Citations

Abstract Pneumonia remains a leading cause of morbidity and mortality despite advances in treatment and therapy. The “Pneumonia: Treatment and Diagnosis” session of the Pittsburgh International Lung Conference examined topics related to improving care of patients with pneumonia. These topics included the process and quality of care for community-acquired pneumonia (CAP), diagnosis and treatment of emerging fungal pathogens, an overview of the strengths and weaknesses of different diagnostic modalities, and an example of how basic science is exploring immunomodulatory strategies for pneumonia treatment. Systematic health care provider and institutional improvements can decrease mortality rates in CAP, particularly in patients with increasingly complex comorbidities. Aspects of current guidelines for the diagnosis and treatment of fungal pneumonia were reviewed through a series of case presentations. Proper treatment of pneumonia hinges on correct pathogen identification but is complicated by the variety of diagnostic assays with variable specificity, sensitivity, and interpretation. In addressing this topic, Dr. Patrick Murray, Ph.D., discussed a range of diagnostic tests for a variety of pathogens and guidelines for their use. In addition to the current state of CAP treatment, Bill (Beibei) Chen, M.D., Ph.D., presented a new potential therapeutic agent called forsythin, an immunomodulatory compound derived from a plant used in traditional Chinese medicine. These topics, ranging from institution-sized policy to interactions at the molecular scale, paint a broad perspective of the efforts against pneumonia.

Chronic passive hepatic congestion (congestive hepatopathy) leads to hepatic fibrosis; however, the mechanisms involved in this process are not well understood. We developed a murine experimental model of congestive hepatopathy through partial ligation of the inferior vena cava (pIVCL). C57BL/6 and transgenic mice overexpressing tissue factor pathway inhibitor (SM22α‐TFPI) were subjected to pIVCL or sham. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, real‐time polymerase chain reaction, and western blot assays. Hepatic fibrosis and portal pressure were significantly increased after pIVCL concurrent with hepatic stellate cell (HSC) activation. Liver stiffness, as assessed by magnetic resonance elastography, correlated with portal pressure and preceded fibrosis in our model. Hepatic sinusoidal thrombosis as evidenced by fibrin deposition was demonstrated both in mice after pIVCL as well as in humans with congestive hepatopathy. Warfarin treatment and TFPI overexpression both had a protective effect on fibrosis development and HSC activation after pIVCL. In vitro studies show that congestion stimulates HSC fibronectin (FN) fibril assembly through direct effects of thrombi as well as by virtue of mechanical strain. Pretreatment with either Mab13 or Cytochalasin‐D, to inhibit β‐integrin or actin polymerization, respectively, significantly reduced fibrin and stretch‐induced FN fibril assembly. Conclusion : Chronic hepatic congestion leads to sinusoidal thrombosis and strain, which in turn promote hepatic fibrosis. These studies mechanistically link congestive hepatopathy to hepatic fibrosis. (H epatology 2015;61:648‐659)

Purpose Lenalidomide has significant single-agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). We demonstrated that lenalidomide can be safely combined with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone); this new combination is known as R2CHOP. The goal of this phase II study was to evaluate the efficacy of this combination in newly diagnosed DLBCL. Patients and Methods Eligible patients were adults with newly diagnosed untreated stages II to IV CD20 + DLBCL. Patients received lenalidomide 25 mg orally per day on days 1 through 10 with standard-dose R-CHOP every 21 days for six cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout. DLBCL molecular subtype was determined by tumor immunohistochemistry and classified as germinal center B-cell (GCB) versus non-GCB in the R2CHOP patients and 87 control patients with DLBCL from the Lymphoma Database who were treated with conventional R-CHOP. Results In all, 64 patients with DLBCL were enrolled, and 60 were evaluable for response. The overall response rate was 98% (59 of 60) with 80% (48 of 60) achieving complete response. Event-free survival and overall survival (OS) rates at 24 months were 59% (95% CI, 48% to 74%) and 78% (95% CI, 68% to 90%), respectively. In R-CHOP patients, 24-month progression-free survival (PFS) and OS were 28% versus 64% (P < .001) and 46% versus 78% (P < .001) in non-GCB DLBCL versus GCB DLBCL, respectively. In contrast, there was no difference in 24-month PFS or OS for R2CHOP patients on the basis of non-GCB and GCB subtype (60% v 59% [P = .83] and 83% v 75% [P = .61] at 2 years, respectively). Conclusion R2CHOP shows promising efficacy in DLBCL. The addition of lenalidomide appears to mitigate a negative impact of non-GCB phenotype on patient outcome.

