Molecular Profiles of Brain and Pulmonary Metastatic Disease in Cancer of Unknown Primary.

Cancers of unknown primary (CUP) are histologically confirmed malignancies but for which further investigation cannot identify a primary site. Improvements in histopathologic modalities for diagnosis have lessened the frequency of CUPs to 3%-5% of all malignancies compared with historical estimates of 5%-10%. Despite this, there is an ongoing debate as to whether CUPs are malignancies where the primary is not found or if they are otherwise a fully separate entity. Improvements in molecular analysis holds promise for improved identification and treatment of CUPs with mixed preliminary results. Here we present a woman with CUP and metastases in her brain and lung. We performed genomic profiling to compare the molecular makeup of each site in order to establish treatment targets. KEY POINTS: Cancer of unknown primary remains a diagnostic and therapeutic challenge. Molecular analysis may provide improvements in diagnosis and novel treatment options. Different sites of metastatic disease have subtle variations in molecular profile. Sequencing of different sites may offer therapeutic options that are either already approved or available in clinical trial.

Cystic neutrophilic granulomatous mastitis with corynebacterium and staphylococcus mimicking breast carcinoma.

Cystic neutrophilic granulomatous mastitis (CNGM) is an increasingly recognized entity in the differential diagnosis of granulomatous inflammation involving the breast. We present the first case report of CNGM mimicking carcinoma of the breast with two mixed bacterial species as the causative pathogens (Corynebacterium and Staphylococcus spp.).

IgG4 Aortitis: A Case Report.

IgG4 aortitis is one of the entities seen in the spectrum of IgG4-related disease (IgG4-RD). It is characterized by serologic (elevated serum IgG4) and histologic features including a lymphoplasmacytic infiltrate with increased numbers of IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis. Some studies have described a correlation between infections and IgG4 aortitis. We describe a patient with an aneurysm of the infrarenal descending abdominal aorta with features of IgG4-RD, as well as culture evidence of Streptococcus sanguis. [Full article available at http://rimed.org/rimedicaljournal-2017-04.asp].

Epstein-Barr virus associated hemophagocytic lymphohistiocytosis in a rheumatic patient receiving abatacept therapy.

Hemophagocytic lymphohistiocytosis (HLH) is a life- threatening hyperinflammatory disease that causes extensive organ damage. It is generally triggered by viral, fungal, or parasitic infections in the setting of hematologic disease-induced immune deficiency. Occurrences in rheumatologic disease are less frequent, with the syndrome developing most often in patients with systemic lupus erythematosus and adult-onset Still disease. It is believed that the immunosuppression induced by rheumatologic disease itself and exacerbation by immunomodulatory therapies predispose to infection and subsequently HLH. Abatacept is a relatively new disease-modifying agent for rheumatoid arthritis (RA) that has been associated with varicella zoster virus, cytomegalovirus, and Epstein-Barr virus (EBV) infections, but not previously in the setting of HLH. Here we report a unique case of EBV-associated HLH in a RA patient receiving abatacept therapy.

Immunohistochemistry of colorectal carcinoma: current practice and evolving applications.

The relatively high incidence of adenocarcinoma of the colon and rectum (colorectal carcinoma) in the general population makes its pathologic diagnosis one of the more frequent exercises in anatomical pathology. Although typically mundane in the primary setting, the correct identification of metastatic colorectal carcinoma or exclusion of metastatic disease from carcinoma arising in other anatomical foci can be problematic. The advent of targeted therapies and refinement of more traditional cytotoxic chemotherapeutic regimens mandates not only a more confident appraisal of site of origin but also assessment of those tumor-specific features that may alter therapeutic decisions. Despite the exponential increase in our understanding of the molecular pathogenesis of colorectal carcinoma, immunohistochemistry remains the foundation for resolution of these problematic cases and the number of antibodies available to the practicing pathologist continues to expand at a steady rate. In some cases, immunohistochemistry may also provide valuable prognostic information, either independently or as a surrogate marker for a specific route of carcinogenesis such as microsatellite instability. This review will focus on the use of new and more established immunohistochemistry markers in the diagnosis of colorectal carcinoma, with an emphasis on aberrant staining patterns of the various colorectal carcinoma subtypes as well as the utility of these markers in specific differential diagnostic settings.

Meeting the biologic challenge of colorectal metastases.

