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Arctic food systems are increasingly challenged by rapid climate change, loss of food security and subsequent weakening of food sovereignty, and destabilization of Indigenous practices. Despite growing scientific knowledge on Arctic food systems, Indigenous communities continue to struggle with a plethora of sustainability challenges. To develop a systemic understanding of these challenges, we performed a systematic review of 526 articles published between 1998 and 2021 on Arctic Indigenous food systems. We used the leverage points framework to structure our analysis to understand to what extent the existing Western scientific body of literature provides the necessary knowledge to understand the food system characteristics that give rise to the current sustainability challenges. We combined deductive qualitative and inductive quantitative approaches to identify gaps in the systemic understanding of Arctic Indigenous food systems. We characterized existing research across the four levels of systemic depth—parameters, feedbacks, design, intent—and identified promising directions for future research. Our analyses show that research on food systems is clustered within six main domains, we term environmental contaminants, diet and health, food security, food culture and economy, changing socio-ecological systems and marine and coast. Based on our analysis, we identify three directions for future research that we believe to be of particular importance to enable sustainability transformations of Arctic Indigenous food systems: (i) the decolonization of research practices, (ii) acknowledging the significance of systemic interdependencies across shallow and deep leverage points, and (iii) transdisciplinary action-oriented research collaborations directing transformative system interventions.

Episodes of Quaternary environmental change shaped the genomes of extant species, influencing their response to contemporary environments, which are changing rapidly. Island endemics are among the most vulnerable to such change, accounting for a disproportionate number of recent extinctions. To prevent extinctions and conserve island biodiversity it is vital to combine knowledge of species' ecologies with their complex evolutionary histories. The Bering Sea has a history of cyclical island isolation and reconnection, coupled with modern rates of climate change that exceed global averages. The endangered Pribilof Island shrew (Sorex pribilofensis) is endemic to St. Paul Island, Alaska, which was isolated from mainland Beringia ~14,000 years ago by rising sea levels. Using ~11,000 single nucleotide polymorphisms, 17 microsatellites and mitochondrial sequence data, we test predictions about the evolutionary processes driving shrew speciation across Beringia. Our data show considerable differentiation of S. pribilofensis from mainland sibling species, relative to levels of divergence between mainland shrews. We also find a genome-wide loss of diversity and extremely low N

The state of Alaska is experiencing increased coastal erosion due to climatic changes that threaten shoreline, infrastructure, and Alaska Native ways of life. While several Alaska Native villages have been impacted by severe erosion, additional communities face burgeoning erosion concerns. St. Paul, a remote island located in the Bering Sea, Alaska, and home to ~450 Unangan, or Aleut, residents, is experiencing relatively new erosion and associated flooding issues. This study aimed to inform St. Paul’s erosion monitoring and climate adaptation strategies by documenting community perceptions of coastal erosion as an ecological and social threat within a broader context of multiple established climate stressors. We interviewed 21 residents to answer: (1) what are the community’s perceptions of erosion on St. Paul in the context of the island’s other environmental concerns?; (2) do current perceptions of erosion affect how local governing and management entities address erosion impacts?; and (3) how does erosion relate to and impact Unangan cultural traditions and heritage? Residents identified six locations of primary concern, owing to how erosion of those areas impact their culture, subsistence practices, and sense of place. We suggest methods in which local entities can better support proactive climate adaptation and mitigation measures and utilize resources for community-driven adaption planning. By documenting perspectives in Indigenous communities on emergent climate impacts, as well as perceptions of adaptation planning and implementation, it can establish the foundation for more collaborative, culturally relevant, and successful community-driven climate adaptation planning.

Snow crab (Chionoecetes opilio) were identified as a potential future target fishery species in federal waters of the Arctic Ocean off Alaska by the Arctic Fishery Management Plan (Arctic FMP) in 2009, but this plan currently prohibits commercial harvest until sufficient information is available to assess a sustainable commercial fishery. One drawback of the current Arctic FMP is that critical population and biomass estimates were based on limited data. Collaborative research efforts in the Chukchi and Beaufort seas over the past decade have yielded a much richer database on snow crab in the Arctic. Using these data, we generated new estimates of weight-at-size, maturity-at-size, fecundity, and biomass to recalculate sustainable yield of snow crab in the U.S. Arctic. Weight-at-size was generally similar for male and female snow crab between the Chukchi and Beaufort seas, with males reaching overall larger sizes than females in both seas and largest male crabs occurring in the Beaufort Sea. Compared with snow crab in other geographic regions, 50% morphometric maturity was reached at a slightly smaller size in the Chukchi Sea; low sample sizes in the Beaufort Sea prevented maturity-at-size analysis. Fecundity-at-size in the Chukchi Sea was similar to known values estimated for snow crab in other regions. Estimated total reproductive output, using fecundity estimates obtained here, suggest that local reproduction may be sufficient to account for a large portion of observed small juvenile benthic snow crab abundances; further investigation is warranted to determine whether Chukchi and Beaufort populations are self-sustaining at this time. Although snow crab had high abundances in the Chukchi Sea, harvestable biomass of male snow crab only occurred in the Beaufort Sea because crab larger than the minimum marketable size (≥ 100 mm carapace width, based on Bering Sea metric) were absent in the Chukchi Sea over the study period. Our biomass estimates in the Chukchi Sea were substantially higher than previous estimates, owing at least in part to high abundances of small crab that were greatly under-sampled with the large-mesh gear such as was used in surveys referenced in the Arctic FMP. Estimates of biomass and sustainable yield for the Beaufort Sea were over twice as high as previous estimates in the Arctic FMP, but harvestable biomass was largely limited to the slope (> 200 m depth) and is unlikely to support commercial harvest. Our results expand overall understanding of arctic snow crab dynamics in light of potential future fisheries or other, non-fishing activities and inform the management of the Alaskan Arctic stock.

