GPRC5D-Targeted CAR T Cells for Myeloma.

BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).

Kaposi sarcoma-associated herpesvirus complement control protein (KCP) and glycoprotein K8.1 are not required for viral infection in vitro or in vivo.

Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causal agent of Kaposi sarcoma, a cancer that appears as tumors on the skin or mucosal surfaces, as well as primary effusion lymphoma and KSHV-associated multicentric Castleman disease, which are B-cell lymphoproliferative disorders. Effective prophylactic and therapeutic strategies against KSHV infection and its associated diseases are needed. To develop these strategies, it is crucial to identify and target viral glycoproteins involved in KSHV infection of host cells. Multiple KSHV glycoproteins expressed on the viral envelope are thought to play a pivotal role in viral infection, but the infection mechanisms involving these glycoproteins remain largely unknown. We investigated the role of two KSHV envelope glycoproteins, KSHV complement control protein (KCP) and K8.1, in viral infection in various cell types in vitro and in vivo. Using our newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP, K8.1, or both, we demonstrated the presence of KCP and K8.1 on the surface of both virions and KSHV-infected cells. We showed that KSHV lacking KCP and/or K8.1 remained infectious in KSHV-susceptible cell lines, including epithelial, endothelial, and fibroblast, when compared to wild-type recombinant KSHV. We also provide the first evidence that KSHV lacking K8.1 or both KCP and K8.1 can infect human B cells in vivo in a humanized mouse model. Thus, these results suggest that neither KCP nor K8.1 is required for KSHV infection of various host cell types and that these glycoproteins do not determine KSHV cell tropism. IMPORTANCE: Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic human gamma-herpesvirus associated with the endothelial malignancy Kaposi sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. Determining how KSHV glycoproteins such as complement control protein (KCP) and K8.1 contribute to the establishment, persistence, and transmission of viral infection will be key for developing effective anti-viral vaccines and therapies to prevent and treat KSHV infection and KSHV-associated diseases. Using newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP and/or K8.1, we show that KCP and K8.1 can be found on the surface of both virions and KSHV-infected cells. Furthermore, we show that KSHV lacking KCP and/or K8.1 remains infectious to diverse cell types susceptible to KSHV in vitro and to human B cells in vivo in a humanized mouse model, thus providing evidence that these viral glycoproteins are not required for KSHV infection.

Combined Whole Body and Multiparametric Prostate Magnetic Resonance Imaging as a 1-Step Approach to the Simultaneous Assessment of Local Recurrence and Metastatic Disease after Radical Prostatectomy.

PURPOSE: We report our initial experience with whole body and dedicated prostate magnetic resonance imaging as a single examination to assess local recurrence and metastatic disease in patients with suspected recurrent prostate cancer after radical prostatectomy. MATERIALS AND METHODS: In this institutional review board approved, retrospective, single center study 76 consecutive patients with clinically suspected recurrent prostate cancer following radical prostatectomy underwent combined whole body and dedicated prostate magnetic resonance imaging at a single session from October 2014 to January 2016. Scans were evaluated to detect disease in the prostate bed and regional nodes, and at distant sites. Comparison was made to other imaging tests, and prostate bed, node and bone biopsies performed within 90 days. RESULTS: Whole body and dedicated prostate magnetic resonance imaging was completed successfully in all patients. Median prostate specific antigen was 0.36 ng/ml (range less than 0.05 to 56.12). Whole body and dedicated prostate magnetic resonance imaging identified suspected disease recurrence in 16 of 76 patients (21%), including local recurrence in the radical prostatectomy bed in 6, nodal metastases in 3, osseous metastases in 4 and multifocal metastatic disease in 3. In 43 patients at least 1 standard staging scan was done in addition to whole body and dedicated prostate magnetic resonance imaging. Concordance was demonstrated between the imaging modalities in 36 of 43 cases (84%). All metastatic lesions detected by other imaging tests were detected on magnetic resonance imaging. In addition, the magnetic resonance imaging modality detected osseous metastases in 4 patients with false-negative findings on other imaging tests, including 2 bone scans and 3 computerized tomography scans. It also excluded osseous disease in 1 patient with positive 18F-fluorodeoxyglucose positron emission tomography/computerized tomography and subsequent negative bone biopsy. CONCLUSIONS: Combined whole body and dedicated prostate magnetic resonance imaging is feasible in a clinical practice setting. It can provide incremental information compared to standard imaging in men with suspected prostate cancer recurrence after radical prostatectomy.

