Cutaneous Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors and Their Management.

Immune checkpoint inhibitors (CPIs) are highly effective in the treatment of various cancers. Immunotherapy enhances antitumor activity by relieving inhibition of T cells responsible for immune surveillance. However, overactivation of T cells leads to immune-related adverse events (irAE), of which cutaneous adverse events are the most common. Examples include pruritus and maculopapular eruption most commonly, psoriasis and bullous dermatoses less commonly, and, rarely, severe, life-threatening eruptions such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. Many of these are autoimmune in nature, and these may present de novo or as recurrence of pre-existing disease. In order to maximize the therapeutic potential of CPIs, it is essential to recognize and effectively manage cutaneous irAE, which can otherwise lead to treatment interruption or discontinuation. This review summarizes the presentation and management of dermatologic adverse events secondary to immune dysregulation as a result of immune checkpoint inhibitor therapy, including the most common (maculopapular eruption, pruritus, lichenoid dermatitis, and vitiligo), less common (psoriasis, bullous pemphigoid, erythema multiforme, eczematous dermatitis, alopecia areata, and granulo-matous and neutrophilic dermatoses), and severe (acute generalized exanthematous pustulosis [AGEP], drug reaction with eosinophilia and systemic symptoms [DRESS], and Stevens-Johnson syndrome or toxic epidermal necrolysis [SJS/TEN]), as well as exacerbation of pre-existing cutaneous autoimmune disease (subacute cutaneous lupus erythematosus, dermatomyositis, eosinophilic fasciitis, leukocytoclastic vasculitis, and scleroderma-like reaction).

[Therapeutic approaches for retinitis pigmentosa]. / Therapeutische Ansätze bei Patienten mit Retinitis pigmentosa.

BACKGROUND: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of hereditary retinal disorders, which lead to progressive loss of vision and finally blindness. Yet there is no approved therapy. Advances in unravelling underlying genetic disorders and pathophysiological mechanisms offer new therapeutic approaches of which some are summarised in this review. METHODS: We performed a systematic literature research for defined key words in PubMed. RESULTS: New approaches to therapy for RP include: gene therapy, pharmacological treatment, neuroprotection, electrical stimulation, retinal prostheses, retinal transplantation and optogenetic therapy. CONCLUSIONS: Recently there have been advances in new approaches for therapy of dystrophic retinal diseases. Advances in the different approaches are being made at different rates. Although there is no approved therapy yet, the future for treating RP at least in some patients looks promising.

The hippocampus as a cognitive graph.

A theory of cognitive mapping is developed that depends only on accepted properties of hippocampal function, namely, long-term potentiation, the place cell phenomenon, and the associative or recurrent connections made among CA3 pyramidal cells. It is proposed that the distance between the firing fields of connected pairs of CA3 place cells is encoded as synaptic resistance (reciprocal synaptic strength). The encoding occurs because pairs of cells with coincident or overlapping fields will tend to fire together in time, thereby causing a decrease in synaptic resistance via long-term potentiation; in contrast, cells with widely separated fields will tend never to fire together, causing no change or perhaps (via long-term depression) an increase in synaptic resistance. A network whose connection pattern mimics that of CA3 and whose connection weights are proportional to synaptic resistance can be formally treated as a weighted, directed graph. In such a graph, a "node" is assigned to each CA3 cell and two nodes are connected by a "directed edge" if and only if the two corresponding cells are connected by a synapse. Weighted, directed graphs can be searched for an optimal path between any pair of nodes with standard algorithms. Here, we are interested in finding the path along which the sum of the synaptic resistances from one cell to another is minimal. Since each cell is a place cell, such a path also corresponds to a path in two-dimensional space. Our basic finding is that minimizing the sum of the synaptic resistances along a path in neural space yields the shortest (optimal) path in unobstructed two-dimensional space, so long as the connectivity of the network is great enough. In addition to being able to find geodesics in unobstructed space, the same network enables solutions to the "detour" and "shortcut" problems, in which it is necessary to find an optimal path around a newly introduced barrier and to take a shorter path through a hole opened up in a preexisting barrier, respectively. We argue that the ability to solve such problems qualifies the proposed hippocampal object as a cognitive map. Graph theory thus provides a sort of existence proof demonstrating that the hippocampus contains the necessary information to function as a map, in the sense postulated by others (O'Keefe, J., and L. Nadel. 1978. The Hippocampus as a Cognitive Map. Clarendon Press, Oxford, UK). It is also possible that the cognitive mapping functions of the hippocampus are carried out by parallel graph searching algorithms implemented as neural processes. This possibility has the great attraction that the hippocampus could then operate in much the same way to find paths in general problem space; it would only be necessary for pyramidal cells to exhibit a strong nonpositional firing correlate.

