Dushyant V. Sahani

Consensus statement on the pathology of IgG4-related disease.

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and—often but not always—elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4–7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4+ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study

PURPOSE To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. PATIENTS AND METHODS In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m(2)/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. RESULTS Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome. CONCLUSION Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.

Biomarkers of response and resistance to antiangiogenic therapy

No validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer for antiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I–III studies. Some of these are measured at baseline (for example VEGF polymorphisms), others are measured during treatment (such as hypertension, MRI-measured Ktrans, circulating angiogenic molecules or collagen IV), and all are mechanistically based. Some of these biomarkers might be pharmacodynamic (for example, increase in circulating VEGF, placental growth factor) while others have potential for predicting clinical benefit or identifying the escape pathways (for example, stromal-cell-derived factor 1α, interleukin-6). Most biomarkers are disease and/or agent specific and all of them need to be validated prospectively. We discuss the current challenges in establishing biomarkers of antiangiogenic therapy, define systemic, circulating, tissue and imaging biomarkers and their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of antiangiogenic therapy.

Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.

PURPOSE To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response. PATIENTS AND METHODS We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment. RESULTS Thirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1alpha, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome. CONCLUSION Sunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC.

Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations

John H. Stone, Arezou Khosroshahi, Vikram Deshpande, John K. C. Chan, J. Godfrey Heathcote, Rob Aalberse, Atsushi Azumi, Donald B. Bloch, William R. Brugge, Mollie N. Carruthers, Wah Cheuk, Lynn Cornell, Carlos Fernandez-Del Castillo, Judith A. Ferry, David Forcione, Gunter Kloppel, Daniel L. Hamilos, Terumi Kamisawa, Satomi Kasashima, Shigeyuki Kawa, Mitsuhiro Kawano, Yasufumi Masaki, Kenji Notohara, Kazuichi Okazaki, Ji Kon Ryu, Takako Saeki, Dushyant Sahani, Yasuharu Sato, Thomas Smyrk, James R. Stone, Masayuki Takahira, Hisanori Umehara, George Webster, Motohisa Yamamoto, Eunhee Yi, Tadashi Yoshino, Giuseppe Zamboni, Yoh Zen, and Suresh Chari

Reducing abdominal CT radiation dose with adaptive statistical iterative reconstruction technique.

Purpose:To assess radiation dose reduction for abdominal computed tomography (CT) examinations with adaptive statistical iterative reconstruction (ASIR) technique. Materials and Methods:With institutional review board approval, retrospective review of weight adapted abdominal CT exams were performed in 156 consecutive patients with ASIR and in 66 patients with filtered back projection (FBP) on a 64-slice MDCT. Patients were categorized into 3 groups of <60 kg (n = 42), 61 to 90 kg (n = 100), and ≥91 kg (n = 80) for weight-based adjustment of automatic exposure control technique. Remaining scan parameters were held constant at 1.375:1 pitch, 120 kVp, 55 mm table feed per rotation, 5 mm section thickness. Two radiologists reviewed all CT examinations for image noise and diagnostic acceptability. CT dose index volume, and dose length product were recorded. Image noise and transverse abdominal diameter were measured in all patients. Data were analyzed using analysis of variance. Results:ASIR allowed for an overall average decrease of 25.1% in CT dose index volume compared with the FBP technique (ASIR, 11.9 ± 3.6 mGy; FBP, 15.9 ± 4.3 mGy) (P < 0.0001). In each of the 3 weight categories, CT examinations reconstructed with ASIR technique were associated with significantly lower radiation dose compared with FBP technique (P < 0.0001). There was also significantly less objective image noise with ASIR (6.9 ± 2.2) than with FBP (9.5 ± 2.0) (P < 0.0001). For the subjective analysis, all ASIR and FBP reconstructed abdominal CTs had optimal or less noise. However, 9% of FBP and 3.8% of ASIR reconstructed CT examinations were diagnostically unacceptable because of the presence of artifacts. Use of ASIR reconstruction kernel results in a blotchy pixilated appearance in 39% of CT sans which however, was mild and did not affect the diagnostic acceptability of images. The critical reproduction of visually sharp anatomic structures was preserved in all but one ASIR 40% reconstructed CT examination. Conclusion:ASIR technique allows radiation dose reduction for abdominal CT examinations whereas improving image noise compared with the FBP technique.

