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ObjectiveRapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co-occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD.MethodsImmunoglobulin G (IgG) from pediatric ROHHAD patients (n = 9), non-inflammatory individuals (n = 100) and relevant pediatric controls (n = 25) was screened using a programmable phage display of the human peptidome (PhIP-Seq). Putative ROHHAD-specific autoantibodies were orthogonally validated using radioactive ligand binding and cell-based assays. Expression of autoantibody targets in ROHHAD tumor and healthy brain tissue was assessed with immunohistochemistry and mass spectrometry, respectively.ResultsAutoantibodies to ZSCAN1 were detected in ROHHAD patients by PhIP-Seq and orthogonally validated in 7/9 ROHHAD patients and 0/125 controls using radioactive ligand binding and cell-based assays. Expression of ZSCAN1 in ROHHAD tumor and healthy human brain tissue was confirmed.InterpretationOur results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of ROHHAD syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Last, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes. ANN NEUROL 2022;92:279-291.

BACKGROUND Gastric linitis plastica (GLP) is a subset of gastric cancer with a poor prognosis. It is difficult to obtain a definitive diagnosis by endoscopic mucosal biopsies, and the usefulness of an endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) for GLP has been recently reported. Meanwhile, autoimmune diseases are occasionally known to coexist with malignant tumors as paraneoplastic syndrome. We herein report the usefulness of an EUS-FNB for detecting GLP and the possibility of paraneoplastic syndrome coexisting with GLP. CASE SUMMARY An 81-year-old man was admitted to our hospital for a 1-mo history of epigastric pain that increased after eating. His laboratory data revealed high levels of serum carbohydrate antigen 19-9 and immunoglobulin-G4. Endoscopic examinations showed giant gastric folds and reddish mucosa; however, no epithelial changes were observed. The gastric lumen was not distensible by air inflation, suggesting GLP. Computed tomography showed the thickened gastric wall, the diffuse enlargement of the pancreas, and the peripancreatic rim, which suggested autoimmune pancreatitis (AIP) coexisting with GLP. Because the pathological findings of the endoscopic biopsy showed no malignancy, he underwent an EUS-FNB and was diagnosed with GLP. He received chemotherapy for unresectable gastric cancer due to peritoneal metastasis, after which both the gastric wall thickening and diffuse enlargement of the pancreas were improved. CONCLUSION An EUS-FNB for GLP with a negative endoscopic biopsy is useful, and AIP may develop as a paraneoplastic syndrome.

BACKGROUND Gastric linitis plastica (GLP) is a subset of gastric cancer with a poor prognosis. It is difficult to obtain a definitive diagnosis by endoscopic mucosal biopsies, and the usefulness of an endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) for GLP has been recently reported. Meanwhile, autoimmune diseases are occasionally known to coexist with malignant tumors as paraneoplastic syndrome. We herein report the usefulness of an EUS-FNB for detecting GLP and the possibility of paraneoplastic syndrome coexisting with GLP. CASE SUMMARY An 81-year-old man was admitted to our hospital for a 1-mo history of epigastric pain that increased after eating. His laboratory data revealed high levels of serum carbohydrate antigen 19-9 and immunoglobulin-G4. Endoscopic examinations showed giant gastric folds and reddish mucosa; however, no epithelial changes were observed. The gastric lumen was not distensible by air inflation, suggesting GLP. Computed tomography showed the thickened gastric wall, the diffuse enlargement of the pancreas, and the peripancreatic rim, which suggested autoimmune pancreatitis (AIP) coexisting with GLP. Because the pathological findings of the endoscopic biopsy showed no malignancy, he underwent an EUS-FNB and was diagnosed with GLP. He received chemotherapy for unresectable gastric cancer due to peritoneal metastasis, after which both the gastric wall thickening and diffuse enlargement of the pancreas were improved. CONCLUSION An EUS-FNB for GLP with a negative endoscopic biopsy is useful, and AIP may develop as a paraneoplastic syndrome.