Persistent organic pollutants (POPs) are highly lipophilic compounds that accumulate at increased concentrations in high tropic level organisms like marine mammals. Marine mammals' reliance on blubber makes them susceptible to accumulating POPs at potentially toxic concentrations. In this study, we analyzed POP concentrations, (polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and methoxylated-BDE (MeOBDE), in the blubber of 16 subsistence harvested sub-adult, male northern fur seals as well as assessed changes in mRNA gene expression of nine relevant biomarkers including the aryl hydrocarbon receptor, thyroid receptor-α, and adiponectin. PBDE and MeOBDE concentrations were significantly lower than PCB and OCP concentrations. A negative relationship was observed between percent lipid in the blubber and contaminant concentrations, both individual and sum. Expression changes in eight biomarkers were correlated with individual and sum contaminant concentrations. This study shows that contaminant concentrations measured are correlated to changes in expression of genes from different physiological systems, metabolism and endocrine, that are important for the regulation of blubber metabolism. Northern fur seals are reliant on blubber as an energy source during times of low food intake. Potential contaminant induced changes in blubber metabolism pathways could have significant impacts on the health of individuals during critical periods.

Between 2014 and 2017, widespread seabird mortality events were documented annually in the Bering and Chukchi seas, concurrent with dramatic reductions of sea ice, warmer than average ocean temperatures, and rapid shifts in marine ecosystems. Among other changes in the marine environment, harmful algal blooms (HABs) that produce the neurotoxins saxitoxin (STX) and domoic acid (DA) have been identified as a growing concern in this region. Although STX and DA have been documented in Alaska (US) for decades, current projections suggest that the incidence of HABs is likely to increase with climate warming and may pose a threat to marine birds and other wildlife. In 2017, a multispecies die-off consisting of primarily Northern Fulmars (Fulmarus glacialis) and Short-tailed Shearwaters (Ardenna tenuirostris) occurred in the Bering and Chukchi seas. To evaluate whether algal toxins may have contributed to bird mortality, we tested carcasses collected from multiple locations in western and northern Alaska for STX and DA. We did not detect DA in any samples, but STX was present in 60% of all individuals tested and in 88% of Northern Fulmars. Toxin concentrations in Northern Fulmars were within the range of those reported from other STX-induced bird die-offs, suggesting that STX may have contributed to mortalities. However, direct neurotoxic action by STX could not be confirmed and starvation appeared to be the proximate cause of death among birds examined in this study.

Recruitment success in sessile benthic invertebrates that produce pelagic larvae is an emergent property of larval supply, settlement rates, and post-settlement survival. While intuitive that larval supply and settlement rates should be positively correlated, previous studies have demonstrated that many factors, such as competition for limited space on hard substrata, may decouple this relationship. Oculina arbuscula is a temperate, broadcast spawning coral and is the only structurally complex Scleractinian occurring on hard bottom reefs of the South Atlantic Bight (SAB), a region located in the North Atlantic Ocean off the southeastern coast of the U.S.A. Planula larvae of this species must settle on hard-bottom substrate that is densely colonized by a diversity of sessile benthic invertebrates, including sponges, bryozoans , and ascidians. To investigate the relative roles of larval supply and competition for space on the recruitment dynamics of O. arbuscula , settlement to and survival on 30 × 30 cm plots was monitored over 5 years on a reef off the coast of Georgia, U.S.A. Treatments consisted of 10 replicates of each of the following: 1) unmanipulated natural substrate, 2) natural substrate initially cleared of encrusting competitors such as sponges and tunicates, and 3) artificial substrate composed of concrete paving tiles. These plots were photographed 3–5 times per year between July 2004 and June 2009. These images showed that O. arbuscula recruits throughout the year in the SAB with a peak in September/October. While recruitment rates were higher than death rates in all treatments and resulted in a net gain of O. arbuscula colonies, recruitment to artificial substrate far-exceeded that found on natural surfaces. The high recruitment rates observed on artificial substrate ruled out the possibility that maintenance of O. arbuscula populations on natural surfaces is limited by larval supply. Competition with other sessile invertebrates, such as ascidians and sponges, also appeared to contribute to differences in recruitment among treatments, however, comparisons between cleared and unmanipulated control plots on natural substrate suggested that the competition effect was small. Based on these findings as well as anecdotal observations suggesting that sediment accumulates less on the artificial substrate, the alternative hypothesis that O. arbuscula populations in this system are controlled by physical factors, especially sedimentation, is proposed and warrants further investigation.