The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study.

The magnitude of the health problem from diabetic neuropathies remains inadequately estimated due to the lack of prospective population-based studies employing standardized and validated assessments of the type and stage of neuropathy as compared with background frequency. All Rochester, Minnesota, residents with diabetes mellitus on January 1, 1986, were invited to participate in a cross-sectional and longitudinal study of diabetic neuropathies (and also of other microvascular and macrovascular complications). Of 64,573 inhabitants on January 1, 1986 in Rochester, 870 (1.3%) had clinically recognized diabetes mellitus (National Diabetes Data Group criteria), of whom 380 were enrolled in the Rochester Diabetic Neuropathy Study. Of these, 102 (26.8%) had insulin-dependent diabetes mellitus (IDDM), and 278 (73.2%) had non-insulin-dependent diabetes mellitus (NIDDM). Approximately 10% of diabetic patients had neurologic deficits attributable to nondiabetic causes. Sixty-six percent of IDDM patients had some form of neuropathy; the frequencies of individual types were as follows: polyneuropathy, 54%; carpal tunnel syndrome, asymptomatic, 22%, and symptomatic, 11%; visceral autonomic neuropathy, 7%, and other varieties, 3%. Among NIDDM patients, 59% had various neuropathies; the individual percentages were 45%, 29%, 6%, 5%, and 3%. Symptomatic degrees of polyneuropathy occurred in only 15% of IDDM and 13% of NIDDM patients. The more severe stage of polyneuropathy, to the point that patients were unable to walk on their heels and also had distal sensory and autonomic deficits (stage 2b) occurred even less frequently--6% of IDDM and 1% of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased weakness after pancreas and kidney transplantation.

BACKGROUND: Already there is evidence that simultaneous pancreas and kidney (SPK), or pancreas after kidney (PAK) transplantation, in patients with type 1 diabetes mellitus and end-stage kidney disease prevents worsening of diabetic polyneuropathy, but neuropathic improvement is delayed and incomplete. METHODS: In 85 patients with type 1 diabetes mellitus who underwent SPK or PAK transplantations, we performed sequential neuromuscular evaluations before, every 3 months after, and yearly after transplantation, quantitating muscle weakness separately from overall severity of polyneuropathy. RESULTS: We found that, on average, the weakness subscore of the Neuropathy Impairment Score of the lower limbs [NIS(LL)-W] was significantly worse at 3, 6, 9, and 12 months (by about 5 points) than at baseline. By contrast, for these times after transplantation, a composite score of nerve conduction abnormalities, an independent measure of severity of polyneuropathy, was not significantly worse and, in fact, was significantly improved. In multivariate analysis, length of hospital stay correlated with the increased weakness. CONCLUSIONS: We conclude that: (1) increased neuromuscular impairment after transplantation is mainly due to muscle weakness and not to worsening polyneuropathy; (2) in multivariate analysis, duration of hospitalization after transplantation was significantly associated with this increased weakness; (3) increased weakness is probably due to development of myopathy, which may be related to graft rejection, immunosuppression, sepsis, and intercurrent infections; (4) in future transplantation trials, weakness should be evaluated separately from neuropathic status, and the lowest efficacious dosages of immunotherapy should be used; and (5) essentially all diabetic patients reported that SPK or PAK transplantation was worthwhile because it freed them from diabetic lifestyle concerns.

Metastasis from untreated uveal melanomas.