Cancer patients often die from symptoms that manifest at a distance from any tumor. Mechanisms underlying these systemic physiological perturbations, called paraneoplastic syndromes, may benefit from investigation in non-mammalian systems. Using a non-metastatic Drosophila adult model, we find that malignant-tumor-produced cytokines drive widespread host activation of JAK-STAT signaling and cause premature lethality. STAT activity is particularly high in cells of the blood-brain barrier (BBB), where it induces aberrant BBB permeability. Remarkably, inhibiting STAT in the BBB not only rescues barrier function but also extends the lifespan of tumor-bearing hosts. We identify BBB damage in other pathological conditions that cause elevated inflammatory signaling, including obesity and infection, where BBB permeability also regulates host survival. IL-6-dependent BBB dysfunction is further seen in a mouse tumor model, and it again promotes host morbidity. Therefore, BBB alterations constitute a conserved lethal tumor-host interaction that also underlies other physiological morbidities.

Dermatomyositis is an inflammatory myopathy with an incidence of 0.5-1 case per 100,000 inhabitants. It is characterized by hallmark cutaneus findings and muscle weakness, although we can occasionally find amyopathic forms. The association with malignancy has been widely described in the literature, as tumors have been detected in up to a third of the cases. The presence of the anti-TIF-1-gamma antibody presents higher rates of neoplasia compared to other forms without this antibody, so it is mandatory to do a tumor screening. Next, we present 2 cases of TIF-1-gamma antibody-associated dermatomyositis associated with malignancy, La dermatomiositis es una miopatía inflamatoria con una incidencia de 0.5-1 caso por 100.000 habitantes. Se caracteriza por lesiones cutáneas típicas y debilidad muscular, aunque ocasionalmente podemos encontrar formas amiopáticas. La asociación con malignidad ha sido ampliamente descrita en la literatura, habiéndose detectado tumores hasta en un tercio de los casos. La presencia del anticuerpo anti-TIF-1-gamma presenta tasas más altas de neoplasia comparada con otras formas sin este anticuerpo, lo que obliga a realizar un despistaje tumoral. A continuación, presentamos 2 casos de dermatomiositis asociada a anticuerpo TIF-1-gamma asociadas a malignidad

ObjectivesTo identify the association between cording and breast cancer-related lymphedema (BCRL); describe time course, location, symptoms and functional impairments.MethodsA total of 1181 patients were prospectively screened for BCRL after breast cancer (BC) surgery, including patient-reported outcome measures (4193) and perometric arm volume measurements (BCRL defined as relative or weight-adjusted volume change [RVC or WAC] ≥10% ≥3 months postoperatively).ResultsA total of 374/1181 patients (31.7%) reported cording first a median of 4.5 months postoperatively, and were more likely to: have body mass index less than 30 kg/m2 ; be less than 55 years of age; have had mastectomy, axillary lymph node dissection, regional lymph node radiation, neoadjuvant chemotherapy (all P < .001), or RVC/WAC ≥10% (P = .002). Patients who reported cording had 2.4 times the odds of developing BCRL compared to those who did not (odds ratio = 2.40; 95% confidence interval = 1.40-4.11; P = .002), and most frequently reported these symptoms: tenderness (61.2%), aching (60.7%), and firmness/tightness (59.8%). On multivariable analysis, cording was significantly correlated with functional difficulty for 17 actions.ConclusionsPatients frequently present with cording, potentially months after BC surgery. Risk factors for and symptoms of cording are identified, and treatment is recommended. Patients reporting cording are at higher risk of BCRL, therefore, cording should be incorporated into BCRL risk stratification.