A Phase Ib/II Study of Gemcitabine and Docetaxel in Combination With Pazopanib for the Neoadjuvant Treatment of Soft Tissue Sarcomas.

LESSONS LEARNED: Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib.Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations. BACKGROUND: For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS. METHODS: Patients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m(2) gemcitabine on days 1 and 8, 75 mg/m(2) docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response. RESULTS: The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ≥ 90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed. CONCLUSION: GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.

Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

PURPOSE: We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. PATIENTS AND METHODS: We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. RESULTS: Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response. CONCLUSIONS: Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649.

Biopsy of suspicious bone lesions in patients with a single known malignancy: prevalence of a second malignancy.

OBJECTIVE: The probability that a suspicious bone lesion in a patient with one known malignancy is actually due to a second, previously unknown primary malignancy has been reported to be 2-8%. We sought to determine this prevalence as well as that of benign diagnoses in a larger number of patients in a tertiary cancer center. MATERIALS AND METHODS: The medical records of 482 consecutive patients (254 women and 228 men) with only one known primary malignancy each (excluding nonmelanoma skin cancer) and who underwent biopsy of a suspicious bone lesion were retrospectively reviewed. The results of bone biopsy were classified as benign, metastasis of the known primary malignancy, due to a second primary malignancy, or nondiagnostic or indeterminate. RESULTS: In 103 of 482 (21%) patients, bone biopsy results were benign, 316 (66%) were due to metastases of the known malignancy, 15 (3%) were due to a second malignancy, and 48 (10%) were nondiagnostic or indeterminate. Second malignancies included osteosarcoma (n = 4); soft-tissue sarcoma (n = 2); lymphoma (n = 2); plasma cell malignancy (n = 2); and lung cancer, thyroid cancer, renal cancer, chondrosarcoma, and carcinoma of unknown primary (n = 1 each). CONCLUSION: In 3% of patients with one known malignancy and a suspicious bone lesion, the lesion was due to a previously unknown second malignancy; in 21% of patients, the lesion was benign. Bone biopsy is recommended in the management of patients with one known cancer and a suspicious bone lesion only if the presence of a second malignancy would alter clinical management.

Myxofibrosarcoma: prevalence and diagnostic value of the "tail sign" on magnetic resonance imaging.

OBJECTIVE: Myxofibrosarcoma frequently shows curvilinear extensions of high T2 signal that also enhance on magnetic resonance imaging; these "tails" represent fascial extension of tumor at histopathological examination. This study was performed to determine whether the tail sign is helpful in distinguishing myxofibrosarcoma from other myxoid-containing neoplasms. MATERIALS AND METHODS: The study group consisted of 44 patients with pathologically proven myxofibrosarcoma; the control group consisted of 52 patients with a variety of other myxoid-predominant tumors. Three musculoskeletal radiologists independently evaluated T2-weighted (and/or short-tau inversion recovery) and post-contrast MR images for the presence of one or more enhancing, high-signal intensity, curvilinear projections from the primary mass. Sensitivity and specificity for the diagnosis of myxofibrosarcoma were calculated for each reader. Interobserver variability was assessed with kappa statistic and percentage agreement. RESULTS: A tail sign was deemed present in 28, 30, and 34 cases of myxofibrosarcoma and in 11, 9, and 5 of the controls for the three readers respectively, yielding a sensitivity of 64-77 % and a specificity of 79-90 %. The interobserver agreement was moderate-to-substantial (kappa=0.626). CONCLUSION: The tail sign at MRI is a moderately specific and sensitive sign for the diagnosis of myxofibrosarcoma relative to other myxoid-containing tumors.

Musculoskeletal tumors and tumor-like conditions: common and avoidable pitfalls at imaging in patients with known or suspected cancer: Part A: benign conditions that may mimic malignancy.