Serous Cystadenoma of the Pancreas: Tumor Growth Rates and Recommendations for Treatment

Objective:To define the natural history and optimal management of serous cystadenoma of the pancreas. Summary Background Data:Serous cystadenoma of the pancreas is the most common benign pancreatic neoplasm. Diagnostic criteria, potential for growth or malignancy, and outcomes are not well defined. As a result, management for patients with serous cystadenomas varies widely in current practice. Methods:A total of 106 patients presenting with serous cystadenoma of the pancreas from 1976–2004 were identified. Hospital records were evaluated for patient and tumor characteristics, diagnostic workup, treatment, and outcome. Twenty-four patients with serial radiographic imaging were identified, and tumor growth curves calculated. Results:Mean age at presentation was 61.5 years and 75% of patients were female. The most common symptoms were abdominal pain (25%), fullness/mass (10%), and jaundice (7%); 47% were asymptomatic. Mean tumor diameter was 4.9 ± 3.1 cm, which did not vary by location. Tumors <4 cm were less likely to be symptomatic than were tumors ≥4 cm (22% vs. 72%, P < 0.001). The median growth rate in the patients who had serial radiography was 0.60 cm/y. For tumors <4 cm at presentation (n = 15), the rate was 0.12 cm/y, whereas for tumors ≥4 cm (n = 9), the rate was 1.98 cm/y (P = 0.0002). Overall, 86 patients underwent surgery, with one perioperative death. Conclusions:Large (>4 cm) serous cystadenomas are more likely to be symptomatic. Although the median growth rate for this neoplasm is only 0.6 cm/y, it is significantly greater in large tumors. Whereas expectant management is reasonable in small asymptomatic tumors, we recommend resection for large serous cystadenomas regardless of the presence or absence of symptoms.

Hepatobiliary-specific MR Contrast Agents: Role in Imaging the Liver and Biliary Tree

Hepatobiliary-specific contrast agents are one of several classes of contrast agents available for magnetic resonance (MR) imaging of the liver. These agents are taken up by functioning hepatocytes and excreted in the bile, and their paramagnetic properties cause shortening of the longitudinal relaxation time (T1) of the liver and biliary tree. The three contrast agents that have been developed are mangafodipir trisodium (Mn-DPDP), gadobenate dimeglumine (Gd-BOPTA), and gadoxetic acid (Gd-EOB-DTPA). These three MR contrast agents vary in mode of administration and dose, mechanism of cellular uptake, degree of excretion through the biliary pathway, and imaging characteristics. In the liver, hepatobiliary-specific agents can be used to improve lesion detection, to characterize lesions as hepatocellular or nonhepatocellular, and to specifically characterize some hepatocellular lesions, notably focal nodular hyperplasia. Biliary excretion of these agents can be used to evaluate the anatomic structure and function of the biliary tree. In the future, hepatobiliary-specific contrast agents may have wider applications, such as grading of cirrhosis and quantification of liver function.

HCC and angiogenesis: possible targets and future directions

Hepatocellular carcinoma (HCC), the most common primary liver tumor, is notoriously resistant to systemic therapies, and often recurs even after aggressive local therapies. HCCs rely on the formation of new blood vessels for growth, and VEGF is critical in this process. A hallmark of new vessel formation in tumors is their structural and functional abnormality. This leads to an abnormal tumor microenvironment characterized by low oxygen tension. The liver is perfused by both arterial and venous blood and the resulting abnormal microenvironment selects for more-aggressive malignancies. Anti-VEGF therapy with sorafenib was the first systemic therapy to demonstrate improved survival in patients with advanced-stage HCC. This important development in the treatment of HCC raises hope as well as critical questions on the future development of targeted agents including other antiangiogenic agents, which hold promise to further increase survival in this aggressive disease.

Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: The Framingham heart study

Obesity is not uniformly associated with the development of metabolic sequelae. Specific patterns of body fat distribution, in particular fatty liver, may preferentially predispose at‐risk individuals to disease. In this study, we characterize the metabolic correlates of fat in the liver in a large community‐based sample with and without respect to visceral fat. Fatty liver was measured by way of multidetector computed tomography of the abdomen in 2,589 individuals from the community‐based Framingham Heart Study. Logistic and linear regression were used to determine the associations of fatty liver with cardio‐metabolic risk factors adjusted for covariates with and without adjustment for other fat depots (body mass index, waist circumference, and visceral adipose tissue). The prevalence of fatty liver was 17%. Compared with participants without fatty liver, individuals with fatty liver had a higher adjusted odds ratio (OR) of diabetes (OR 2.98, 95% confidence interval [CI] 2.12‐4.21), metabolic syndrome (OR 5.22, 95% CI 4.15‐6.57), hypertension (OR 2.73, 95% CI 2.16‐3.44), impaired fasting glucose (OR 2.95, 95% CI 2.32‐3.75), insulin resistance (OR 6.16, 95% CI 4.90‐7.76); higher triglycerides, systolic blood pressure (SBP), and diastolic blood pressure (DBP); and lower high‐density lipoprotein (HDL) and adiponectin levels (P < 0.001 for all). After adjustment for other fat depots, fatty liver remained associated with diabetes, hypertension, impaired fasting glucose, metabolic syndrome, HDL, triglycerides, and adiponectin levels (all P < 0.001), whereas associations with SBP and DBP were attenuated (P > 0.05). Conclusion: Fatty liver is a prevalent condition and is characterized by dysglycemia and dyslipidemia independent of visceral adipose tissue and other obesity measures. This work begins to dissect the specific links between fat depots and metabolic disease. (HEPATOLOGY 2010;)