The opsoclonus-myoclonus syndrome is a rare medical condition associated with an autounmmune etiology, it can be paraneoplasic, parainfectios or idiopatic. The patients present with truncal and limb ataxia, falls, opsocolunus and myoclonus. Also they could present a certain degree of encephalopathy, cerebelar damage signs and sleep disturbances. In the case of the pediatric population an evaluation for neuroblastoma must be done; in adults presenting with encephalopathy a complete evaluation must be done looking an underlying neoplasia. The acute neurological symtomps can be controlled with immunotherapy and there have been a partial response to the antitumoral medication, but the long term outcome is characterized for the presence of neuropsicological deficit., El síndrome opsoclonus-mioclonus es una condición rara, asociada con una etiología de carácter autoinmune, tanto paraneoplásica, parainfecciosa o idiopática. Estos pacientes se presentan con ataxia del tronco y extremidades, con caídas, opsoclonus, mioclonías, y se puede acompañar de diversos grados de encefalopatía, signos cerebelosos y alteraciones del sueño. En el caso de la población pediátrica, se debe evaluar por neuroblastoma; y en adultos con encefalopatía asociada se debe realizar una evaluación exhaustiva para detectar malignidad oculta. Mientras que los síntomas neurológicos agudos pueden controlarse mediante inmunoterapia, y se ha visto respuesta parcial a tratamiento antitumoral, el resultado a largo plazo se caracteriza por la presencia de déficit neuropsicológico.

A 37-year-old man with a history of seminoma presented with vertigo, ataxia, and diplopia. An autoantibody specific for kelch-like protein 11 (KLHL11) was identified with the use of programmable phage display. Immunoassays were used to identify KLHL11 IgG in 12 other men with similar neurologic features and testicular disease. Immunostaining of the patient's IgG on mouse brain tissue showed sparse but distinctive points of staining in multiple brain regions, with enrichment in perivascular and perimeningeal tissues. The onset of the neurologic syndrome preceded the diagnosis of seminoma in 9 of the 13 patients. An age-adjusted estimate of the prevalence of autoimmune KLHL11 encephalitis in Olmsted County, Minnesota, was 2.79 cases per 100,000 men. (Funded by the Rochester Epidemiology Project and others.).

IntroductionThymic epithelial tumors (TETs) are associated with paraneoplastic/autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs.MethodsThe International Thymic Malignancy Interest Group retrospective database was examined to determine (1) baseline and treatment characteristics associated with PN/AI syndromes and (2) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis.ResultsA total of 6670 patients with known PN/AI syndrome status from 1951 to 2012 were identified. PN/AI syndromes were associated with younger age, female sex, thymoma histologic type, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the group with a PN/AI syndrome than in the group without a PN/AI syndrome (10-year CIR 17.3% versus 21.2%, respectively [p = 0.0003]). The OS was improved in the group with a PN/AI syndrome compared to the group without a PN/AI syndrome (median OS 21.6 years versus 17.0 years, respectively [hazard ratio = 0.63, 95% confidence interval: 0.54-0.74, p < 0.0001]). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor.DiscussionPreviously, there have been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest data set in the world for TETs, PN/AI syndromes were associated with favorable features (i.e., earlier stage and complete resection status) but were not an independent prognostic factor for patients with TETs.

Paraneoplastic pemphigus is a rare autoimmune blistering disease generally associated with malignancy. The clinical presentation consists typically of painful and diffuse erosive stomatitis that may be accompanied by polymorphic skin lesions and systemic involvement. Diagnosis is based on clinical manifestations and confirmed by histology and immunological testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents. We report a case of buccal paraneoplastic pemphigus resistant to ibrutinib and rituximab successfully treated with azathioprine and polyclonal immunoglobulins., info:eu-repo/semantics/published

In conclusion, looking through the presented works and data at the first saint petersburg annual meeting allowed the participants to obtain a reliable view of the most recent and upcoming evidence that might affect our practice in autoimmune diseases. After this meeting, clinicians became more familiar with the key role that diets (curcumin, capsaicin, chocolate and salt), adjuvants, viral agents and microbiome playing in promoting/protecting to/from the development of autoimmune diseases. Moreover, participants became more aware of the contribution of serological tests to the diagnosis and classification of autoimmune diseases. Therefore, we are convinced that this is the real added value of meetings which are capable of gathering researchers from different areas to provide a fertile field for contamination and future projects.