A wide range of musculoskeletal tumors and tumor-like conditions may be encountered when patients undergo radiological examinations. The imaging features of certain normal, reactive, benign neoplastic, inflammatory, traumatic, and degenerative processes in the musculoskeletal system may mimic malignant tumor; misinterpretation of the imaging findings can lead to inappropriate clinical management of the patient. This review describes and illustrates a number of such mimics that we have commonly encountered in our oncological imaging practice, and provides suggestions for avoiding each of these pitfalls. Because many orthopaedic surgeons interpret radiological images themselves, they need to be as aware as radiologists about these issues.

Musculoskeletal tumours and tumour-like conditions: common and avoidable pitfalls at imaging in patients with known or suspected cancer: Part B: malignant mimics of benign tumours.

A wide range of musculoskeletal tumours and tumour-like conditions may be encountered when patients undergo radiological examinations. Some malignant musculoskeletal lesions may mimic benign tumours at imaging, being confused with benign cystic lesions or haematomas. Also, inappropriately selected magnetic resonance (MR) image sequences or computed tomography (CT) display windows can lead to misdiagnosis. Many orthopaedic surgeons interpret radiological images themselves, and therefore need to be as aware of these issues as radiologists are. This review describes and illustrates a number of such errors that commonly occur, and provides suggestions for avoiding these pitfalls.

Increased trunk fat is associated with altered gene expression in breast tissue of normal weight women.

Increased trunk fat is associated with an elevated risk of breast cancer in normal-weight postmenopausal women. The main objective of this study was to determine whether levels of trunk fat are associated with changes in breast gene expression in normal-weight women. Non-tumorous breast tissue was collected from 32 normal BMI women who underwent mastectomy for breast cancer risk reduction or treatment. Body composition was measured by dual-energy x-ray absorptiometry. High levels of trunk fat were associated with a large number of differentially expressed genes and changes in multiple pathways and processes potentially linked to breast cancer pathogenesis. High levels of trunk fat were also associated with an elevated immune score and increased levels of leptin, CCL2, VEGF-C, IL6, and aromatase. Collectively, these results help to explain why high levels of trunk fat are associated with an increased risk of breast cancer in normal BMI women.

Percutaneous CT-guided bone biopsy: diagnosis of malignancy in lesions with initially indeterminate biopsy results and CT features associated with diagnostic or indeterminate results.

OBJECTIVE: The purpose of our study was to determine the proportion of bone lesions with indeterminate results after initial percutaneous CT-guided bone biopsy that ultimately are found to be malignant and whether CT features are associated with diagnostic outcomes. MATERIALS AND METHODS: The results of 800 consecutive percutaneous CT-guided bone biopsies performed at a tertiary cancer center were reviewed. The initial histopathologic diagnosis was classified as diagnostic or indeterminate. On the basis of follow-up information, indeterminate results were subcategorized as benign, malignant, or persistently indeterminate. Two readers independently analyzed the CT images. RESULTS: Initial percutaneous CT-guided bone biopsy was diagnostic in 69% and indeterminate in 31%. Malignancy was diagnosed in 90% of initially diagnostic results. In lesions with initially indeterminate results, a diagnosis was subsequently made in 62%; 39% of subsequent diagnoses were malignant as of the last available follow-up. CT features associated with diagnostic results included cortical destruction and large extraosseous mass (p < 0.05). More lesional sclerosis and presence of fat were associated with indeterminate results (p < 0.001). CT features associated with malignant results included less-extensive sclerosis and lesser sclerotic rim (p < 0.05). Increased age, female sex, and a cancer history were associated with higher risk of malignancy among patients with diagnostic results at initial biopsy. CONCLUSION: Bone lesions that initially yield indeterminate results at percutaneous CT-guided bone biopsy often are subsequently shown to be malignant; vigorous pursuit of a diagnosis is recommended if initial results are indeterminate. Lesions showing fat or more sclerosis are more likely to be indeterminate; lesions with less sclerosis or smaller sclerotic rim are more likely to yield malignant results.

Bone lesions on baseline staging rectal MRI: prevalence and significance in patients with rectal adenocarcinoma.