Abstract Background: Gliomas are primary malignant brain tumors with significant morbidity and mortality. Single nucleotide polymorphisms (SNPs) mapped to 8q24 have been shown to be associated with glioma development. Recently, we identified seven SNPs (through tag SNP genotyping/imputation, pooled next-generation sequencing using long-range PCR, and validation SNP genotyping) that are highly associated with the risk of developing glioma. After stratifying by histologic and tumor subtype, one SNP, rs55705857, in the 8q24.21 region near CCDC26 was significantly associated with oligodendroglial tumors and IDH mutated astrocytic gliomas with high odds ratios (ORs ∼6.0) (Jenkins et al. Nature Genet. 44:1122;2012). By array comparative genomic hybridization (aCGH), a significant proportion of oligodendroglial tumors and IDH mutated astrocytomas have been shown to duplicate 8q24 (Kitange et al., Genes Chr Cancer 42:68;2005; Nousmehr et al. Cancer Cell 17:510;2010). We were interested in learning if the germline risk allele of rs55705857 is associated with gliomas that duplicate 8q24. We were also interested in learning if the risk allele is preferentially gained in gliomas that duplicate 8q24. Methods: We performed aCGH on 217 tumor samples. rs55705857 germline genotype was available on 120 of the patients; of which 30 carried the risk (G) allele. In addition, we sequenced the rs55805857 region in 48 gliomas, 15 of which exhibited gain or duplication of chromosome 8, 8q, or 8q24. The ratio of the Sanger-sequencing peak heights at and around rs55705857 was used to determine which allele (risk or wild-type) was gained. Results: All 15 duplications included rs55705857 and the immediately adjacent regions. Of the 30 patients who carried the germline risk (G) allele for rs55707857, 8 (26.7%) exhibited duplication of 8q24 upon aCGH analysis of their glioma. Of the 90 patients who only carried the wild-type (A) allele, 7 (7.5%) exhibited duplications of 8q24 upon aCGH analysis of their glioma. This difference in proportion is statistically significant (p=0.024, Fischer exact test). Of the 15 tumors with duplication of 8q24, 8 came from patients who were germline rs55705857 heterozygotes (AG). Of these 8 germline heterozygotes with duplication of 8q24, 4 gained the risk (G) allele, 2 gained the wild-type (A) allele and 2 exhibited gain of both alleles in their tumor specimens. Conclusions: While the results require replication, our data suggest that carrying the risk allele for rs55705857 predisposes to the development of gliomas that subsequently duplicate 8q24. However, gliomas with duplication of 8q24 do not preferentially gain the risk rs55705857 allele. This result implies that, while the duplication always includes the rs55705857 region, the risk allele or region is not the direct target of the duplication. Citation Format: Amanda L. Rynearson, Kirsten A. Schowalter, Stephanie R. Fink, Thomas M. Kollmeyer, Chandralekha Halder, Gobinda Sarkar, Alissa A. Caron, Rachel A. Pauley, Daniel H. Lachance, Brian Patrick O'Neill, Robert B. Jenkins. The germline rs55705857 risk allele is not preferentially gained in gliomas with 8q24 duplication. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4207. doi:10.1158/1538-7445.AM2013-4207

Abstract Introduction. Up to now PCNSL incidence in the US was presumed to be increasing in all age groups independent of changes in nosology, new diagnostic techniques, and HIV infection. The intent of our study was, firstly, to extend our prior study of PCNSL incidence in the US (Olson et al, Cancer 2002;95:1504-10) with an additional decade of SEER data; and, secondly, to determine time trends during the HAART era in the US. Methods. PCNSL age-adjusted incidence rates from 1973-2007 were obtained from the nine SEER registries used in the Olson et al. study. Similarly, the same exclusion criteria were used to remove PCNSL most likely associated with HIV (never married males and females; persons of unknown marital status; all cases reported in the San Francisco registry). To assess the accuracy of the criteria in removing HIV associated cases, incidence rates of Kaposi sarcoma (KS) were assessed with and without the use of the same exclusion criteria. Results. The incidence of PCNSL in the general population decreased from 1995 to 2000. Following this decrease, the incidence stabilized and is now beginning to increase in the last 5 years. Stratifying the incidence rate by age group and employing the exclusion criteria, PCNSL incidence has remained stable in the 20-64 year old population, but has steadily increased in the 65+ population. Removing the exclusion criteria did not alter the data for the 65+ population but demonstrated a sharp drop in incidence after 1996 for the 20-64 year old population. Applying the same HIV exclusion criteria the incidence of KS resulted in no appreciable change in incidence rates over the same time frame. Conclusion. The incidence rate of PCNSL is increasing. This increase is driven by a continued increase in incidence among the 65+ population while the incidence for those aged 20-64 has stabilized during the same time frame. An effect of HAART on PCNSL incidence in the US is suggested by the decline in the incidence among the 20-64 year old population without the HIV exclusion criteria. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1926. doi:10.1158/1538-7445.AM2011-1926