In conclusion, looking through the presented works and data at the first saint petersburg annual meeting allowed the participants to obtain a reliable view of the most recent and upcoming evidence that might affect our practice in autoimmune diseases. After this meeting, clinicians became more familiar with the key role that diets (curcumin, capsaicin, chocolate and salt), adjuvants, viral agents and microbiome playing in promoting/protecting to/from the development of autoimmune diseases. Moreover, participants became more aware of the contribution of serological tests to the diagnosis and classification of autoimmune diseases. Therefore, we are convinced that this is the real added value of meetings which are capable of gathering researchers from different areas to provide a fertile field for contamination and future projects.

PurposeTo develop diagnostic criteria for nonparaneoplastic autoimmune retinopathy (AIR) through expert panel consensus and to examine treatment patterns among clinical experts.DesignModified Delphi process.MethodsA survey of uveitis specialists in the American Uveitis Society, a face-to-face meeting (AIR Workshop) held at the National Eye Institute, and 2 iterations of expert panel surveys were used in a modified Delphi process. The expert panel consisted of 17 experts, including uveitis specialists and researchers with expertise in antiretinal antibody detection. Supermajority consensus was used and defined as 75% of experts in agreement.ResultsThere was unanimous agreement among experts regarding the categorization of autoimmune retinopathies as nonparaneoplastic and paraneoplastic, including cancer-associated retinopathy and melanoma-associated retinopathy. Diagnostic criteria and tests essential to the diagnosis of nonparaneoplastic AIR and multiple supportive criteria reached consensus. For treatment, experts agreed that corticosteroids and conventional immunosuppressives should be used (prescribed) as first- or second-line treatments, though a consensus agreed that biologics and intravenous immunoglobulin were considered appropriate in the treatment of nonparaneoplastic AIR patients regardless of the stage of disease. Experts agreed that more evidence is needed to treat nonparaneoplastic AIR patients with long-term immunomodulatory therapy and that there is enough equipoise to justify randomized, placebo-controlled trials to determine if nonparaneoplastic AIR patients should be treated with long-term immunomodulatory therapy. Regarding antiretinal antibody detection, consensus agreed that a standardized assay system is needed to detect serum antiretinal antibodies. Consensus agreed that an ideal assay should have a 2-tier design and that Western blot and immunohistochemistry should be the methods used to identify antiretinal antibodies.ConclusionsConsensus wa

"Introduction: Paraneoplastic pemphigus is an autoimmune disease associated with an underlying tumor. Several cases have been reported as unusual pemphigus vulgaris, erythema multiforme, or paraneoplastic bullous disease,1 but the incidence of the condition is unknown.2 Response to treatment is generally poor, with significant morbidity and mortality. This condition is clinically characterized by severe mucositis and polymorphic blistering skin eruptions, and histologically by acantholysis, keratinocyte necrosis, and interface dermatitis.3 Immunoprecipitation and immunoblot testing detect autoantibodies against desmosomal polypeptides.4 We describe a case of paraneoplastic pemphigus associated with an abdominal inflammatory myofibroblastic tumor in a 7-year-old girl."

PurposeTo develop diagnostic criteria for nonparaneoplastic autoimmune retinopathy (AIR) through expert panel consensus and to examine treatment patterns among clinical experts.DesignModified Delphi process.MethodsA survey of uveitis specialists in the American Uveitis Society, a face-to-face meeting (AIR Workshop) held at the National Eye Institute, and 2 iterations of expert panel surveys were used in a modified Delphi process. The expert panel consisted of 17 experts, including uveitis specialists and researchers with expertise in antiretinal antibody detection. Supermajority consensus was used and defined as 75% of experts in agreement.ResultsThere was unanimous agreement among experts regarding the categorization of autoimmune retinopathies as nonparaneoplastic and paraneoplastic, including cancer-associated retinopathy and melanoma-associated retinopathy. Diagnostic criteria and tests essential to the diagnosis of nonparaneoplastic AIR and multiple supportive criteria reached consensus. For treatment, experts agreed that corticosteroids and conventional immunosuppressives should be used (prescribed) as first- or second-line treatments, though a consensus agreed that biologics and intravenous immunoglobulin were considered appropriate in the treatment of nonparaneoplastic AIR patients regardless of the stage of disease. Experts agreed that more evidence is needed to treat nonparaneoplastic AIR patients with long-term immunomodulatory therapy and that there is enough equipoise to justify randomized, placebo-controlled trials to determine if nonparaneoplastic AIR patients should be treated with long-term immunomodulatory therapy. Regarding antiretinal antibody detection, consensus agreed that a standardized assay system is needed to detect serum antiretinal antibodies. Consensus agreed that an ideal assay should have a 2-tier design and that Western blot and immunohistochemistry should be the methods used to identify antiretinal antibodies.ConclusionsConsensus wa

