microscopy showed that CLL involved the nodes, liver, spleen, bowel, and kidneys. The coronary artery walls were infiltrated with leukemia cells invading the tunica media and the atheromatous plaque. Infiltration of the coronary arteries by CLL is not common and the possible role in coronary syndromes is discussed.

Lymphoproliferative lesions of the lacrimal gland: clinicopathological, immunohistochemical and molecular genetic analysis.

BACKGROUND: Lacrimal gland lymphoproliferative disorders are usually classified as orbital adnexal tumours. Because the lacrimal gland is the only orbital structure with native lymphocytes, we examined cases with primary involvement of the gland. METHODS: The 14 cases were selected from a review of all cases in the surgical pathology files of the Ottawa Hospital between 1992 and 2003. The lesions were categorized according to the latest World Health Organization classification of tumours of lymphoid tissues. We conducted a clinical, histopathological, immunohistochemical, immunophenotypic and molecular genetic analysis of the cases. RESULTS: The 8 female and 6 male patients, aged 20 to 88 (mean 60) years, were followed for an average of 4 years (range 11 months to 13 years). All presented with supratemporal orbital swelling. The 5 primary lymphomas, of mucosa-associated lymphoid tissue (MALT), were confined to the lacrimal gland (stage IE); 1 tumour transformed to diffuse large B-cell lymphoma, necessitating chemotherapy, and the other 4 were treated with radiation. One of the 5 patients had previously had Sjögren's syndrome. The 6 secondary lymphomas (4 follicular) presented either concurrently with systemic lymphoma or up to 12 years afterwards and were treated in a variety of ways; all the patients had an orbital relapse. At the last follow-up assessment, 6 of the patients with lymphoma had no evidence of disease, 3 were alive with disease, 2 had died (1 of lymphoma, the other with no evidence of disease), and the status of 1 patient was not known. Of the 3 patients with reactive proliferations, 2 had reactive lymphoid hyperplasia (associated with Sjögren's syndrome in 1), and 1 had Rosai-Dorfman disease. All 9 lymphomas that underwent molecular genetic analysis were of B-cell lineage, and 8 had a monoclonal rearrangement in the immunoglobulin heavy-chain gene (IgH); the 9th lymphoma showed an oligoclonal rearrangement. One lymphoma showed the t(14;18) translocation, typical of follicular lymphoma; no lymphoma showed the t(11;18) translocation, commonly found in MALT lymphoma (but only 2 cases were studied). Molecular genetic analysis was performed in 2 of the cases of reactive lymphoid hyperplasia: monoclonal IgH rearrangement was detected in 1 case (the patient with Sjögren's syndrome), oligoclonal rearrangement in the other. INTERPRETATION: Lacrimal gland lymphomas are B-cell tumours that develop in older adults. Primary tumours, a hIgH proportion of which have MALT characteristics, have a favourable prognosis. Molecular genetic studies may be useful when morphologic and immunophenotypic studies give equivocal results.

Multiple cutaneous and uterine leiomyomas associated with gastric GIST.

BACKGROUND: There are a number of reports documenting familial cases of leiomyomatosis cutis associated with uterine leiomyomata. However, to our knowledge, the association of gastrointestinal stromal tumour (GIST) with this entity has not as yet been reported. We report an interesting case of cutaneous leiomyomatosis, metachronous uterine leiomyomata, and a gastric GIST in a 43-year-old woman. OBSERVATION: The patient had previously undergone two separate uterine myomectomies at ages 25 and 26 years, respectively, followed by a hysterectomy at 27 years. At 36 years she underwent partial gastrectomy for excision of GIST and this was followed by the development of extensive, symptomatic cutaneous leiomyomata at 43 years. In the report, we have documented histological, immunohistochemical and clinical observations and furthermore report on the therapeutic measures undertaken. CONCLUSION: We report an interesting association of cutaneous leiomyomatosis, uterine leiomyomas and GIST.

Pathologic study and clinical significance of Hürthle cell papillary thyroid carcinoma.