A T1 sequence on routine baseline staging rectal magnetic resonance imaging (MRI) is thought to help detect bone lesions. Our primary aim was to evaluate the incidence of bone lesions encountered on baseline staging rectal MRI, particularly the prevalence of bone metastases. This retrospective study included patients with rectal adenocarcinoma who underwent baseline rectal MRI at our institution between January 2010 and December 2017. The MRI report was reviewed for presence of bone lesions. When found, lesion type, presence of axial T1 non-fat-suppressed sequence, primary tumor T-stage, and presence of other organ metastases were recorded. In the absence of bone biopsy, the reference standard was follow-up imaging via computed tomography (CT), MRI, and/or positron emission tomography/CT (PET/CT) ≥ 1 year after the baseline MRI. The Wilcoxon rank-sum test and Fisher's exact test were used to compare clinicopathologic data of patients with malignant or benign bone lesions. A total of 1197 patients were included. 62/1197 patients (mean age 56.8 years (SD: 13.8), with 39 men) had bone lesions on baseline imaging, with 6 being bone metastases (0.5%, 95% CI 0.2%-1.1%). Of the 6 patients with bone metastases, 5/6 had other metastases (i.e., liver, lung) at baseline. Bone metastases on baseline rectal MRI performed for rectal adenocarcinoma are extremely rare. Furthermore, bone metastases without other organ (i.e., liver, lung) involvement is extremely rare.

Effects of Adiposity and Exercise on Breast Tissue and Systemic Metabo-Inflammatory Factors in Women at High Risk or Diagnosed with Breast Cancer.

Excess body fat and sedentary behavior are associated with increased breast cancer risk and mortality, including in normal weight women. To investigate underlying mechanisms, we examined whether adiposity and exercise impact the breast microenvironment (e.g., inflammation and aromatase expression) and circulating metabo-inflammatory factors. In a cross-sectional cohort study, breast white adipose tissue (WAT) and blood were collected from 100 women undergoing mastectomy for breast cancer risk reduction or treatment. Self-reported exercise behavior, body composition measured by dual-energy x-ray absorptiometry (DXA), and waist:hip ratio were obtained prior to surgery. Breast WAT inflammation (B-WATi) was assessed by IHC and aromatase expression was assessed by quantitative PCR. Metabolic and inflammatory blood biomarkers that are predictive of breast cancer risk and progression were measured. B-WATi was present in 56 of 100 patients and was associated with older age, elevated BMI, postmenopausal status, decreased exercise, hypertension and dyslipidemia (Ps < 0.001). Total body fat and trunk fat correlated with B-WATi and breast aromatase levels (Ps < 0.001). Circulating C-reactive protein, IL6, insulin, and leptin positively correlated with body fat and breast aromatase levels, while negative correlations were observed for adiponectin and sex hormone binding globulin (P < 0.001). Inverse relationships were observed with exercise (Ps < 0.05). In a subgroup of 39 women with normal BMI, body fat levels positively correlated with B-WATi and aromatase expression (Ps < 0.05). In conclusion, elevated body fat levels and decreased exercise are associated with protumorigenic micro- and host environments in normal, overweight, and obese individuals. These findings support the development of BMI-agnostic lifestyle interventions that target adiposity. PREVENTION RELEVANCE: We report that individuals with high body fat and low exercise levels have breast inflammation, higher breast aromatase expression, and levels of circulating metabo-inflammatory factors that have been associated with increased breast cancer risk. These findings support interventions to lower adiposity, even among normal weight individuals, to prevent tumor growth.

SEROPREVALENCE OF TOXOPLASMA GONDII IN MARKET HOGS COLLECTED FROM U.S. SLAUGHTERHOUSES.

Foodborne pathogens continue to pose a public health risk and can cause serious illness and outbreaks of disease in consumers. The consumption of raw or undercooked infected meat, such as pork containing infectious stages of Toxoplasma gondii, may be a major route of transmission to humans. Given the occasional presence of T. gondii in pork meat and the frequent use of pork for products not intended to be cooked, such as dry-cured ham, a potential risk exists for T. gondii transmission to consumers of these products. The purpose of this study was to determine the seroprevalence of T. gondii in U.S. market hogs and sows at slaughter. A total of 20,209 sera samples collected from 22 U.S. slaughterhouses, including 15 of the top 25 largest slaughter plants in the United States, were tested for T. gondii antibodies using a commercial ELISA assay. Seroprevalence in this study was 0.74%, with a herd prevalence of 10.86%. We compared seroprevalence of T. gondii in market hogs vs. sows from a separate but geographically similar set of slaughterhouse locations, with serum samples screened using the T. gondii modified agglutination test. This set of market hogs demonstrated 0% seroprevalence for T. gondii, while sows from geographically similar but separate slaughter facilities demonstrated a seroprevalence of 1.03%. Overall, both analyses show low seroprevalence of T. gondii in U.S market hogs and sows, respectively, and a marked drop in prevalence in market hogs and sows compared to previous studies.