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a rare panencephalitis that can present with severe cardiac dysrhythmias. We present a case of a 19-year-old woman with no significant medical history who presented with progressive changes in mental status and profound ictal asystole that necessitated the placement of an external temporary pacemaker. She was diagnosed with and treated for anti-NMDA receptor encephalitis, and she recovered after a prolonged and complicated hospitalization. We review the pathophysiology and management of anti-NMDA receptor encephalitis, as well as its cardiac manifestations.

Rare and diagnostically challenging, paraneoplastic syndromes can appear months to years before detection of their underlying neoplasms and are associated with rapidly progressive neurologic deficits, including cochleovestibulopathy and death. Less than 20 cases of paraneoplastic cochleovestibulopathy have been reported in the online database PubMed. We present three recent cases: one patient with a history of B-cell follicular lymphoma who developed dermatomyositis and hearing loss before detection of lymphoma recurrence in his anterior chest wall, a second patient with sudden asymmetric hearing loss, found to have a 12-cm renal mass before death, and a third with fluctuating bilateral hearing loss who was ultimately found to have a thymoma. Although characterized as type VI (non-immune rapidly progressive sensorineural hearing loss) within the Harris autoimmune inner ear disease classification system, the mechanism of paraneoplastic cochleovestibulopathy is not well understood. Although specific anti-neuronal antibodies such as anti-Hu may be associated with other paraneoplastic neurologic disorders, these antibodies have limited diagnostic utility with paraneoplastic cochleovestibulopathy. Steroids have limited efficacy with regard to hearing recovery, whereas intravenous immunoglobulin has been shown to be of benefit. These recent cases demonstrate how auditory and vestibular deficits may be indicative of a rare but potentially life-threatening occult neoplasm where timely diagnosis is critical. We believe that understanding paraneoplastic cochleovestibulopathy is of interest across a broad range of clinical practices.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a rare panencephalitis that can present with severe cardiac dysrhythmias. We present a case of a 19-year-old woman with no significant medical history who presented with progressive changes in mental status and profound ictal asystole that necessitated the placement of an external temporary pacemaker. She was diagnosed with and treated for anti-NMDA receptor encephalitis, and she recovered after a prolonged and complicated hospitalization. We review the pathophysiology and management of anti-NMDA receptor encephalitis, as well as its cardiac manifestations.

Rare and diagnostically challenging, paraneoplastic syndromes can appear months to years before detection of their underlying neoplasms and are associated with rapidly progressive neurologic deficits, including cochleovestibulopathy and death. Less than 20 cases of paraneoplastic cochleovestibulopathy have been reported in the online database PubMed. We present three recent cases: one patient with a history of B-cell follicular lymphoma who developed dermatomyositis and hearing loss before detection of lymphoma recurrence in his anterior chest wall, a second patient with sudden asymmetric hearing loss, found to have a 12-cm renal mass before death, and a third with fluctuating bilateral hearing loss who was ultimately found to have a thymoma. Although characterized as type VI (non-immune rapidly progressive sensorineural hearing loss) within the Harris autoimmune inner ear disease classification system, the mechanism of paraneoplastic cochleovestibulopathy is not well understood. Although specific anti-neuronal antibodies such as anti-Hu may be associated with other paraneoplastic neurologic disorders, these antibodies have limited diagnostic utility with paraneoplastic cochleovestibulopathy. Steroids have limited efficacy with regard to hearing recovery, whereas intravenous immunoglobulin has been shown to be of benefit. These recent cases demonstrate how auditory and vestibular deficits may be indicative of a rare but potentially life-threatening occult neoplasm where timely diagnosis is critical. We believe that understanding paraneoplastic cochleovestibulopathy is of interest across a broad range of clinical practices.