The mesenchymal gene program has been shown to promote the metastatic progression of ovarian cancer; however, specific proteins induced by this program that lead to these metastatic behaviors have not been identified. Using patient derived tumor cells and established human ovarian tumor cell lines, we find that the Epithelial-to –Mesenchymal Transition inducing factor TWIST1 drives expression of Discoidin Domain Receptor 2 (DDR2), a receptor tyrosine kinase (RTK) that recognizes fibrillar collagen as ligand. The expression and action of DDR2 was critical for mesothelial cell clearance, invasion and migration in ovarian tumor cells. It does so, in part, by upregulating expression and activity of matrix remodeling enzymes that lead to increased cleavage of fibronectin and spreading of tumor cells. Additionally, DDR2 stabilizes SNAIL1, allowing for sustained mesenchymal phenotype. In patient derived ovarian cancer specimens, DDR2 expression correlated with enhanced invasiveness. DDR2 expression was associated with advanced stage ovarian tumors and metastases. In vivo studies demonstrated that the presence of DDR2 is critical for ovarian cancer metastasis. These findings indicate that the collagen receptor DDR2 is critical for multiple steps of ovarian cancer progression to metastasis, and thus, identifies DDR2 as a potential new target for the treatment of metastatic ovarian cancer.

The optimal strategy for adjuvant therapy in stage IIIC endometrial cancer has not been determined. Our aim was to evaluate survival benefit of different treatments and to investigate if benefit varied by histologic grade.We identified 199 patients with stage IIIC endometrial cancer from 2000 to 2012 through the Siteman Cancer Center registry. All patients underwent surgical staging followed by no adjuvant therapy (NAT), radiation (RT), chemotherapy (CT) or chemoradiation (CRT). The association between adjuvant treatment and overall survival was explored using Kaplan-Meier plots and multivariable Cox regression analysis. Multivariable analysis was stratified by low- or high-grade to explore the interaction between grade and treatment.Most patients received CRT (50.3%) followed by CT (23.1%), RT (16.1%) and NAT (10.5%). Survival after CRT was superior to NAT (p0.001), RT (p=0.010) and CT (p0.001). After adjusting for covariates, treatment with RT, CT and CRT led to a 57% (p=0.024), 62% (p=0.003) and 83% (p0.001) reduction in risk of death compared to NAT, respectively. With CRT as the reference, the adjusted hazard of death was higher with NAT (5.94, p0.001), RT (2.56, p=0.009) and CT (2.24, p=0.004). Stratifying by grade, RT and CRT led to a 67% (p=0.039) and 85% (p0.001) reduction in death, compared to NAT in low-grade patients. CT and CRT led to a 72% (p=0.003) and 83% (p0.001) reduction in death, compared to NAT in high-grade patients.Our findings suggest that CRT should be the preferred adjuvant treatment strategy for patients with stage IIIC endometrial cancer.

Highlights • DICER1 mutations play a significant role in gynecologic malignancy. • DICER1 may be involved in the sarcomagenesis of endometrial adenosarcoma. • The knowledge of a genetic mutation can help clarify a patient's medical history.

We used stomach content and stable δ 13 C and δ 15 N isotope analyses to investigate male and female snow crab diets over a range of body sizes (30–130 mm carapace width) in five regions of the Pacific Arctic (southern and northern Chukchi Sea, western, central, and Canadian Beaufort Sea). Snow crab stomach contents from the southern Chukchi Sea were also compared to available prey biomass and abundance. Snow crabs consumed four main prey taxa: polychaetes, decapod crustaceans (crabs, amphipods), echinoderms (mainly ophiuroids), and mollusks (bivalves, gastropods). Both approaches revealed regional differences. Crab diets in the two Chukchi regions were similar to those in the western Beaufort (highest bivalve, amphipod, and crustacean consumption). The Canadian Beaufort region was most unique in prey composition and in stable isotope values. We also observed a trend of decreasing carbon stable isotopes in crabs from the Chukchi to those in the Canadian Beaufort, likely reflecting the increasing use of terrestrial carbon sources towards the eastern regions of the Beaufort Sea from Mackenzie River influx. Cannibalism on snow crabs was higher in the Chukchi regions relative to the Beaufort regions. We suggest that cannibalism may have an impact on recruitment in the Chukchi Sea via reduction of cohort strength after settlement to the benthos, as known from the Canadian Atlantic. Prey composition varied with crab size only in some size classes in the southern Chukchi and central Beaufort, while stable isotope results showed no size-dependent differences. Slightly although significantly higher mean carbon isotope values for males in the southern Chukchi may not be reflective of a gender-specific pattern but rather be driven by low sample size. Finally, the lack of prey selection relative to availability in crabs in the southern Chukchi suggests that crabs consume individual prey taxa in relative proportions to prey field abundances. The present study is the first to provide a baseline of the omnivorous role of snow crabs across the entire Pacific Arctic, as well as evidence for cannibalism in the Chukchi Sea. In light of climate change predictions for the Alaska Arctic, and the potential for future fisheries harvest of snow crabs in this region, continued monitoring of snow crabs, including population and trophic dynamics, is increasingly important to assess snow crab impacts on benthic communities and vice versa.