Imaging characteristics of primary osteosarcoma: nonconventional subtypes.

Osteosarcoma (OS) is a common primary malignant tumor of bone that produces osteoid matrix. According to the World Health Organization, OS of bone is classified into eight subtypes with distinct biologic behaviors and clinical outcomes: conventional, telangiectatic, small cell, low-grade central, secondary, parosteal, periosteal, and high-grade surface. Imaging plays a crucial role in the diagnosis of each subtype of OS and ultimately in patients' survival because the diagnosis is based on a combination of histopathologic and imaging features. Conventional OS is the most common subtype of OS and is readily identified at radiography as an intramedullary mass with immature cloudlike bone formation in the metaphyses of long bones. The imaging features of less common subtypes of primary OS are variable and frequently overlap with those of multiple benign and malignant entities, creating substantial diagnostic challenges. For accurate diagnosis, it is important to be aware of radiographic and cross-sectional imaging features that allow differentiation of each nonconventional subtype of OS from its mimics.

Imaging findings, prevalence and outcome of de novo and secondary malignant fibrous histiocytoma of bone.

OBJECTIVE: To evaluate the radiographic and magnetic resonance (MR) imaging features of primary and secondary malignant fibrous histiocytoma in bone and determine the demographics, prevalence and outcome of patients with this tumor. MATERIALS AND METHODS: A retrospective search of files from two institutions identified 28 patients with malignant fibrous histiocytoma (MFH) of bone. Microscope slides were reviewed to confirm diagnosis and identify any pre-existing lesions. Medical records were reviewed with respect to patients' demographic characteristics and outcomes. RESULTS: Radiographic features demonstrated an aggressive osteolytic lesion with a permeative pattern of bone destruction. Periosteal reaction was seen in three of 13 lesions. T1-weighted images (T1WIs) demonstrated signal intensity iso- to slightly hyperintense to muscle. T2-weighted images (T2WIs) demonstrated mildly higher signal intensity than that of muscle. The 5-year survival rate was 53%. The tumor arose secondarily in pre-existing lesions in 43% of patients. Metastases occurred in 46% of patients during the course of the disease, with pulmonary and osseous metastases being the most common. CONCLUSION: Secondary MFH of bone was slightly less common than primary MFH and had a prognosis similar to that of primary MFH of bone. MR imaging showed variable and somewhat unusual low to intermediate T2 signal characteristics for a radiographically malignant osteolytic lesion.

Immunomodulatory Activity of a Colony-stimulating Factor-1 Receptor Inhibitor in Patients with Advanced Refractory Breast or Prostate Cancer: A Phase I Study.

PURPOSE: Tumor-associated macrophages correlate with increased invasiveness, growth, and immunosuppression. Activation of the colony-stimulating factor-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. This phase I study evaluated the immunologic and clinical activity, and safety profile of CSF-1R inhibition with the mAb LY3022855. PATIENTS AND METHODS: Patients with advanced refractory metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) were treated with LY3022855 intravenously in 6-week cycles in cohorts: (A) 1.25 mg/kg every 2 weeks (Q2W); (B) 1.0 mg/kg on weeks 1, 2, 4, and 5; (C) 100 mg once weekly; (D)100 mg Q2W. mCRPC patients were enrolled in cohorts A and B; patients with MBC were enrolled in all cohorts. Efficacy was assessed by RECIST and Prostate Cancer Clinical Trials Working Group 2 criteria. RESULTS: Thirty-four patients (22 MBC; 12 mCRPC) received ≥1 dose of LY3022855. At day 8, circulating CSF-1 levels increased and proinflammatory monocytes CD14DIMCD16BRIGHT decreased. Best RECIST response was stable disease in five patients with MBC (23%; duration, 82-302 days) and three patients with mCRPC (25%; duration, 50-124 days). Two patients with MBC (cohort A) had durable stable disease >9 months and a third patient with MBC had palpable reduction in a nontarget neck mass. Immune-related gene activation in tumor biopsies posttreatment was observed. Common any grade treatment-related adverse events were fatigue, decreased appetite, nausea, asymptomatic increased lipase, and creatine phosphokinase. CONCLUSIONS: LY3022855 was well tolerated and showed evidence of immune modulation. Clinically meaningful stable disease >9 months was observed in two patients with MBC.