From 1969 to 1985, 224 cases of choroidal or ciliary body malignant melanoma had metastatic evaluations at the Mayo Clinic, Rochester, Minn. Five cases (2.2%) were found to have evidence of metastasis during the pretreatment evaluation. In each case, metastatic melanoma was verified histologically. Prior to enucleation or radiation treatment, we recommend a general medical evaluation, liver enzyme studies, and chest roentgenogram. Computed tomography (CT) of the liver should be performed if liver involvement is suggested by either the general medical evaluation or liver enzyme studies. Although CT of the liver in the initial surveillance of patients with choroidal or ciliary body melanoma is routinely performed at our institution, CT is not likely to produce a high yield of detectable disease in the presence of normal liver enzyme levels.

Structure and function of the corneal endothelium in diabetes mellitus type I and type II.

OBJECTIVE: To measure and compare corneal endothelial morphologic characteristics and function in subjects with diabetes mellitus types I and II. DESIGN: Forty-nine patients with diabetes mellitus type I and 60 patients with diabetes mellitus type II were recruited from the active practice of the Mayo Clinic, Rochester, Minn. Thirty-one normal subjects, divided by age into two overlapping groups of 20 each, served as controls. Corneal endothelial permeability and corneal autofluorescence were measured by fluorophotometry. Central corneal endothelial photographs were taken with a wide-field specular microscope, which also measured the corneal thickness. RESULTS: Neither the type I nor the type II diabetics differed from their controls in endothelial permeability and endothelial cell density. The type I diabetics had polymegethism, pleomorphism, increased corneal thickness, and increased corneal autofluorescence compared with their controls. Similar measured values were found in the type II diabetics, but they did not differ significantly from those of their age-matched controls. The type II diabetics were older than the type I diabetics, and the older control group showed changes similar to those seen in the diabetics; these changes were presumably associated with aging. The severity of retinopathy was significantly correlated only with corneal autofluorescence. CONCLUSION: The corneas of patients with type I diabetes mellitus exhibit abnormalities in endothelial cell morphologic characteristics and corneal autofluorescence. The changes resemble those that occur with aging in normal subjects, making them difficult to discern as abnormal in type II diabetics, who are usually older. We found no abnormalities in endothelial permeability in either type I or type II diabetics.

Altered fronto-central PINV topography and the primary negative syndrome in schizophrenia.

Postimperative negative variation (PINV) was recorded during a warned reaction time paradigm in 16 chronic DSM-IIIR schizophrenics in remission. Clinical symptoms were assessed by BPRS, SANS and the anhedonia scale of the Chapman Questionnaire. Ten healthy controls were studied in the same manner. Over the fronto-central area we found a significantly elevated PINV amplitude with an altered topographical distribution in the patient group. The difference values 'PINV Cz-PINV Fz' were correlated negatively with primary negative symptoms of schizophrenia.

Ocular lymphoma in a patient with chronic lymphocytic leukemia.

PURPOSE: To treat large-cell lymphoma in a patient with chronic lymphocytic leukemia and bilateral vitreous cells. METHODS: The patient underwent a diganostic vitrectomy. RESULTS: Biopsy of the vitreous specimen disclosed large B-cell lymphoma. Large B-cell lymphoma occurring in patients with chronic lymphocytic leukemia is referred to as Richter's syndrome. CONCLUSIONS: Large-cell lymphoma of Richter's syndrome can occur in the eye. This case expands the clinical spectrum of organ involvement in Richter's syndrome.

Vitreous hemorrhage and retinal vein rupture.

PURPOSE/METHODS: We examined a 23-year-old woman who had a sudden onset of floaters after self-induced emesis. RESULTS/CONCLUSIONS: Examination showed a dense vitreous hemorrhage originating from a rupture site in the wall of the superotemporal branch vein. We postulate a preexisting weakness in the retinal vein wall as a predisposing factor to rupture. This mechanism may explain some cases of vitreous hemorrhage associated with a Valsalva maneuver.

Aqueous humor dynamics in patients with diabetes mellitus.