Background Mayer-Rokitansky-Küster-Hauser syndrome is a rare entity with proposed genetic underpinnings. Ovarian carcinoma has well-described genetic associations and syndromes, although much of the etiology of the disease remains unknown. Cases Two sisters present in the 1970s with primary amenorrhea, 46, XX karyotypes, and absent uteri consistent with MRKH syndrome. In the 2010s, both sisters again present for care. Case 1 presents one sister with stage IIIC serous ovarian adenocarcinoma and negative BRCA panel. Case No 2 presents the other sister with stage IIIC serous ovarian adenocarcinoma and a negative panel for 32 genetic variants associated with ovarian carcinoma. Conclusion The familial association of two rare diseases and negative genetic workup could point to a new genetic understanding of reproductive structure development and ovarian carcinogenesis., Highlights • Mayer-Rokitansky-Küster-Hauser syndrome can have familial associations. • Ovarian carcinoma risk factors include genetic mutations. • Rare syndromes with familial associations may have underlying genetic associations.

Trophic structure and resilience of regional benthic food webs were studied on the Alaska Beaufort Sea shelf across 3 geographic regions (east, central, and west) and 2 depth ranges (14 to 90 m (shallow) and 100 to 220 m (deep)). Carbon (δ 13 C) and nitrogen (δ 15 N) isotope ratios were measured from water column and sediment particulate organic matter (POM) as markers of primary food sources and from common benthic invertebrate taxa. Isotopic niche space (δ 13 C� δ 15 N) occupied by benthic taxa provided measures of community-wide trophic redundancy and separation. δ 13 C values of the water column and sediment POM were patchy but generally indica- tive of terrestrial input across the shelf, especially near the mouth of the Colville River (< �25.5‰). Food web structures in the shallow and deep western Beaufort regions, however, reflected marine carbon inputs, with most consumers occupying intermediate trophic levels (TLs) and food webs of intermediate trophic redundancy and separation relative to the other regions. In the central shal- low and east regions, the terrestrial carbon found in sediments was mirrored in consumer tissues. The central deep region contained the highest proportions of higher TL taxa, particularly within the predator feeding guild, possibly reflecting resource partitioning of a limited prey spectrum. The comparatively large isotopic niche space in the central deep region, with high trophic niche separation but low trophic redundancy, suggests that this region may be most vulnerable to per- turbations. This study provides a valuable new understanding of benthic food web dynamics in the understudied Alaska Beaufort Sea region and represents a baseline for future comparison.

// Laura M. Divine 1, * , Mai R. Nguyen 1, * , Eric Meller 1 , Riva A. Desai 1 , Batool Arif 1 , Erinn B. Rankin 2, 3 , Katherine H. Bligard 1 , Cherise Meyerson 4 , Ian S. Hagemann 1, 4 , Maria Massad 1 , Premal H. Thaker 1 , Andrea R. Hagemann 1 , Carolyn K. McCourt 1 , Matt A. Powell 1 , David G. Mutch 1 , Katherine C. Fuh 1, 5 1 Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA 2 Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA, USA 3 Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, CA, USA 4 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA 5 Center for Reproductive Health Sciences (CRepHS), Washington University in St. Louis, St. Louis, MO, USA * These authors have contributed equally to this work Correspondence to: Katherine C. Fuh, email: kfuh@wudosis.wustl.edu Keywords: AXL, endometrial cancer, uPA, MMP, ARK1 Received: May 12, 2016 Accepted: September 24, 2016 Published: October 13, 2016 ABSTRACT The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro , genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer.

No standardized treatment strategies exist for patients with gynecologic malignancies complicated by brain metastases. Identification of poor outcome characteristics, long-term survival indicators, and molecular markers could help individualize and optimize treatment.This retrospective cohort study included 100 gynecologic cancer patients with brain metastases treated at our institution between January 1990 and June 2009. Primary outcome was overall survival (OS) from time of diagnosis of brain metastases. We used univariate and multivariate analyses to evaluate associations between OS and clinical factors. We used immunohistochemistry to examine expression of five molecular markers in primary tumors and brain metastases in a subset of patients and matched controls. Statistical tests included the Student's paired t-test (for marker expression) and Kaplan-Meier test (for correlations).On univariate analysis, primary ovarian disease, CA-12581units/mL at brain metastases diagnosis, and isolated versus multi-focal metastases were all associated with longer survival. Isolated brain metastasis remained the only significant predictor on multivariate analysis (HR 2.66; CI 1.19-5.93; p=0.017). Expression of vascular endothelial growth factor A (VEGF-A) was higher in metastatic brain samples than in primary tumors of controls (p0.0001). None of the molecular markers were significantly associated with survival.Multi-modality therapy may lead to improved clinical outcomes, and VEGF therapy should be investigated in treatment of brain metastases.