Contemporary imaging in sarcoma.

Sarcomas are a heterogeneous group of >50 subtypes of neoplasm. It is imperative to obtain appropriate imaging of these tumors in order to adequately assess, characterize, and stage bone and soft tissue sarcomas. Anatomic imaging such as radiographs, computed tomography, and magnetic resonance imaging (MRI) remain the foundation for both biopsy planning and postoperative evaluation of these neoplasms. However, anatomic imaging may not be entirely accurate in the evaluation of treatment response. Newer techniques, such (18)F-fluorodeoxyglucose positron emission tomography, are being used to evaluate distant metastases. Newer radiopharmaceuticals, such as (18)F-fluorodeoxythymidine, are being developed to assist in the differentiation between benign and low-grade malignant neoplasms. Newer functional imaging techniques, such as dynamic contrast-enhanced MRI and diffusion-weighted imaging, among others, are being developed to evaluate treatment response.

Recurrence patterns of intraductal papillary mucinous neoplasms of the pancreas on enhanced computed tomography.

OBJECTIVE: To characterize imaging features and findings in recurrent intraductal papillary mucinous neoplasms (IPMN); thereby reconciling the "field defect" theory with the appearance of recurrences distant from the resection margin. METHODS: Computed tomography findings were reviewed in 89 patients who were resected with IPMN. At follow-up, the appearance of the pancreatic duct, features of recurrent masses, evidence of enhancement, calcifications, lymphadenopathy, and metastases were recorded. RESULTS: Fourteen (16%) of the 89 patients had evidence of recurrence. Nine (64%) of the 14 patients demonstrated evidence for local recurrence. Ten recurrent lesions were noted in 9 patients. Patients with recurrence demonstrated an increase of pancreatic ductal dilatation of 3.3 mm, whereas patients without recurrence either had no dilatation or dilatation which then decreased over time. CONCLUSIONS: Computed tomography findings suspicious for tumor recurrence include enlarging mass (either solid, cystic or both), progressive ductal dilatation, or extrapancreatic disease. There was a lack of correlation between margin status and location of recurrence within the pancreas consistent with the global field defect theory of IPMN.

Hepatic abnormalities identified by staging MRI and accuracy of MRI of patients with uveal melanoma.

BACKGROUND: Metastases to the liver are often the first finding in patients with uveal melanoma with extraocular disease, but little has been published on the utility of staging MRI at initial diagnosis. We aimed to evaluate the proportion of abnormal hepatic findings on baseline MRI and accuracy of MRI in patients with newly diagnosed uveal melanoma. METHODS: This is a single-centre, retrospective, institutional review board-approved study of 145 consecutive patients diagnosed with uveal melanoma, at Memorial Sloan Kettering Cancer Center between 2004 and 2016, who had staging MRI within 1 month of diagnosis. Scans were classified as normal or abnormal, and further distinguished as abnormal non-metastatic, uncharacterisable lesions and suspicious for metastasis. Where available, follow-up MRI (at ~1 year) or biopsies were reviewed. RESULTS: MRI in 145 patients revealed 62% (90) with abnormal hepatic findings; out of these 87% (78) had non-metastatic benign findings, 6.7% (6) had unclassifiable lesions and 6.7% (6) were suspicious for metastasis (6). Abnormal non-metastatic findings included 72 focal (36 solitary and 36 multiple) and 12 diffuse lesions. Lesions suspicious for metastases were found in 6 of 145 patients (4%), despite normal liver function tests. Of these, five had confirmed liver metastases and one patient had a stable, presumed non-metastatic lesion on follow-up. In this study, the sensitivity and specificity of staging MRI for all findings were 83.3% (95% CI 35.9 to 99.6) and 99.0% (95% CI 94.3 to 99.9), respectively. CONCLUSION: Staging MRI of patients with newly diagnosed uveal melanoma accurately identified early metastases. Furthermore, imaging revealed hepatic abnormalities in the majority of patients, although as expected few of these represented metastatic disease.