BackgroundMetabolic and transcriptomic differences between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) compartments, particularly in the context of obesity, may play a role in colorectal carcinogenesis. We investigated the differential functions of their metabolic compositions.ObjectivesBiochemical differences between adipose tissues (VAT compared with SAT) in patients with colorectal carcinoma (CRC) were investigated by using mass spectrometry metabolomics and gene expression profiling. Metabolite compositions were compared between VAT, SAT, and serum metabolites. The relation between patients' tumor stage and metabolic profiles was assessed.DesignPresurgery blood and paired VAT and SAT samples during tumor surgery were obtained from 59 CRC patients (tumor stages I-IV) of the ColoCare cohort. Gas chromatography time-of-flight mass spectrometry and liquid chromatography quadrupole time-of-flight mass spectrometry were used to measure 1065 metabolites in adipose tissue (333 identified compounds) and 1810 metabolites in serum (467 identified compounds). Adipose tissue gene expression was measured by using Illumina's HumanHT-12 Expression BeadChips.ResultsCompared with SAT, VAT displayed elevated markers of inflammatory lipid metabolism, free arachidonic acid, phospholipases (PLA2G10), and prostaglandin synthesis-related enzymes (PTGD/PTGS2S). Plasmalogen concentrations were lower in VAT than in SAT, which was supported by lower gene expression of FAR1, the rate-limiting enzyme for ether-lipid synthesis in VAT. Serum sphingomyelin concentrations were inversely correlated (P = 0.0001) with SAT adipose triglycerides. Logistic regression identified lipids in patients' adipose tissues, which were associated with CRC tumor stage.ConclusionsAs one of the first studies, we comprehensively assessed differences in metabolic, lipidomic, and transcriptomic profiles between paired human VAT and SAT and their association with CRC tumor stage. We identified m

Posterior reversible encephalopathy syndrome (PRES) is a neurological entity characterized by seizures, headache, and reversible subcortical vasogenic edema. It is associated with many etiologies, most often hypertension, chronic renal failure, and chemotherapy. Hypercalcemia is rarely associated with PRES.

The syndrome of Leser–Trélat (LT) is characterized by the sudden appearance of multiple seborrhoeic keratoses (SKs) in association with internal occult malignancy. Usually, the syndrome has been associated with adenocarcinoma, most frequently of the gastrointestinal tract and breast. The pathogenesis is unclear but might be explained by circulating tumor-associated growth factors. We present two thoracic malignancies associated with LT: adenocarcinoma of the lung (ACL) and pleural malignant mesothelioma (MM). Both malignant tumors expressed high levels of epidermal growth factor receptors (EGFR) detected by immunohistochemistry (IHC), with membranous staining on the majority of malignant cells corresponding to maximum IHC scores of 290 and 300, respectively, for the MM and the ACL. SKs revealed a universal membranous staining throughout the entire epithelium with no difference in EGFR expression between the two cases and two controls with no malignant history. By fluorescence in situ hybridization, no amplification of the EGFR gene in malignant tumors as well as in SK lesions was observed. Further investigations are needed to see whether tumor-associated EGFR ligands/EGFR autocrine loops in malignant cells expressing high levels of EGFR protein on the surface might play a role for the development of SKs, as well as for the growth of malignant tumors in LT.

The syndrome of Leser–Trélat (LT) is characterized by the sudden appearance of multiple seborrhoeic keratoses (SKs) in association with internal occult malignancy. Usually, the syndrome has been associated with adenocarcinoma, most frequently of the gastrointestinal tract and breast. The pathogenesis is unclear but might be explained by circulating tumor-associated growth factors. We present two thoracic malignancies associated with LT: adenocarcinoma of the lung (ACL) and pleural malignant mesothelioma (MM). Both malignant tumors expressed high levels of epidermal growth factor receptors (EGFR) detected by immunohistochemistry (IHC), with membranous staining on the majority of malignant cells corresponding to maximum IHC scores of 290 and 300, respectively, for the MM and the ACL. SKs revealed a universal membranous staining throughout the entire epithelium with no difference in EGFR expression between the two cases and two controls with no malignant history. By fluorescence in situ hybridization, no amplification of the EGFR gene in malignant tumors as well as in SK lesions was observed. Further investigations are needed to see whether tumor-associated EGFR ligands/EGFR autocrine loops in malignant cells expressing high levels of EGFR protein on the surface might play a role for the development of SKs, as well as for the growth of malignant tumors in LT.