The entities covered in this chapter are uterine serous carcinoma (USC), carcinosarcoma, and clear-cell carcinoma together with tumors of mixed histology. Overall, these represent 3–10 % of all endometrial cancers but they are responsible for a significant percentage of endometrial cancer mortality. Recent strides in chemotherapy for some of these cancers offer hope that their addition, either alone or as a part of combined modality treatment including radiation, will lead to improvements in survival.

Resume Introduction Le lymphome de Hodgkin (LH) est une hemopathie lymphoide caracterisee par la presence de cellules de Reed-Sternberg ou de Hodgkin en histologie. Son evolution est marquee par une survie superieure a 80 %. Etats des connaissances L’atteinte thoracique initiale est frequente, surtout mediastinale, plus que parenchymateuse pulmonaire ou pleurale. Dans ces deux derniers cas, elle change le pronostic et un diagnostic est donc necessaire. Les complications des traitements du LH etaient representees, precocement, par les infections. Actuellement, ce sont plutot les atteintes fonctionnelles respiratoires apres radiotherapie mediastinale et chimiotherapie (incluant de la bleomycine) qui surviennent frequemment dans le suivi du LH. Par ailleurs, certaines atteintes granulomateuses precedent, accompagnent ou emaillent l’evolution du LH et le diagnostic differentiel avec des localisations specifiques est souvent difficile. Enfin, ces patients sont plus a risque de voir apparaitre des neoplasies, notamment bronchiques, a long terme. Perspectives et conclusions Les patients porteurs de LH ont maintenant une faible mortalite imputable directement a la maladie en comparaison de celle, souvent plus tardive, rapportee aux traitements. L’enjeu actuel est de developper des protocoles therapeutiques moins toxiques mais tout aussi efficaces.

Published data on transplantation in Waldenstrom's macroglobulinemia (WM) are still limited. We present a retrospective multicentric study of 27 WM patients who underwent 19 autologous (median age, 54 years) and 10 allogeneic (median age, 46 years) transplantations. Median time between diagnosis and transplantation was 36 months; 66% of patients had received three or more treatment lines and 72 % had chemosensitive disease. High-dose therapy (HDT) and autologous transplantation induced a 95% response rate (RR), including 10 major responses. With a median follow-up of 18 months, 12 patients are alive at 10 to 81 months and eight are free of disease progression at 10 to 34 months. The toxic mortality rate (TRM) was 6%. Allogeneic transplantation was preceded by HDT in nine patients and by a nonmyeloablative regimen in one patient. The RR was 80%, including seven major responses. With a median follow-up of 20.5 months, six patients are alive and free of progression at 3 to 76 months. Four patients died, all from toxicity, resulting in a TRM of 40%. HDT followed by autologous transplantation is feasible in WM, even in heavily pretreated patients, with some prolonged responses but a high relapse rate. Conversely, allogeneic transplantation is more toxic, but likely induces a graft-versus-WM effect and may, for some patients, result in long-term disease control.

Human pappilomavirus (HPV) has been recognized as the most common sexually transmitted disease in the world and over 100 different HPV types have been identified. Persistent HPV infection has been closely linked to the development of invasive cervical cancer. Although surgical and ablative therapies have been the mainstay of treatment, vaccination against the main oncogenic type of HPV is a reasonable preventive strategy for HPV-induced cervical cancer.

Three decades ago, the Honorable Guido Calabresi argued in "A Common Law for the Age of Statutes" that courts should update anachronistic statutes in a way analogous to common law reasoning. His argument never gained fervent support. Nevertheless, the Supreme Court, in Shelby County v. Holder, adopted strikingly similar reasoning. This Article examines the Court’s use of Calabresian reasoning in its approach to statutory anachronism, extrapolates from Shelby County—as well as several other cases—a broad definition of the constitutional doctrine employed by the Court, and shows how the Court’s new doctrine is less susceptible to criticism than Calabresi’s.

