Immune checkpoint inhibitor refractory colitis leading to total colectomy in a melanoma patient.

Immunotherapy is becoming more and more relevant in the treatment of advanced melanoma. Proper management of its side effects can prevent severe complications. We describe the case of a 73-year-old patient with severe refractory colitis secondary to immunotherapy. The patient has been treated for 6 months with Nivolumab, an anti-PD-1, as adjuvant therapy for locally advanced melanoma. He was admitted to the hospital with a deteriorating general condition associated with severe diarrhea and rectal bleeding for 3 weeks. Despite three lines of treatment (high dose corticosteroids, infliximab, mycophenolate mofetil), the patient still presented clinical and endoscopic colitis, with additional infectious complications. The patient required surgical management for total colectomy. In this article we present one of the rare cases of autoimmune colitis that did not respond to various immunosuppressive treatments and required surgery.

Oral Delivery of Therapeutic Proteins and Peptides: An Overview of Current Technologies and Recommendations for Bridging from Approved Intravenous or Subcutaneous Administration to Novel Oral Regimens.

Since the early 1980s, therapeutic proteins and peptides have become established as an important class of pharmaceuticals. Due to their low oral bioavailability, which results from pre-systemic degradation and poor gastrointestinal absorption, most therapeutic proteins and peptides are administered intravenously. While subcutaneous formulations of some therapeutic proteins and peptides have been shown to improve patient convenience and reduce medical resource utilization, oral administration is generally the preferred administration route. Some therapeutic proteins and peptides employing novel oral delivery technologies have reached late-stage clinical development. To develop a new oral formulation of a therapeutic protein or peptide currently marketed as an injectable product, technical, nonclinical, and clinical studies are required to demonstrate similar safety and efficacy compared with the existing administration route. Since there is little experience with oral therapeutic proteins and peptides, this review provides recommendations for bridging from an approved intravenous or subcutaneous regimen to novel oral administration of the same therapeutic protein or peptide, based on precedents from intravenous-to-subcutaneous bridging approaches for trastuzumab, rituximab, tocilizumab, and bortezomib. If the pharmacokinetic/pharmacodynamic relationship is well characterized, demonstration of comparability in prespecified pharmacokinetic parameters might form a basis for establishing similar efficacy and safety of the oral formulation vs. the reference product. Although oral administration of therapeutic proteins and peptides remains challenging, given recent progress with novel delivery technologies, intravenous/subcutaneous-to-oral nonclinical and clinical bridging programs may soon be utilized to support approval of new oral formulations.

Leukoencephalopathy, cerebral calcifications, and cysts: new observations.

We describe three cases of the rare syndrome of leukoencephalopathy, brain calcifications, and cysts. Conventional MRI, proton spectroscopy, and diffusion-weighted imaging yielded additional information on the disease. Imaging findings favor increased water content rather than a demyelinating process in the pathophysiology of this disease. Clinical features of Coats disease and consanguinity were also encountered.

Impaired temporo-occipital blood flow in an atypical CLN1 case with late infantile onset and granular osmiophilic deposits.

A 5-year-old boy presented with frequent absences. Speech began to regress. He became ataxic, barely able to walk. Studies with Xe-133 and hexamethylpropylene amine oxime single-photon emission computed tomography revealed sharply decreased cerebral blood flow, especially in the occipital area. Landau-Kleffner syndrome was suspected but a sleep electroencephalogram showed few abnormalities. He was started on clorazepate and diltiazem. A skin biopsy to rule out possible CLN2 revealed, instead of the predicted curvilinear profiles, granular osmiophilic deposits, consistent with infantile neuronal ceroid lipofuscinosis (CLN1). The family reported increased seizure frequency and consulted with a colleague, who advised them to resume valproate and discontinue diltiazem. The boy died shortly thereafter. Decreased cerebral blood flow is a new finding in CLN1 with delayed onset. Calcium-channel blockers improve cerebral blood flow and perhaps delay clinical regression.

Angelman syndrome: correlations between epilepsy phenotypes and genotypes.

We compared epilepsy phenotypes with genotypes of Angelman syndrome (AS), including chromosome 15q11-13 deletions (class I), uniparental disomy (class II), methylation imprinting abnormalities (class III), and mutation in the UBE3A gene (class IV). Twenty patients were prospectively selected based on clinical cytogenetic and molecular diagnosis of AS. All patients had 6 to 72 hours of closed-circuit television videotaping and digitized electroencephalogrpahic (EEG) telemetry. Patients from all genotypic classes had characteristic EEGs with diffuse bifrontally dominant high-amplitude 1- to 3-Hz notched or triphasic or polyphasic slow waves, or slow and sharp waves. Class I patients had severe intractable epilepsy, most frequently with atypical absences and myoclonias and less frequently with generalized extensor tonic seizures or flexor spasms. Epileptic spasms were recorded in AS patients as old as 41 years. Aged-matched class II, III, and IV patients had either no epilepsy or drug-responsive mild epilepsy with relatively infrequent atypical absences, myoclonias, or atonic seizures. In conclusion, maternally inherited chromosome 15q11-13 deletions produce severe epilepsy. Loss-of-function UBE3A mutations, uniparental disomy, or methylation imprint abnormalities in AS are associated with relatively mild epilepsy. Involvement of other genes in the chromosome 15q11-13 deletion, such as GABRB3, may explain severe epilepsy in AS.

Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain.

Neuronal changes in the brain of a Rett syndrome patient were examined in a frontal lobe biopsy performed at age 3 years and in the postmortem brain at age 15 years. In the brain biopsy, frontal cortex contained numerous scattered pyramidal neurons with cytoplasmic vacuolation and increased cytoplasmic density, with no neuronophagia or inflammation detected; electron microscopy showed these neurons to have large, lucent-appearing mitochondria, very abundant ribosomal content, and some lipofuscin granules. Postmortem brain 12 years later showed scattered neurons in frontal cortex, substantia nigra, and cerebellar folia, with increased electron density of the cytoplasm, stacks of ribosomal endoplasmic reticulum, and large amounts of disorganized membranous material, including autophagic-type organelles. Mitochondria of these neurons contained electron-dense, finely granular matrix inclusions; in the substantia nigra, some spherical mitochondrial inclusions completely filled the matrix space. Golgi preparations of (autopsy) frontal cortex and cerebellar folia showed truncation and thickening of dendrites and a degenerate appearance of cortical pyramidal neurons, similar to changes found in aged brain. Synaptophysin immunohistochemistry indicated that the density of synapses was not greatly altered compared to controls in frontal cortex and cerebellum. The patient also had a second genetic defect, severe combined immunodeficiency with thymic aplasia, which may be X-linked.

Rett syndrome associated with tuberous sclerosis in a male and in a female: evidence for arrested motor and mental development.

Two sporadic cases of tuberous sclerosis presented with flexion spasms in a male and early intractable seizures evolving into a Lennox-Gastaut syndrome in a female. Early hypotonia and lack of substantial motor development are key features of the Rett syndrome, more easily overlooked than hand-wringing. Clumsy self-feeding and immature ambulation were the highest achievements in the second case now aged 36 years. Immaturity rather than degeneration, dementia, or assumed tissue destruction, is the capital feature of many disorders of early brain development leading to profound motor as well as mental retardation. Studying unusual clinical combinations is more likely to shed light on the underlying etiology than focusing on procrustean syndrome definitions.

Multiple sulfatase deficiency: clinical, neuropathological, ultrastructural and biochemical studies.

We describe the clinical, pathological, ultrastructural and biochemical features in the case of a 15-year-old boy with multiple sulfatase deficiency. Clinical abnormalities included hypotonia, retarded psychomotor development, hepatosplenomegaly, pigmentary degeneration of the retina, myoclonic seizures, aortic insufficiency and quadriplegia. Urinalysis revealed increased heparan sulfate. At necropsy, aortic and mitral valves revealed nodular thickening and periodic acid-Schiff (PAS)-positive, metachromatic granules in renal proximal tubules. The brain weighed 400 g and demonstrated cerebral and cerebellar atrophy with a retrocerebellar meningeal cyst. Cortical neurons contained periodic acid-Schiff-positive and cresyl violet-reactive granules. White matter demonstrated brown metachromasia and intense fibrillary gliosis. Conjunctival fibroblasts contained amorphous vacuoles with dense osmiophilic nucleoid cores. Pleomorphic extracellular, intraneural and intraglial inclusions were noted in the brain. Activities of arylsulfatase A, B and C were diminished markedly in autopsied tissue from brain, liver, and kidney (0, 0 and less than 10% of control activities, respectively). Partial deficiencies of iduronate sulfatase and heparan sulfatase were noted in different tissues. Variable decreased enzyme activities were expressed in leukocytes: arylsulfatase A, less than 33%; B, 40%; and C, 90%; heparan sulfatase, 2%; and iduronate sulfatase was not detectable. Near normal activities were found in cultured fibroblasts.

Ninety-five percent splenectomy for massive splenomegaly: a new surgical approach.

Subtotal splenectomy for children with Gaucher's disease has been a major contribution. When spleens of massive size are mobilized for partial resection, it may be technically difficult to remove more than 80% to 85% and still maintain hilar blood supply. The short gastric vessels are enlarged in patients who have marked splenomegaly and provide sufficient vascularity to support the 5% of remaining spleen that is desired in these patients. When the upper pole of the spleen is retained, as in the present case, the cut surface is relatively small and hemostasis is technically easier to achieve than when resection is performed closer to the center of the spleen.

Bone-marrow transplantation for metachromatic leucodystrophy.

An 11-month-old boy with late infantile metachromatic leucodystrophy was given a bone-marrow transplant (BMT) from an HLA-identical sister; 6 months later his cerebrospinal fluid leucocytes were exclusively of donor origin. Coupled with the patient's continued developmental progress, as assessed 33 months after the procedure, the findings suggest that BMT may be an effective treatment for some congenital metabolic disorders which affect the central nervous system.