The term limbic encephalitis (LE) was first introduced in 1968. While this disease was initially considered rare and is often fatal with very few treatment options, several reports published in the last decade provide a better description of this condition as well as possible causes and some cases of successful treatment. The clinical manifestation of LE is primarily defined by the subacute onset of short-term memory loss, seizures, confusion and psychiatric symptoms suggesting the involvement of the limbic system. In addition, EEG often shows focal or generalized slow wave or epileptiform activity, and MRI findings reveal hyperintense signals of the medial temporal lobes in T2-weighted or FLAIR images. The current literature suggests that LE is not a single disorder but is comprised of a group of autoimmune disorders predominantly affecting the limbic system. Before the diagnosis of LE can be determined, other causes of subacute encephalopathy must be excluded, especially those resulting from infectious aetiologies. LE has previously been regarded as a paraneoplastic phenomenon associated with the classical onconeuronal antibodies that are primarily directed against intracellular antigens. However, recent literature suggests that LE is also associated with antibodies that are directed against cell surface antigens, and these cases of LE display a much weaker association to the neoplasm. The treatment options for LE largely depend on the aetiology of the disease and involve the removal of the primary neoplasm. Therefore, a search for the underlying tumour is mandatory. In addition, immunotherapy has been successful in a significant number of patients where LE is not associated with cancer.

Los sí­ndromes paraneoplásicos neurológicos son entidades relativamente frecuentes dentro de los sí­ndromes paraneoplásicos y presentan la particularidad de que en más de la mitad de los casos el cáncer que los genera se halla aún en una etapa curable. Revisaremos la patogenia, los cuadros más frecuentes y el tratamiento de cada uno., The neurological paraneoplastic syndromes are relatively frequent entities inside the paraneoplastic syndromes and they present the particularity that in more than half of the cases the cancer that generates them is still in a curable stage. We will revise the patogeny, the most frequent entities and the treatment of each one.

Amphiphysin, a synaptic vesicle protein, is an auto-immune target in rare cases of paraneoplastic neurological disorders. We report two additional cases with distinct neurological syndromes and paraneoplastic anti-amphiphysin antibodies. The first patient, a 59-year-old man, presented with cerebellar and cranial nerve dysfunction and small cell lung carcinoma. The second, a 77-year-old woman, presented with left brachial plexopathy followed by sensorimotor neuropathy and breast carcinoma.

Autocrine motility factor (AMF) is expressed by human breast cancer cells, such as MCF7 where its expression is stimulated by heregulin. Tumor cells constitutively secreting mouse AMF caused periosteal new bone formation in two different models of metastasis-an osteoblastic response similar to what is found with about 15% of breast cancers metastatic to bone. Whenever serum AMF concentrations were significantly increased, the animals displayed tumor-associated weight loss (cachexia), a major cause of morbidity and mortality in advanced disease. The effects of AMF on bone were independent of PTHrP, which plays a central role in ostolytic bone metastases. We also have determined the clearance rate of AMF from the mouse circulation. The species-specific effects of AMF remain little understood; so we undertook to clarify the stucture: function relationships involved. We cloned, sequenced and expressed rabbit AMF, for which the x-ray crystallographic data were already partially solved. These results have been published. We also developed a recombinant protein expression system for the mouse and human factors, which we now prepare in 100mg batches. The human factor has been crystallized and the x-ray structure solved to 1.8A., Original contains color plates: All DTIC reproductions will be in black and white.

