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Purpose: Melanocortin 1 receptor (MC1R) has been shown in animal models to be a target for effective radionuclide therapy. This first-in-human clinical trial studied the safety and biodistribution of two novel MC1R-targeted imaging tracers designed to support the development of MC1R-targeted alpha particle therapy through image-based identification of MC1R and radiation dosimetry. Imaging was compared to MC1R expression by immunohistochemistry (IHC) of subjects’ melanoma tumors. Methods: Subjects with stage IV melanoma were randomized to receive either [203Pb]VMT01 SPECT/CT imaging followed by [68Ga]VMT02 PET/CT imaging approximately 1 month later, or vice versa in a cross-over design during their normal melanoma treatment course. Patient selection included a positive [18F]FDG PET/CT within 30 days of imaging tracer injection. 555 - 925 mBq of [203Pb]VMT01 was injected IV with imaging performed at 1, 4, and 24 hours. 74 - 277 mBq [68Ga]VMT02 was injected IV and imaging performed dynamically up to 1 hour, and at 2 and 3 hours. Due to an interruption in drug supply, only 3 subjects received [203Pb]VMT01 imaging. Key FDG-avid melanoma lesions were marked and presented to three experienced Radiologists serving as blinded reviewers. The blinded reviewers compared [18F]FDG PET/CT to experimental imaging and scored scans and key lesions on multiple metrics. Imaging positivity was defined as tumor uptake and retention of tracer in ≥ 1 melanoma tumors above background liver activity. Melanoma biopsy tissue was obtained and MC1R IHC performed as available. Results: 7 subjects were enrolled; 6 were imaged and 5 had available pathology. 3 of 6 imaged subjects had MC1R positive tumors via experimental imaging tracers. [68Ga]VMT02 PET/CT at 3 hours led to the best tumor to background ratio, and [203Pb]VMT01 SPECT/CT showed tumor retention at 24 hours. 4 of 5 subjects had positive MC1R staining by IHC. Of the 3 subjects with negative imaging, 2 had positive staining by IHC. Of the 3 subjects with positive imaging, 2 had available biopsies and all stained positive for MC1R by IHC. Conclusion: A subgroup of advanced melanoma patients were identified to express MC1R using new MC1R-targeted imaging agents. Full concordance between imaging and IHC of positive scans, but not with negative scans, suggests that IHC is a more sensitive biomarker detection method. Additional testing is needed to establish frequency of positive MC1R imaging in stage IV melanoma and its correlation to histological findings and treatment outcomes. Preferential tumor retention provides proof-of-concept that the MC1R-targeting therapy trial for [212Pb]VMT01 alpha-emitting therapy will deliver localized radiation to high MC1R expressing tumors as screened by [203Pb]VMT01 or [68Ga]VMT02. Imaging quality is sufficient for subject selection and dosimetry but may exclude subjects with MC1R receptor expression only detectable by IHC. Citation Format: Brenna M. Marks, Matthew Block, Geoffrey B. Johnson, Carrie B. Hruska, Mukesh K. Pandey, Andrew Paulsen, Michael K. Schultz, Michael A. McDonald, Edwin A. Sagastume, Frances L. Johnson. MC1R imaging and histology in the targeted imaging of melanoma for alpha-particle radiotherapy (TIMAR1) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT104.

The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.

Left atrial (LA) size, as determined by transthoracic echocardiography (TTE), predicts the risk of atrial fibrillation and stroke and the success of cardioversion. Transesophageal echocardiography (TEE) is increasingly used in these clinical situations. However, unlike TTE, measurement of LA size by TEE has not been standardized. To validate TEE measurement, we determined LA dimensions in 4 standard views by TTE at the same time in 121 patients undergoing TEE. The mid-esophageal basal short-axis view at the level of the aortic valve (TEE 30-60) was the only view in which complete visualization of a LA axis of measurement could be obtained with an acceptably high yield (97.2%). The measurement from this view provided a value that had the highest correlation between TTE and TEE (r = 0.758, P < .0001, 95% confidence interval 0.68-0.86; bias 0.37 ± 1 cm). Overall, TEE underestimated the LA dimension by 9% compared with TTE. These results suggest that the short-axis view at the level of the aortic valve is the preferred site for measuring the LA dimension by TEE. (J Am Soc Echocardiogr 2002;15:143-9.)