To evaluate a possible implication of cytokines in the pathogenesis of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome, we studied five consecutive patients with this condition, of which four had sclerotic bone lesions and four had multicentric Castleman's disease. Interleukin-1 beta (IL-1 beta) and IL- 6 serum levels were determined in these patients (13 serum samples) and in patients with multiple myeloma (5) and Waldenstrom's macroglobulinemia (5). In situ hybridization of the relevant mRNAs was performed on lymph node specimens of two patients with POEMS syndrome who had Castleman's disease. Elevated serum levels of IL-1 beta (13/13 samples), and IL-6 (7/13 samples) were found in patients with POEMS syndrome. In the other patients, serum IL-1 beta was undetectable or slightly increased and IL-6 was elevated in a single patient with Waldenstrom's macroglobulinemia. Abundant IL-1 beta mRNA-producing cells were present in interfollicular spaces in the two tested patients, while IL-6 mRNA-producing cells were rare. We conclude that IL-1 beta and IL-6 serum levels may be chronically elevated in patients with POEMS syndrome, and that lymph node may be one site of IL-1 beta overproduction. These results are in keeping with the hypothesis that cytokines mediate systemic manifestations of POEMS syndrome.

Hodgkin's lymphoma is defined by a malignant prolifération of Reed-Sternberg or Hodgkin cells that are clonally related B-cell-derived malignant cells. This disease is characterized by a good outcome (cure rate more than 80%). Initial thoracic involvement is usual and the more frequent localization is the mediastinum, following by the lung parenchyma and the pleura. In the last two cases, histological diagnosis is warranted since this involvement modified the staging and the prognosis of the disease.Early one, infectious diseases were the most frequent complications. Functional deficiency following mediastinal radiotherapy and chemotherapy (including bleomycin) is often detected, whatever this is associated with symptom or CT scan abnormalities. Granulomatous disease can be associated at any time during the disease and differential diagnosis from relapse is often difficult. Finally, these patients have an increased risk of developing solid cancers and particularly lung cancers.Hodgkin lymphoma patients are more likely to die from acute and late treatment-related toxicities and the major task is to reduce treatment associated toxicity while maintaining cure rate.

Intermediate or unfavourable stage Hodgkin's lymphoma (HL) definition relies upon at least three different scoring systems defined by cooperative groups (EORTC, GHSG and Canadian-ECOG). We aimed to investigate their efficacy and their correlation with International Prognostic Score (IPS) for advanced HL.We studied a population of 1156 patients with localized stage HL treated prospectively within GELA centres in H8 (518 patients) and H9 (638 patients) protocols. Median age: 30 yr, 18%, Female 50%; stage I: 25%; stage II: 75%. According to scoring systems 70% had 0-1 EORTC factors; 60% 0-1 GHSG factors and 82% 0-1 Canadian factors. The IPS for advanced stages was available only in H9 study with 64% 0-1 factor.Survival curves according to each of the different scoring systems could significantly discriminate the subgroup populations. When a multivariate Cox analysis was performed for overall survival (OS) including all the scoring system variables: age45 yr, sex male, Haemoglobin10.5 g/dL, lymphocytes600/microL, B symptoms with elevated ESR, extra nodal sites did retain an independent significant value. Probability of OS was 99%, 98%, 92%, 82% and 73% for patients with 1-5 factors, respectively P0.0001.These factors are similar for most of them with those described in the IPS when stages III and IV are replaced by extra nodal localization. This new score should be validated in other prospective trials, as it will simplify the Hodgkin prognostic scoring systems for localized and advanced stages.

A multilaboratory study was conducted to compare the automated BAX® system and the standard cultural methods for detection of Listeria monocytogenes in foods. Six food types (frankfurters, soft cheese, smoked salmon, raw, ground beef, fresh radishes, and frozen peas) were analyzed by each method. For each food type, 3 inoculation levels were tested: high (average of 2 CFU/g), low (average of 0.2 CFU/g) and uninoculated controls. A total of 25 laboratories representing government and industry participated. Of the 2335 samples analyzed, 1109 were positive by the BAX system and 1115 were positive by the standard method. A Chi square analysis of each of the 6 food types, at the 3 inoculation levels tested, was performed. For all foods, except radishes, the BAX system performed as well as or better than the standard reference methods based on the Chi square results.

Despite high-dose therapy and ASCT some patients with aggressive HD fail to achieve long-term survival.Forty-three patients with induction failure (n = 19) or very unfavorable (UF) relapse (n = 24) from HD were included in a multicentric study of tandem ASCT. They planned to receive two course of IVA75 with GCSF and blood stem cell collection. ASCT1 was conditioned with CBV + mitoxantrone (30 mg/m2) and ASCT2 (cytarabine 6 g/m2 melphalan 140 mg/m2 and total body irradiation at 12 Gy or busulfan 16 (n = 4) than 12 mg/kg). After salvage therapy, response50% was observed in 63% of the patients (six patients were included for refractory relapse). Four patients had no ASCT for disease progression; seven patients had only ASCT1 (disease progression, n = 3) and thirty-two patients (74%) received the two ASCT.Hematologic recovery was normal after ASCT1 but delayed platelet recovery was observed after ASCT2 with busulfan in the conditioning regimen. Two VOD with one fatal occurred with busulfan at 16 mg/kg and one hemorrhagic cystic, no further grade 4 toxicity was observed with the reduced doses of busulfan (12 mg/kg). After ASCT2, 83% of these UF patients were in remission and 20% relapsed within the first year. On an intent-to-treat analysis, 22 of 43 patients are in continuous CR (including 8 patients with induction failure). For the whole population (n = 43) and for patients receiving the two ASCT (n = 32), the two-year survival from the date of progression were respectively at 65% and at 74%.Double ASCT is feasible in very UF relapse from HD and may lead to some prolonged remission.