PURPOSE: We measured aqueous dynamic variables in subjects with diabetes mellitus and correlated them with severity of retinopathy and metabolic control to determine whether diabetes affects the anterior circulation of the eye as it affects the posterior (retinal) circulation. METHODS: Sixty-one subjects with diabetes mellitus type 1 and 60 subjects with diabetes mellitus type 2 were recruited from the active practice of the Mayo Clinic. Thirty-two normal subjects, divided by age into two overlapping groups of 20 each, served as contemporaneous control subjects. The diabetic subjects were stratified into four groups according to severity of retinopathy. Aqueous humor flow was measured by clearance of topically applied fluorescein with a spectrofluorophotometer; outflow facility was measured by tonography; and intraocular pressure was measured by applanation tonometry. RESULTS: In type 1 diabetics, the mean intraocular pressure was slightly greater (14 +/- 3 mm Hg), compared with control subjects (12 +/- 2 mm Hg [P = .002]), while aqueous humor flow was slightly less (2.5 +/- 0.6 microliter/min), compared with control subjects (2.9 +/- 0.5 microliter/min [P = .023]). In type 2 diabetics, the intraocular pressure was 14 +/- 3 mm Hg, which did not differ from that of control subjects (14 +/- 3 mm Hg [P = .258]). Aqueous humor flow in type 2 diabetics (2.5 +/- 0.7 microliter/min) did not differ significantly from that of the control group (2.5 +/- 0.7 microliter/min [P = .961]). Tonographic facility of outflow was not significantly different in type 1 and type 2 diabetics and the control subjects. There was no significant correlation in aqueous humor flow, intraocular pressure, or tonographic facility of outflow to severity of retinopathy or hemoglobin A1c in either type 1 or type 2 diabetics. CONCLUSIONS: The dynamics of aqueous humor are not affected to any clinically significant extent in the early or middle stages of diabetic retinopathy. However, there is a tendency toward less aqueous humor flow in the advanced stages of retinopathy.

Whipple disease presenting as posterior uveitis without prominent gastrointestinal symptoms.

PURPOSE: To describe the clinical presentation and course of Whipple disease in an adult. METHODS: A 34-year-old man with phthisis bulbi in the right eye secondary to uveitis-induced neovascular glaucoma presented with severe acute posterior uveitis in the left eye. He underwent esophagogastroduodenoscopy and jejunal biopsy for evaluation of anemia. The posterior uveitis was treated with a subtenon injection of triamcinolone. RESULT: The diagnosis of Whipple disease was confirmed by polymerase chain reaction analysis of the jejunal biopsy that demonstrated Tropheryma whippelii rDNA. CONCLUSION: Although Whipple disease is typically evident with malabsorption, it can also present as uveitis without prominent gastrointestinal symptoms.

Structural and functional studies of the corneal endothelium in diabetes mellitus.

We performed specular microscopy, anterior segment ocular fluorophotometry, corneal pachymetry, and tonometry on 14 patients with chronic type I diabetes and nonproliferative retinopathy and on 14 age-matched control subjects. The eyes of patients with diabetes had an increased coefficient of variation of endothelial cell area, a decreased percentage of hexagonal endothelial cells, increased corneal autofluorescence, and increased intraocular pressure, which confirmed previous studies. There was no difference, however, in corneal thickness or endothelial permeability to fluorescein. Thus, we were unable to detect any abnormality in endothelial function in these diabetic corneas in the unstressed state, despite structurally abnormal endothelial cells.

Prognostic factors in choroidal and ciliary body melanomas with extrascleral extension.

In a retrospective study, 50 (8.2%) of 610 patients with malignant melanoma of the ciliary body or choroid had extrascleral extension. Of 46 patients for whom follow-up data were available, 24 (52%) survived five years, 20 (42%) survived ten years, and 17 (37%) survived 15 years. Factors that seemed to affect survival significantly included intraocular tumor size and extraocular tumor size and location. Our observations did not support the role of primary exenteration. Five patients (11%) with extrascleral extension had orbital recurrences and all died within 31 months of surgery regardless of treatment.

Aqueous humor flow in unilateral carotid stenosis.