The debate over gun control has taken place in complete isolation from geographical considerations. It focuses on, for the most part, whether legalization would bring about more or fewer accidental deaths, and murders of innocents, than prohibition, and in the USA on the precise meaning of the second amendment to the Constitution. However, these deliberations, argue the authors of the present paper, can be enriched by incorporating into them a spatial context. When this is done, and they are combined with the property rights philosophy of libertarianism, some very different conclusions are drawn.

In the context of immunity, genomic sequence, epigenetic, and environmental factor diversity combine to propagate variable gene expression and immune function among individuals. We hypothesize that we can harness gene expression variability across people to study molecular immune phenotypes and predict individual responses to immune stimuli. To test this we used RNA-Seq to derive a set of genes whose expression is stable over time and differential among healthy people in peripheral blood CD4+ cells. This gene set, which we term the molecular immune response signature (MIRS), identifies transcriptomic “fingerprints” in each healthy person. The same gene set also identifies unique signatures in independent stage IV melanoma patients, and, intriguingly, groups the cancer patients with a particular subset of healthy people. We further clarified the subset by selecting MIRS genes that differentiate it from the other healthy subset. To test if a larger population of melanoma patients grouped with the same healthy subset we clustered additional independent patients with the healthy subsets using these genes. Each of the patient samples grouped with the cancer-associated healthy subset (p=0.00195). We also tested if the gene set would segregate an additional independent cohort of healthy donors into two subsets and found that it did. This, and the fact that no known demographics differentiate the healthy subsets, suggests the observed healthy phenotype may relate to a cancer-like phenotype. Pathway analysis implicates Th1-skewing in the cancer-associated healthy subset. Future directions include further understanding the biological impacts of the phenotype and using the MIRS to predict individual responses to immunotherapeutics.

Author(s): Yun, Juanita H; Block, Matthew; Botvinick, Elias H | Abstract: PURPOSE:Although left ventricular systolic function seems to be accurately represented on gated SPECT myocardial perfusion imaging, specific patterns of wall motion (WM) and thickening after coronary bypass graft surgery (CABG), demonstrated by other imaging methods, have not been characterized for gated SPECT myocardial perfusion imaging. METHODS:Gated SPECT myocardial perfusion imaging was studied in 30 consecutive patients after CABG (group 1) and 40 non-CABG patients-30 with normal stress perfusion studies (group 2) and 10 with known previous anterior wall infarction (group 3). Two expert readers evaluated epicardial and endocardial systolic WM. Regional WM and the thickening percentage were obtained using CEQUAL 20 segment bull's eye analysis and compiled into regional values. RESULTS:Qualitatively, the post-CABG patients had hypokinetic septum, a hyperdynamic lateral wall, and preservation of anterior WM. In 25 of 30 (83.3%) patients, an anterior systolic epicardial "swing" was evident and was different from the inward endocardial and epicardial motion seen in groups 2 and 3. Septal WM was decreased in group 1 compared with group 2 (2.9 vs. 6.0 mm, l 0.001), with no significant difference in septal thickening. This was not different from the reduced septal motion seen in group 3 (4.1 mm), which was accompanied by both reduced thickening and abnormalities of anterior WM. Lateral WM was increased in group 1 compared with group 2 (9.9 vs. 8.2, l 0.001), with no significant difference in lateral wall thickening (34.6% vs. 39%). CONCLUSIONS:There is a characteristic contraction pattern on gated SPECT myocardial perfusion imaging in post-CABG patients distinguished by apparent septal hypokinesis with preservation of septal wall thickening, apparent increase in endocardial lateral WM, and an anterior epicardial "swing," different from the contraction pattern seen in normal patients and those with previous anterior wall infarction. The related perfusion pattern aids in evaluation of the mechanism of these findings.