Abstract Background: Estrogen receptor beta (ERβ), unlike ERα, classically functions as a tumor suppressor in vitro. However, ERβ's biological functions in vivo and predictive/prognostic value in breast cancer are controversial. Methods: Expression of ERβ protein was determined using a well characterized and validated ERβ specific monoclonal antibody that only recognizes the full-length form of this receptor (PPG5/10) in the following 3 cohorts: 1) a cohort with all breast cancer subtypes (n = 182), 2) a prospective NCCTG adjuvant tamoxifen trial for postmenopausal women with ERα positive breast cancer with long-term follow-up (n = 198) and 3) a cohort of 80 triple negative breast cancers (TNBCs). To elucidate the biological functions of ERβ in breast cancer, novel ERβ expressing MCF7 and MDA-MB-231 cell lines were developed and characterized using multiple techniques and were examined for responsiveness to various ERβ targeted therapies. Results: About one-third of all breast tumors, regardless of sub-type, were shown to express nuclear ERβ and this expression was independent of ERα or HER2. In the NCCTG 89-30-52 cohort, breast cancer recurrence rates were significantly associated with ERβ protein expression with 10 year recurrence rates of 25%, 15% and 4% for zero, low or high levels of ERβ expression respectively. Interestingly, in TNBCs, nuclear ERβ was expressed at intermediate or high levels in 24% of tumors. In the triple negative MDA-MB-231 cell line, expression of ERβ led to inhibition of proliferation and induction of apoptosis in response to estrogen and multiple ERβ specific agonists. Conversely, these same treatments induced proliferation of ERβ-expressing MCF7 cells which endogenously express ERα. However, ERβ expression sensitized MCF7 cells to the anti-proliferative effects of anti-estrogens. Microarray analysis and RT-PCR profiling of MDA-MB-231-ERβ cells revealed that estrogen and ERβ agonists highly induced the expression of multiple cystatins, a family of small secreted cysteine protease inhibitors which function as tumor suppressors, and potently inhibited canonical TGFβ signaling. Conditioned media isolated from estrogen or ERβ agonist treated MDA-MB-231-ERβ cells suppressed the proliferation rates and inhibited TGFβ signaling in other TNBC cell lines, effects that were completely reversed following the depletion of cystatins from the conditioned media. Conclusions: These data demonstrate that ERβ is expressed in a substantial proportion of breast cancers and may have value as a predictive and/or prognostic biomarker. Therapeutic targeting of ERβ may have clinical benefit in multiple breast cancer sub-types; however, the specific drug of choice may vary based on ERα status. Specifically, we have demonstrated that ERβ expression in ERα+ MCF7 cells sensitizes them to the effectiveness of anti-estrogens, an observation that was confirmed in women enrolled in a prospective adjuvant tamoxifen trial. In TNBCs, where targeted therapies are lacking, our data suggest that targeting ERβ with either estrogen or ERβ specific agonists will elicit anti-tumor effects through the induction of cystatins and inhibition of TGFβ signaling resulting in tumor regression and improved patient outcomes. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-03.

Several groups have reported cases of rectal cancer with carcinomatous involvement of the lumbosacral plexus and sciatic, obturator, pudendal, or spinal nerves. To our best knowledge, clear examples of perineural tumor spread in rectal carcinoma have not yet been described. We retrospectively reviewed clinical data and imaging studies of three patients with primary or recurrent rectal cancer involving the lumbosacral plexus. Imaging studies included MRI and 18FDG PET/CT scans in all (n = 3) patients, histological samples were available in two (n = 2). Imaging studies demonstrated distinct features of tumor spread from the organ to the plexus and beyond in all cases (n = 3), histological specimens demonstrated perineural involvement thus supporting our theory (n = 2). We present these three cases of perineural tumor spread in rectal cancer as a proof of concept. We hypothesize that not only our cases, but other similar reported cases can be explained anatomically by extension of the rectal cancer to the inferior hypogastric plexus with perineural tumor spread to the lumbosacral plexus using the pelvic and sacral splanchnic nerves as conduits. Once the tumor reaches the lumbosacral plexus, it can continue to spread proximally or distally. We believe that perineural spread of colon cancer represents an important, under‐recognized mechanism of recurrence to neighboring major nerves in the pelvis. Clin. Anat. 28:136–143, 2015. © 2014 Wiley Periodicals, Inc.