An overview of colorectal cancer discussed (Philip Paty) the good outcome after primary management with local control in 90-95 % of colon and 85 % in rectal cancer patients with major progression to metastases and to death related to hematogenous dissemination. The major disease pathways include the APC, aneuploid pathway involving mutations of P53, KRAS, SMAD 4, or the CMP/MSI pathway, mismatched repair defect as characterized by Lynch syndrome, the major hereditary form which may also have KRAS and P53 mutations. The common sporadic colorectal cancers are MS1 high, with many patients having BRAF and KRAS mutations. The sentinel node biopsy in colorectal cancer surgery may provide more definitive staging and perhaps modification of the extent of resection with better outcome as suggested by Dr. Saha. The identification of sentinel lymph nodes outside of the planned bowel resection may increase the resection biologically indicated by the sentinel lymph node location leading to better outcome. In a small study by Dr. Saha, the operation was enhanced in 21 % by extending the length of bowel resection, which increased node recovery to 18.5 nodes versus 12 nodes with the more conventional resection, increasing nodal recovery, and positivity to 60 % with reduction to five year recurrence rate to 9 % versus 27 % with the conventional resection. A new (Swiss) technique for pathologic node examination, the OSNA (the One Step Nucleic Acid diagnostic system), was presented which demonstrated increased detection of micro-metastases in a focused pathology study of 22 patients (Zuber) to 11 out of 15 patients versus the 7 micro-metastases identified by the standard single slide per node, and compared to 14 out of 15 with an intensive multi-slide technique. This suggests value in pursuing OSNA study by other centers with relevant clinical trials to establish its true value. An analysis of liver resection for metastatic colorectal cancer (CRC) emphasized the value of 10-year follow-up (DeAngelica). The 10-year survival of 102 patients among 612 patients was 17 % (Memorial Sloan Kettering data). At the five-year point 99 of 102 survivors were NED and 86 have been free of disease since the resection. The usual five-year figure after hepatic resection reveals that one-third of five-year survivors die from recurrence of distant disease suggesting the value of longer term follow-up in these patients. An additional question reviewed related to the role of neoadjuvant systemic chemotherapy (with response rates in the 50 % range) to produce down staging of the hepatic metastases and allow one to retrieve these patients with possible residual disease. In a series of 116 patients who had hepatic resection of CRC metastases in presence of regional node metastases, post neoadjuvant chemotherapy (normally not candidates for resection) these patients were demonstrated to have a 95 % recurrence at median time of 9 months. This raises a cautionary note to the literature report of five-year survivals in the 20-30 % range for hepatic metastases in presence of extra hepatic disease. Such may reflect patient selection rather than a true measure of the biology of disease, and warrant clinical trial evaluation. Lastly, regional therapy and overall systemic therapy were addressed by Dr. Kemeny. The CALGB study of hepatic artery infusion (HAI) with FUDR, dexamethasone versus 5FU leucovorin showed an overall survival of 24.4 months with HAI versus 20 months with systemic therapy (P = 0.0034). An adjuvant trial of HAI at MSK in 156 patients showed an overall survival benefit at 2 year and recent long term 10yr follow-up showing a significant overall survival of 41 % with HAI versus 27 % with systemic therapy (5FU leucovorin). In the neoadjuvant Nordlinger trial for hepatic metastases, there was a significant outcome differences-the preoperative therapy group had 9.2 % increase of progression free survival versus the surgery alone group which suggests the value of combining neoadjuvant surgery in good risk liver resection candidates. Conclude the final lesson from this well presented mini symposium confirms the need for continued evaluation of the numerous discussion points by clinical trial.

Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach.

There has been an increasing role for molecular diagnostics in the diagnosis and management of cancer, and colorectal carcinoma is no exception. Recent molecular advances have elucidated 3 broad molecular subtypes of colorectal cancer, including chromosomal instability, microsatellite instability, and cytosine-phosphoguanine island methylator phenotype, which will be discussed. Also, the common syndromes associated with colorectal carcinoma will be reviewed with a focus on the differentiation between Lynch syndrome and microsatellite unstable tumors. Molecular biomarkers for predictive and prognostic markers are also becoming widely used, and due to the clinical use of monoclonal antibodies to the epidermal growth factor receptor, an emphasis is placed on that pathway.

Massive cardiac fibroma.

Nonmyxomatous tumors of the heart are exceedingly rare in adults. We report a case of symptomatic, massive, right ventricular cardiac fibroma found in an adult. Despite multiple (preoperative) biopsies, diagnosis was made only after surgical excision.