Hürthle cell papillary thyroid carcinoma is a variant of papillary thyroid carcinoma (PTC). Its pathologic and clinical significance has not been well documented. The authors studied the relative incidence of Hürthle cell PTC and the relationship of Hürthle cell PTC to other variants of thyroid carcinoma. Three hundred eighty consecutive cases of thyroid carcinoma were reviewed to identify cases with focal or extensive areas of Hürthle cell PTC, classic PTC, Hürthle cell carcinoma (ie, non-Hürthle cell PTC), and follicular carcinoma. In addition, the status of lymphoid infiltrate in the tumor, stromal invasion with desmoplastic reaction, vascular invasion, and distant and lymph node metastasis were noted by microscopic examination, review of clinical charts, or both. A total of 24 (HCs) and 42 PTCs with Hürthle cells were identified. The latter category was divided into pure Hürthle cell PTC or extensive Hürthle cell (HPTC) (28 cases) and PTC or Hürthle cell carcinoma with focal areas of Hürthle cell PTC (14 cases). The Hürthle cell PTC/Hürthle cell carcinoma ratio was lower than that of PTC/follicular carcinoma (39:289) (P = 0.001). Follicular or solid structures were present in all HPTCs. HPTCs were associated with frequent stromal intrathyroid and extrathyroid invasion, but they tended to have a lower rate of lymph node metastasis (8/28) compared with classic PTC with stromal invasion (108:200) (P = 0.12) and a lower rate of distant metastasis (2:28) compared with Hürthle cell carcinoma (15:24) (P = 0.02) or follicular carcinoma (13:39) (P = 0.04). Warthin-like Hürthle cell PTC (10 cases) was associated with extrathyroid invasion in five cases. In Hürthle cell PTC associated with tall cell variant (10 cases), areas of gradual transition between Hürthle cell PTC and tall cell variant were identified. The latter variant showed the highest rate of extrathyroid stromal and vascular invasion with distant metastasis and patient death compared with all Hürthle cell PTCs and classic PTCs. In conclusion, Hürthle cell PTC is frequently associated with tall cell variant. It has a higher potential for extrathyroid invasion than classic PTC and has vascular invasion and distant metastasis characteristics intermediate between those of classic PTC and Hürthle cell carcinoma with or follicular carcinoma. Hürthle cell PTC tends to show a greater likelihood of extrathyroid invasion when associated with Warthin-like features and tall cell variant PTC, and higher vascular invasion and distant metastasis when associated with tall cell variant.

Distribution of subtypes of metastatic renal-cell carcinoma: correlating findings of fine-needle aspiration biopsy and surgical pathology.

Clear-cell (CRCC), papillary (PRCC), and chromophobe (CHRCC) renal-cell carcinoma (RCC) are the three most frequent subtypes of RCC. The rate and distribution of their metastatic lesions have not been well studied in cytopathological materials. Sixty-two fine-needle aspiration biopsy cases of metastatic RCC were studied and correlated with surgical pathology of RCCs with and without metastasis. Special stains for glycogen and immunostaining for cytokeratins, vimentin epithelial membrane antigen (EMA), and carcinoembryonic antigens, and electron microscopic studies were performed. Fifty-nine cases of CRCC and three of PRCC subtypes were retrieved from the cytopathology files at the Ottawa Hospital in a period of 10 years. Of these cases, 10 metastatic CRCC and one metastatic PRCC were diagnosed prior to the diagnosis of the primary tumor. CHRCC and sarcomatoid RCC were not represented in cytopathological specimens. CRCC displayed characteristic filmy cytoplasm and nuclei with prominent nucleoli. PRCC was characterized by dense cytoplasm, large nuclei with prominent nucleoli, and papillary architectures. In addition, all RCCs were characterized by the presence of glycogen and the absence of mucin by using histochemical techniques and electron microscopic studies and positive reactivity for cytokeratins (CK) and vimentin (VIM). In the same period, there were a total of 380 patients with RCC divided into 310 CRCCs, 55 PRCCs, and 15 CHRCCs associated with metastases in 142, 9, and 1 case, respectively. CRCC is by far the most common subtype found in metastases sampled in cytopathology. PRCC, CHRCC, and sarcomatoid RCC were underrepresented. Awareness of this propensity of RCC and the characteristic cytopathological, histochemical, immunohistochemical, and ultrastructural features are helpful in the diagnosis of metastatic RCC.

Isolated pleural PTLD after cardiac transplantation.