Peripheral hemodynamics in patients with Fabry's disease.

Altered vasomotor activity has been reported as a clinically prominent feature of Fabry's disease (angiokeratoma corporis diffusum universale). While symptomatic cardiovascular involvement occurs eventually in most patients with this disorder, little is known concerning the effect of Fabry's disease on peripheral hemodynamics. Peripheral hemodynamics in the extremities and digits were studied in eight patients with Fabry's disease by means of segmental and venous occlusion pneumoplethysmography and thermal probes, and the results obtained were compared with those of 10 normal subjects. Forearm vascular resistance in Fabry's disease patients was significantly higher (p less than 0.01) than that in normal subjects. Forearm venous capacitance in Fabry's disease was significantly lower (p less than 0.01). Segmental pulse volume amplitudes showed no significant difference in any segments (upper arm, wrist, thigh, above and below knee, and the calf) between the two groups. Finger and toe blood flow, finger and toe pulse volume, and temperature in the resting state were all significantly less (p less than 0.01, p less than 0.05: p less than 0.01, p less than 0.01: p less than 0.05, p less than 0.05, respectively) than those in normal subjects. Finger and toe blood flow and pulse volume after vasodilation procedures were significantly less (p less than 0.05, p less than 0.01: p less than 0.05, p less than 0.01, respectively) than those in normal subjects despite equal elevation of digital temperature obtained after vasodilation in both groups. These findings indicate the presence of vasoconstrictive process in both resistance vessels and capacitances vessels in cutaneous and skeletal muscular beds. A limited response in the cutaneous circulation to vasodilation procedures also was seen. These data suggest the possibility that latent enhanced sympathoadrenal discharge as well as the accumulation of glycolipid in the autonomic nervous system and vessel walls plays an important role in the disturbed pathophysiology of this disorder.

Neutral lipid storage with acid lipase deficiency: a new variant of Wolman's disease with features of the Senior syndrome.

A girl presented with small stature, obesity, tapetoretinal degeneration, deafness, psychomotor regression, seizures, acanthosis nigricans, hepatomegaly, and chronic tubulointerstitial nephropathy. She died at age ten with renal insufficiency and uncontrolled seizures. Histochemistry showed lipid storage in hepatocytes, histiocytes, smooth muscles and, to a much lesser extent, kidney tubules and cortical neurons. The liver had increased cholesterol esters (5-fold) and triacylglycerols (8-fold), and decreased phospholipids (50%). Methyllumbelliferyl-oleate, oleylcholestrol, trioleylglycerol, and tripalmitylglycerol lipase activities were markedly reduced in the liver, in the range found in Wolman's disease. In cirrhotic fatty livers these activities ranged from 7-87% of the normal mean. The patient's brain had limited neutral lipid storage and normal methyllumbelliferyl-oleate lipase. Trioleylglycerol lipase activity was 14-60% of controls; tripalmitylglycerol lipase activity 14-25% of controls; and oleylcholestrol lipase activity 12-33% of controls.

Multisystem triglyceride storage disorder with impaired long-chain fatty acid oxidation.

A five-year-old girl presented with congenital ichthyosis, hepatosplenomegaly, vacuolized granulocytes (Jordans' anomaly), and myopathy. Pathological, ultrastructural, and biochemical studies revealed nonlysosomal, multisystemic triglyceride storage. The cultured fibroblasts had increased uptake but decreased oxidation of labeled oleate. The patient failed to produce ketone bodies on fasting. A medium-chain triglyceride diet reversed the hepatomegaly. These studies are all consistent with a partial defect in the catabolism of long-chain fatty acids. This newly identified syndrome is presumably transmitted as an autosomal recessive trait.

Cultured skin fibroblasts in storage disorders. An analysis of ultrastructural features.

Electron microscopic studies were performed on cultured fibroblasts from patients with metachromatic leukodystrophy, Fabry's, Gaucher's, Niemann-Pick's (Type A and C), Sanfilippo's (Type A and B) disease, chondroitin-4-sulfate mucopolysaccharidosis, lipofuscinosis (Spielmeyer-Vogt's disease) and ceroid-lipofuscinosis (Batten's disease with curvilinear bodies). Specific cytoplasmic inclusions with a limiting membrane were identified in Fabry's disease, Niemann-Pick syndrome, chondroitin-4-sulfate mucopolysaccharidosis and Sanfilippo's Type B disease. In Fabry's disease, the lipid inclusions tended to form stacks of parallel and concentric membranes. In Niemann-Pick syndrome, the lipid inclusions were made of wavy, loosely packed membranes. In chondroitin-4-sulfate mucopolysaccharidosis and Sanfilippo B, the lysosomes were enlarged and contained a reticular matrix with little electron-dense material. No specific ultrastructural changes were observed in Gaucher's, Sanfilippo's (Type A) disease, metachromatic leukodystrophy (sulfatidosis) and Batten's disease.