The dual functions of receptor interacting protein 1 in fas-induced hepatocyte death during sepsis.

In examining the liver's response to sepsis, our laboratory has found that septic hepatocytes exhibit a higher degree of necrosis when compared with septic thymocytes, which typically die through the canonical apoptotic pathway. Recently, an adaptor protein associated with the Fas/TNF death receptor pathway, receptor interacting protein 1 (RIP1), has been shown to be critical for determining whether a cell's death is apoptotic or necrotic. We propose to test the central hypothesis that RIP1 activation by death receptor (Fas) during sepsis determines whether the hepatocytes' fate is apoptotic versus necrotic. We approached this problem by delivering RIP1 siRNA in vivo to C57BL/6 mice and observing changes in mortality after septic challenge. Contrary to our hypothesis, RIP1-silenced mice did not survive as long as scrambled sequence injected controls (22.2% vs. 50.0% 14 days after cecal ligation and puncture, respectively). When we used a pharmacological/synthetic antagonist of RIP1 kinase, necrostatin 1 (Nec1), and examined the mortality of Nec1-treated mice, there was no difference from the RIP1 siRNA-treated mice (20.0% vs. 22.2%, respectively). Furthermore, we carried out a series of comparative histological studies, which indicated that septic mice pretreated with Nec1 exhibited a preservation of liver glycogen stores (represented by periodic acid Schiff stain) versus siRNA-treated mice, which exhibit lower glycogen stores as well as altered morphology. Furthermore, the histological studies also revealed that Nec1 treatment in septic mice increases caspase 3 activity. We speculate that these contradictatory findings are due to the dual-signaling responsibilities of RIP1, where the RIP1 kinase domain can induce death through Fas ligation while also initiating prosurvival signaling through nuclear factor κB (NF-κB).

Pathobiology of colorectal cancer hepatic metastases with an emphasis on prognostic factors.

Colorectal cancer is the second leading cause of cancer related death in the United States. The majority of these deaths are due to metastasis, with the liver easily accounting as the most common site of deposit. While there are multiple steps in the CRC hepatic metastatic cascade, this review attempts to summarize the different processes involved, focusing on the most recent discoveries, as well as the associated effects in relation to prognosis.

A human immunodeficiency virus-positive infant with probable congenital histoplasmosis in a nonendemic area.

A 5-week-old infant presented with a fever, and was diagnosed with congenital human immunodeficiency virus and histoplasmosis. Both infections were likely transmitted vertically. The child was effectively treated with antifungal medications and highly active antiretroviral therapy. This represents the first case of delayed presentation of vertically transmitted histoplasmosis, and the first case in a nonendemic area.

Florid histiocytic hemophagocytosis following therapy with long acting G-CSF (pegfilgrastim).

We describe a case of histiocytic hemophagocytosis and increase in blasts in the bone marrow after administration of long acting G-CSF (pegfilgrastim) in a 71-year-old man with underlying myelodysplasia. Pegfilgrastim was discontinued, with resolution of the hemophagocytosis and marked decrease in blasts from 30 to 5%. We postulate that pegfilgrastim provided a continuous stimulation of the monocyte/macrophage system, resulting in histiocytic hemophagocytosis. We recommend caution in defining indications for the use of long acting preparations of G-CSF.

Synthesis and biologically relevant properties of polyphosphazene polyacids.

Polyphosphazene polyacids show potential as immunostimulating compounds and materials for microencapsulation. Their synthesis requires multistep chemical transition from a hydrolytically unstable macromolecular precursor, poly(dichlorophosphazene), to a water-soluble polyelectrolyte. Insufficient synthetic control in these reactions can lead to molecular weight variations and formation of macromolecules with "structural defects" resulting in significant variations in polymer performance. Simple and reproducible "one pot-one solvent" method is reported for the preparation of polyphosphazene polyacids-poly[di(carboxylatophenoxy)phosphazene] and its copolymers. Molecular weight characteristics and polymer compositions were studied as a function of reaction parameters. Macromolecular byproducts, incompletely substituted polymers containing hydroxyl groups and partially deprotected polymers containing propyl ester functionalities, were synthesized and characterized. It was demonstrated, that the presence of such groups can affect polymer characteristics, such as hydrolytic degradation profiles, immunostimulating activity, and microsphere forming properties. In vivo studies showed that the immunostimulating activity of polyphosphazene polyacids correlates with the content of acid functionalities in the polymer.