High-dose therapy with autologous stem cell transplantation (ASCT) has been widely proposed for patients with relapsed Hodgkin's disease (HD). From 1982 to 1993, we selected (from the French registry for bone marrow transplantation) 280 patients, who underwent ASCT for relapsed HD after initial treatment including chemotherapy. Patient characteristics at diagnosis were: sex ratio (M/F): 1.5; median age: 30 years (5-59 years), stage I, II: 43%; III, IV: 57%; 32% had chemotherapy, 68% chemo+ radiotherapy. All patients achieved complete remission after first-line therapy and subsequently relapsed. The median interval between diagnosis and high-dose therapy was 34 months. First relapse occurred in 78% of the patients at a median end-of-treatment to relapse time of 18 months. All patients received salvage chemotherapy before high-dose therapy, and the median time between relapse and high-dose therapy was 5 months. After this regimen, 84% of the patients were considered to have chemosensitive relapse. Conditioning regimens were: BEAM: 60%; CBV/BEAC: 26%. Transplant-related mortality was 6%. With a median follow-up of 3 years after high-dose therapy, overall and progression-free survivals at 4 years were 66 and 60%, respectively. Neither the conditioning regimen nor the stem cell source affected survival. Good prognostic factors for survival were: chemosensitivity of relapse (P0.01) and first relapse vs further relapse (P0.05). For 214 patients in first relapse, other significant factors for survival were: end-of-treatment to relapse interval12 months (P0.05) and nodal vs extranodal relapse (P0.001). These two prognostic factors were used to validate a prognostic model with three significantly different subgroups: 0 (n = 59), 1 (n = 125), or 2 factors (n = 30) with 4-year survival, respectively, at 93, 59 and 43% (P0.001). Salvage therapy can be tailored in patients with relapsing HD: conventional treatment in the good prognosis group (0 factor), high-dose therapy after response to second line regimen (1 factor) and more intensive treatments for the bad prognosis group (2 factors).

ObjectiveThe objective of this study was to determine the costs and outcomes of inguinal-femoral lymph node dissection (IF-LND) versus sentinel lymph node biopsy (SLNB) for the management of early-stage vulvar cancer.MethodsA cost-effectiveness model compared 2 different strategies for the management of early-stage vulvar cancer: (1) vulvectomy and SLNB and (2) vulvectomy and IF-LND. Probabilities of inguinal-femoral node metastases and recurrence rates associated with each strategy were estimated from published data. Actual payer costs of surgery and radiation therapy were obtained using 2012 CPT codes and Medicare payment information. Rates and costs of postoperative complications including lymphedema, lymphocyst formation, and infection were estimated and included in a separate model. Cost-effectiveness ratios were determined for each strategy. Sensitivity analyses were performed to evaluate pertinent uncertainties in the models.ResultsFor the estimated 3000 women diagnosed annually with early-stage vulvar cancer in the United States, the annual cost of the SLNB strategy is $65.2 million compared with $76.8 million for the IF-LND strategy. Three-year inguinal-femoral recurrence-free survival was similar between groups (96.9% vs 97.3%). This translates into a lower cost-effectiveness ratio for the SLNB strategy ($22,416), compared with the IF-LND strategy ($26,344). When adding complication costs to the model, cost-effectiveness ratios further favor the SLNB strategy ($23,711 vs $31,198). Sensitivity analysis revealed that the SLNB strategy remained cost-effective until the recurrence rate after a negative sentinel lymph node approaches 9%.ConclusionsSentinel lymph node biopsy is the most cost-effective strategy for the management of patients with early-stage vulvar cancer due to lower treatment costs and lower costs due to complications.

To evaluate a possible implication of cytokines in the pathogenesis of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome, we studied five consecutive patients with this condition, of which four had sclerotic bone lesions and four had multicentric Castleman's disease. Interleukin-1 beta (IL-1 beta) and IL-6 serum levels were determined in these patients (13 serum samples) and in patients with multiple myeloma (5) and Waldenström's macroglobulinemia (5). In situ hybridization of the relevant mRNAs was performed on lymph node specimens of two patients with POEMS syndrome who had Castleman's disease. Elevated serum levels of IL-1 beta (13/13 samples), and IL-6 (7/13 samples) were found in patients with POEMS syndrome. In the other patients, serum IL-1 beta was undetectable or slightly increased and IL-6 was elevated in a single patient with Waldenström's macroglobulinemia. Abundant IL-1 beta mRNA-producing cells were present in interfollicular spaces in the two tested patients, while IL-6 mRNA-producing cells were rare. We conclude that IL-1 beta and IL-6 serum levels may be chronically elevated in patients with POEMS syndrome, and that lymph node may be one site of IL-1 beta overproduction. These results are in keeping with the hypothesis that cytokines mediate systemic manifestations of POEMS syndrome.