Paraneoplastic limbic encephalitis is a rare clinical entity, associated most often with the oat cell carcinoma of the lung. Clinically, it presents with affective changes in personality, memory loss, confusional state, hallucinations, and seizures; with dementia being the common feature as the disorder progresses. Response to treatment is disappointingly poor.

Autocrine motility factor (AMF) is a l25kDa dimeric protein with two distinct functions: Intracellularly, it is an essential, ubiquitously expressed glycolytic enzyme. Extracellularly, it is also found in the circulation of patients with cancer, particularly with advanced, metastatic disease. Release of the extracellular form is by an unknown mechanism, but the factor binds to a known receptor with high affinity and has a number of effects, including stimulation of cell motility and differentiation of monocytic cells. We show here that AMF is a potent stimulator of the formation of osteoclasts, cells which resorb bone. The effect is species-specific by about lOOX between mouse and human AMFs and their receptors. The dose-response is bell-shaped with maximum effects at 1ng/m1. In vitro mouse AMF induces RANK ligand expression in a bone marrow stromal line. RANK ligand is the central regulator of osteoclast formation. Cells secreting mouse AMF formed tumors in the muscles of nude mice and caused several dramatic effects compared to equal-sized control tumors: 1) Systemically, AMF secretion caused severe weight loss (cachexia). 2) Locally, AMF stimulated formation of disorganized new bone between the tumor and the surface of the femur. The data suggest that AMF is a novel stimulator of local changes in bone during metastasis and may also be a systemic mediator of cachexia, a serious complication of neoplasia.

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In recent years a continuous stream of new information on clinical, pathological and immunological aspects of paraneoplastic neurological syndromes has been published. In this survey, we will discuss current opinions on the value of anti-neuronal antibody detection for establishing a diagnosis of one of the paraneoplastic syndromes of the central nervous system.

We describe the case of a 72-year-old man who developed unilateral digital necrosis, four years after diagnosis of chronic myeloid leukemia (CML). The etiology of this paraneoplastic phenomenon appears multiple. The digital necrosis responded well to an aggressive varied treatment. The unusual association of CML with digital necrosis and the etiology of this rare paraneoplastic complication are discussed.

The serum and CSF of two women with a severe subacute pancerebellar syndrome contained high titers of antibodies directed against antigens present in the perikaryon of Purkinje cells. In Western blots performed on human Purkinje cells extracts these antibodies reacted with two groups of proteins the molecular weights of which were estimated to 34-38 and 62 kilodaltons (anti-Yo antibodies). Complementary investigations revealed a tubar adenocarcinoma in the first case, an ovarian carcinoma in the second. The tubar tumoral cells also contained the protein of the highest molecular weight. Compared to the serum, the CSF contained a higher proportion of anti-Yo antibodies per mg IgG, and a fraction of the latter was likely synthesized intrathecally. These antibodies may be involved in the almost total disappearance of the Purkinje cells, as observed at autopsy of both cases.

Although hypertension, sustained or paroxysmal, is usually a cardinal feature of pheochromocytoma, cases in which patients with this disorder were normotensive have been reported. To extend further the clinical spectrum associated with this tumor, we describe a normotensive patient in whom fever of unknown origin, anemia, thrombocytosis, abnormalities of hepatic function and pronounced elevation of the erythrocyte sedimentation rate were the presenting features of a norepinephrine- and dopamine-secreting pheochromocytoma. Complete resolution of the fever and of the hematologic and biochemical abnormalities followed removal of this benign neoplasm.

Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: NotDefined.j, info:eu-repo/semantics/published

Although hypertension, sustained or paroxysmal, is usually a cardinal feature of pheochromocytoma, cases in which patients with this disorder were normotensive have been reported. To extend further the clinical spectrum associated with this tumor, we describe a normotensive patient in whom fever of unknown origin, anemia, thrombocytosis, abnormalities of hepatic function and pronounced elevation of the erythrocyte sedimentation rate were the presenting features of a norepinephrine- and dopamine-secreting pheochromocytoma. Complete resolution of the fever and of the hematologic and biochemical abnormalities followed removal of this benign neoplasm.

Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: NotDefined.j, info:eu-repo/semantics/published