Our purpose was to study the relationship between carotid artery occlusive disease and aqueous flow in human subjects. Aqueous humor flow was measured by fluorophotometry in seven patients with unilateral carotid artery disease documented by oculoplethysmography. The mean (+/- SD) flow was 2.03 +/- 0.38 microliter/min in the affected eyes, 2.44 +/- 0.66 microliter/min in the unaffected contralateral eyes, and 2.56 +/- 0.61 microliter/min in a group of 14 age-matched controls. A statistically significant difference (p < 0.05) in the aqueous flow rate was seen between the affected and unaffected eyes and between the affected and control eyes. Aqueous flow in the unaffected and control eyes was not statistically different. The anterior chamber volumes and intraocular pressures were also not significantly different among groups. Severe carotid artery disease may reduce aqueous humor formation by lowering ciliary body blood flow to a point beyond which the eye cannot compensate.

Changes in serum copper level during detoxification of acutely poisoned drug addicts.

Although it is known that drug addicts are a high-risk group for disruption of many homeostatic processes, little is know about changes in serum trace elements concentrations after taking the psychoactive substances. The aim of the study was to check the influence of the taking homemade heroin on serum level of copper. Blood samples were taken from 30 opiate addicts, and copper concentrations were measured by the means of atomic absorption spectrophotometry. The result of the study show that in the examined group, copper serum concentrations (1.35 mg/L) upon admission to the clinic were higher than in the control group (1.11 mg/L) but decreased during hospitalization (1.18 mg/L). There was no correlation between duration of stay at the hospital and changes in serum copper concentration.

Fetal hemoglobin as a possible marker of susceptibility to working conditions for certain men exposed to industrial pollutants.

In 43 from 222 men (19.4%) employed in a coking plant a higher than normal concentration of fetal hemoglobin (HbF) was found, whereas an elevated level of HbF was detected in only two from 87 persons (2.3%) working in the cold rolling mill of the steel mill 'Huta Sendzimira', Krakow, Poland. Subjects employed in the coking mill worked in a much more polluted atmosphere than those in the cold rolling mill. It is speculated that synthesis of HbF may be a marker of the effect of unfavorable working conditions on some susceptible persons.

Carbofuran poisoning of pregnant woman and fetus per ingestion.

A case of carbamate pesticide poisoning of a pregnant woman by carbofuran ingestion is presented. The mother recovered from the poisoning in the hospital but necrosis of the fetus was found. Toxicological findings of the liver, brain, and kidney of the fetus revealed carbofuran in concentrations comparable with the mother's blood. Our findings in the case contribute to the research on permeation of the placental barrier by chemical substances.

[Specific anesthetic procedures in acute poisoning]. / Specyfika postepowania anestezjologicznego w ostrych zatruciach.

The decline of mortality rate in acute poisoning is connected with a completely altered method of treatment, namely the method of intensive treatment and extracorporeal elimination of the poisons. The anaesthetist plays a specific role in the treatment of acute poisoning since he cooperates with toxicologist and takes active part both in reanimation and intensive treatment of the poisoned. Anaesthetic procedure in toxicology is used as causal therapy and the part it plays is specific especially in extracorporeal elimination of the poison from the body. The authors of these studies discussed the methods of anaesthetic treatment in acute poisoning and presented its dynamic use in the period from 1966 to 1937 in the Toxicological Clinic of the Medical Academy in Kraków.

[Ultrasonographic examinations of the liver in poisoning with Amanita Phalloides]. / Badania ultrasonograficzne watroby w zatruciu muchomorem sromotnikowym.

11 persons poisoned by Amanita phalloides with a clinical picture of the Amanita phalloides syndrome of various gravity were subjected to ultrasonographic tests of the liver. A group of the sick had control test after they had been cured. In ultrasonographic pictures the size of the organ, the changes of the structure and the vascular picture and the dynamics of the changes in connection with the clinical picture and the results of the biochemical tests were estimated. The ultrasonographic changes are not symptomatic for Amanita phalloides poisoning, but similarly to scintigraphic test of the liver they may serve as an exemplification of the morphological changes of the organ and the estimation of the dynamics of changes. Ultrasonographic tests, in case of Amanita phalloides poisoning, should be treated as complementary, providing an insight into the liver structure, without being detrimental to the patient.