Intravenous (i.v.) infusions of Ig concentrates are an effective but expensive treatment for patients with autoimmune thrombocytopenic purpura (AITP). The optimal treatment protocol and the long-term results are uncertain, and the precise mechanism by which the platelet count increases is poorly understood. Twenty adult patients with chronic AITP were enrolled in a prospective study to compare the respective efficacy of two high-dose IVIgG induction regimens (1 g v 2 g/kg body weight) and the long-term effect of six 1 g/kg body weight i.v. IgG reinfusions. An initial response was observed in all 18 evaluable patients: the platelet count increased to a mean value of 251 x 10(9)/L (range 72 to 836 x 10(9)/L) and the mean pretreatment platelet count was multiplied by 14.6. No difference in efficiency was observed between the two i.v. IgG dosages. The degree of the platelet count increment correlated in both groups with the increase in the clearance of antibody-coated red blood cells, measured by an isotopic method, but not with the serum IgG elevation. Treatment was considered to have failed in 11 patients, 90 days after the last i.v. IgG reinfusion (D90), because the platelet counts were comparable with pretreatment values. In contrast, a complete response was observed at D90 in five patients (mean platelet count: 184 x 10(9)/L; range: 150 to 250 x 10(9)/L) and a partial response at D90 was obtained in the remaining two patients (platelet counts: 70 and 104 x 10(9)/L). Five of the 7 responders at D90 kept a platelet count above 50 x 10(9)/L during the entire follow-up period (mean 33 months; range: 5 to 66) with no further treatment; unfortunately, no clinical or biologic criteria were found to be predictive of the long-term response. This study shows that an i.v. IgG infusion regimen of 1 g/kg body weight could safely replace the classical 2 g/kg body weight dosage, at least in patients who do not have life-threatening thrombocytopenia. Moreover, repeated i.v. IgG reinfusion could be an alternative for AITP patients in whom splenectomy is contraindicated.

Fourteen files of patients having had Hodgkin's disease have been analyzed retrospectively to assess the justification of systematic surveillance after complete remission has been achieved. The data of successive CT exams, compared with the findings of clinical and biological studies performed on the same dates, confirm the primordial role of imaging, since computed tomography was predictive for 7 of 18 events (14 relapses and 4 second progressions). The occurrence of subphrenic recurrence in 3 cases for which the initial site was mediastinal leads to discussing the merits of a yearly thoraco-abdomino-pelvic examination during the two years following complete remission.

Unusual corneal crystalline opacities at the level of Bowman's membrane and superficial stroma were observed in 3 patients with benign monoclonal gammopathy. Corneal immunohistochemical examination showed that the deposits consisted of immunoglobulin crystals identical to the paraprotein found in the serum (with the same light chain: Kappa in 2 cases and Lambda in the third case). The factors and mechanisms governing intracorneal immunoglobulin deposition in the cornea are discussed.

We describe our experience with a washing procedure used on cryopreserved, thawed bone marrow (BM) and peripheral blood stem cell (PBSC) grafts prior to autologous transplantation in 50 and 12 patients respectively. The procedure consists of a stepwise dilution with 2% human serum albumin and centrifugation performed either manually or using a blood cell processor (Cobe 2991). In vitro studies showed mean recoveries of 80.8% for BM nucleated cells and 73.9% for BM hematopoietic progenitors (CFU-GM). The corresponding recoveries for PBSC were 89.1 and 93.9%. After 4 h storage at +20 degrees C of the manipulated grafts, no significant loss of CFU-GM was observed. We conclude that the technique is simple and efficient for washing large numbers of hematopoietic stem cells. This method may avoid the clinical complications often arising with unwashed grafts.

Resume Chez les patients presentant des lesions lymphoproliferatives (myelome ou lymphome) de la moelle osseuse, la semiologie des lesions focales est basee sur l’interpretation du signal T1 et T2. La presence d’une infiltration tumorale diffuse est de diagnostic plus difficile avec une diminution globale du signal T1, une augmentation du signal T2. Cependant, ces modifications de signal pathologique peuvent etre difficiles a distinguer d’aspect normal de la moelle osseuse qui se modifie principalement en fonction de l’âge. Au cours de cette seance, seront successivement abordes : – les techniques qui peuvent etre utilisees pour etudier la perfusion de la moelle osseuse, – le traitement et l’interpretation des resultat, – les resultats normaux, – les resultats dans les pathologies lymphoproliferatives, – l’interet dans l’evaluation de la reponse au traitement en rapport avec le role de la neoangiogenese tumorale dans ces pathologies.