UNLABELLED: PREAMBLE: Epstein-Barr virus infection (EBV) and immunosuppression promote emergence of posttransplant lymphoproliferative disorders (PTLD) in patients undergoing organ transplantation. OBJECTIVE: We report a case of PTLD confined to the pleura. FINDINGS: The patient was a 62-year-old male who had undergone cardiac transplant in 1993 for ischemic heart disease. Seven years later, he presented with dyspnea and bilateral pleural effusions. The CT scan revealed left sided pleural base thickening. The cytology of the pleural fluid and fine needle aspirate of the pleura was both suggestive of PTLD. However, the tissue submitted for ancillary studies did not contain the diagnostic material. A clinical decision was made to withdraw immunosuppressive therapy and start rituximab. His clinical course was complicated by Pneumocystis carinii pneumonia and he died 4 months after the diagnosis of PTLD. Autopsy revealed bilateral pleural effusions with pleural nodules involving the visceral and parietal pleura of both lungs. Immunohistochemistry demonstrated B cell lineage with kappa/lambda ratio of 1. PCR studies done on the pleural nodules (postmortem specimen) revealed the presence of EBV DNA and absence of human herpes virus 8 (HHV8) DNA. In situ hybridization revealed positive staining for EBV RNA within the neoplasm. CONCLUSION: Pleural-based PTLD is rare. Cytology in conjunction with immunophenotyping and molecular studies can be useful for a definitive diagnosis. In our case, cytology sample was suggestive of PTLD. PCR studies performed on the antemortem specimen confirmed the presence of monoclonal IgH gene rearrangement, while the postmortem specimen revealed oligoclonal IgH gene rearrangement. The change from monoclonal to oligoclonal IgH gene rearrangement suggests reversion of monoclonal to polyclonal PTLD following rituximab and CHOP therapy. We also demonstrated EBV DNA and RNA in the tumor nodules, supporting EBV-induced PTLD.

Fatal splenic arterial aneurysmal rupture associated with chronic pancreatitis.

Splenic arterial aneurysms (SAA) are rare and are usually atherosclerotic and/or related to pregnancy. Because pregnancy is the most important predisposing factor, the strong predilection of SAA for women is not surprising. The authors report a case of SAA rupture in a man with chronic pancreatitis as the predisposing factor. A 56-year-old man with abdominal pain and hematemesis was resuscitated and underwent endoscopy, but he died 18 hours later of massive hematemesis before definitive surgery could be carried out. At autopsy, there was chronic pancreatitis with fibrous adhesions tethering the tail of the pancreas, spleen, and posterior wall of the stomach together. The SAA was indented into the posterior wall of the stomach, into which it had ruptured from without. He also had alcoholic cirrhosis but no esophageal varices or conventional gastric ulcers. Other important predisposing factors such as abdominal trauma, infective endocarditis, polyarteritis nodosa, and segmental medial arteriopathy were absent. Histologic examination confirmed the rupture of the SAA. The SAA had Monckeberg medial calcinosis but little evidence of atherosclerosis. The well-documented complications of acute and chronic pancreatitis include shock, abscess, pseudocyst formation, and duodenal obstruction. This report describes the rare complication of SAA rupture, which may be fatal.

Differentiated thyroid carcinomas with vascular invasion: a comparative study of follicular, Hürthle cell and papillary thyroid carcinoma.

AIM: Non-medullary thyroid carcinomas arise from follicular cells. The purpose of this study is to correlate clinical and pathological properties of these tumours with the rate of distant metastasis from a series of thyroid tumours excised at one institution. METHODS: A total of 311 non-medullary thyroid tumours were identified and divided into: 29 follicular carcinoma (FC), 12 Hürthle cell carcinoma (HC), 13 Hürthle cell papillary thyroid carcinoma (HPTC) with vascular invasion (VI), 32 papillary thyroid carcinoma (PTC) with VI and 225 PTC without VI. The mean follow-up was 6.5 years with a range of 1-17 years. The tumours were histologically subdivided into minimal or wide invasion for FC and HC and focal or extensive invasion for PTC and HPTC, and stratified according to status of VI. RESULTS: The rate of distant metastasis was similar for FC, malignant Hürthle cell tumours and PTC with VI, and increased with extent of invasion. VI was seen in 12% of all PTC and 0% of HPTC in this study. PTC without VI were associated with a much lower potential of distant metastasis, were smaller in size and occurred in patients of younger age than PTC with VI. In addition, there was a tendency for increased potential for distant metastases with increased tumour size and patient age for all groups of tumours in the study. Patient age and tumour size appeared to play a smaller role than that of VI in predicting distant metastasis. CONCLUSIONS: Our study suggests that the rate of distant metastasis relates to VI, patient age and tumour size, regardless of Hürthle cell, FC or PTC differentiation. PTC of large size, and in patients older than 45 years, have a high propensity for vascular invasion.