ABSTRACT Purpose To present and discuss a case of herniation of subconjunctival orbital fat, a very rare but benign condition. Case Report An 84‐year‐old man presented to the eye clinic for a cataract surgery consultation but also had a secondary complaint about yellow lesions on the bulbar conjunctiva of both eyes. Examination with biomicroscopy revealed protruding orbital masses superotemporally in both eyes, with the right lesion being larger than the left. After thorough testing, these lesions were diagnosed as being subconjuntival herniated orbital fat (HOF), and the patient underwent surgical excision of the lesions. Conclusions In cases of HOF, appropriate and accurate testing is essential, as this condition can mimic several other neoplasms, all of which require specialized treatment strategies. If cosmesis is unacceptable to the patient or the lesion impedes normal ocular function, a subconjunctival excision of the excess fat may be performed with little concern of recurrence. This article discusses a case of HOF, with an explanation of testing and treatment options.

AbstractBackgroundThe utility of diagnostic imaging in paraneoplastic autoimmune multiorgan syndrome (PAMS) is unknown.MethodsWe examined the role of diagnostic imaging in patients with PAMS evaluated at our tertiary referral center (at Mayo Clinic, Rochester, MN, USA) and in the English literature between January 1, 1996, and August 31, 2012.ResultsWe included 17 patients from our institution and 208 patients from the literature review. Of these 225 patients, 113 (50.2%) were not known to have a malignancy diagnosis at the time of PAMS diagnosis. Of the 123 patients from our institution and from the literature reported to undergo imaging studies, conventional computed tomography (CT) was the predominant imaging modality (n = 110; 89.4%); 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET)/CT was also used, albeit infrequently (n = 12; 9.8%). When CT was included in imaging to identify or confirm the presence of a malignancy, imaging was successful in all patients who ultimately were diagnosed with an associated malignancy. At our institution, a relatively high percentage (n = 7; 41%) of patients had 18F‐FDG PET/CT, which not only identified all tumors found on CT but also facilitated staging of lymphoma and guided biopsy procedures.ConclusionDiagnostic imaging is frequently utilized in PAMS with unknown malignancy. Both conventional CT and 18F‐FDG PET/CT are likely to detect the typical underlying neoplasms. Relative to conventional CT, 18F‐FDG PET/CT may provide additional useful information regarding prognosis for the likely underlying malignancies, although there is a paucity of reports describing the use of this modality for this purpose.

BackgroundTricuspid annular plane systolic excursion measured by M‐mode (MM‐TAPSE) has been validated as a marker of right ventricular systolic performance. A similar measurement by 2D imaging (2D‐TAPSE) can be obtained. We sought to determine the correlation and strength of agreement between MM‐TAPSE and 2D‐TAPSE in children.MethodsEchocardiographic studies performed for clinical indications were reviewed retrospectively. All consecutive subjects ≤18 years of age were included. The cohort was divided into those with normal echocardiographic findings and those with disorders affecting the right ventricle. Digitally recorded images were analyzed for both MM‐TAPSE and 2D‐TAPSE. Measurements of 2D‐TAPSE were made in an apical four‐chamber view, from the tricuspid valve annulus to a consistent point at the apex of the imaging sector at end‐diastole and end‐systole, with the difference representing the 2D‐TAPSE value.ResultsA total of 329 subjects (mean age 9.0 ± 6.1 years) met entry criteria. Correlation coefficient between MM‐TAPSE and 2D‐TAPSE was 0.90. Bland–Altman analysis showed agreement between the two methods to be within 1.2 ± 2.6 mm (mean percentage difference of 6.5%). About 1 mm difference between MM‐TAPSE and 2D‐TAPSE was consistently observed in all diagnostic subgroups, and across all age categories.ConclusionMM‐TAPSE and 2D‐TAPSE correlate strongly, with 2D‐TAPSE being consistently about 1 mm less than values obtained by the M‐mode technique. We conclude that 2D‐TAPSE can provide a reliable alternative to MM‐TAPSE to quantitatively measure right ventricular systolic function and may be especially useful in situations where retrospective comparisons are sought.