Backround: Heart block and bradycardia during sleep has been reported in patients with obesity. The occurrence of bradyarrythmias in patients after undergoing bariatric surgery has not been reported. Methods: Over a period of 6 months, 3 patients who underwent laparoscopic weight reduction surgery developed prolonged heart block during sleep. Clinical course and follow-up are presented. Results: All 3 patients were diagnosed with sleep apnea. For 2 of these patients this was a new diagnosis. The episodes of heart block coincided with their episodes of sleep apnea. During follow-up of at least 6 months, no patient has had any adverse consequences related to their nocturnal heart block. Conclusion: Heart block during sleep is sometimes seen in patients undergoing bariatric surgery. The cause is sleep apnea, which often is worsened in the postoperative state due to narcotic analgesics. These patients require treatment of their sleep apnea, not pacemakers.

The development of a rapid rate of regeneration of osteomalacic bone in a patient treated for acute granulocytic leukemia has been demonstrated for the first time. This positive bone balance was most intense at the time of maximal depletion of leukemic tissue. The authors postulate that new formation of osteomalcic bone is due to inability to maintain the rate of calcification parallel to that of bone formation. A similar abnormality occurs in egg-laying birds, in rapidly growing children on a diet suboptimal in vitamin D who have rickets, and in some patients with osteoblastic metastases.

1. A case of coexistenst chronic lymphatic leukemia and polycythemia vera is described. 2. The source of the erythrocytosis was not apparent. Erythroid hypoplasia was seen in the bone marrow, and there was no apparent extramedullary hematopoiesis in specimens of liver or spleen. 3. Plasma iron contenst was inordinately low, and this was confirmed by a correspondingly high plasma iron-binding capacity. No stainable iron could be demonstrated in the tissues examined. 4. The curve for plasma iron clearance was best satisfied by two components of different negative slopes. The more rapid had a half-time of 0.2 hours and probably represented removal of iron for erythropoiesis. The slower had a half-time of 10.2 and probably represented extrahematopoietic iron utilization. 5. Erythrocyte radioiron utilization was greater than normal and approximated 100 per cent within nine days. This could have been a manifestation of depleted iron stores, accelerated erythropoiesis, or both.

A plastic tissue embedding technic which is rapid and simple enough for routine clinical and research usage has been described. Tissues were routinely processed at 2 µ and 4 µ in a hospital laboratory within 16 hours. The quality of the sections was superior to those obtained with paraffin so that cell types are clearly recognizable. Advantages of this process over paraffin embedding include ease of storage and superior preservation of cytological detail.

Practically all prior investigations of the effect of therapy upon the spleen of patients with leukemias and lymphomas have been limited to studies made at autopsy. It is the purpose of this paper to investigate the histopathologic effects of treatment of these diseases by comparing the morphology of biopsy specimens obtained following treatment with a control biopsy obtained immediately prior to therapy. Materials and Methods Technic: Biopsy of the spleen was performed with a Vim-Silverman needle by transthoracic or transabdominal route (1). A piece of tissue about half to two-thirds as thick as the lead in a pencil (1 mm.) and varying from 1 to 3 cm. in length (usually 2 to 3 cm.) was obtained. The larger spleens were biopsied transabdominally, since this is probably safer in the thrombopenic patient, a category into which most of the cases fell. There were no serious complications except for a temporary fall in blood pressure in a single instance. Splenic tissue was prepared by the Maximow technic: Imm...

During the past three years we have had the unusual opportunity to observe 12 patients for as long as 27 months prior to the development of acute myelogenous or stem cell leukemia. During the preleukemic phase, the transitional phase to acute leukemia, as well as thereafter until death, their clinical courses were recorded, frequent complete peripheral blood cell counts were made, and serial biopsies of the bone marrow and, in some cases, biopsies of liver and spleen were obtained. Interest in the preleukemic phase of human acute leukemia has been heightened by recent studies in induced mouse leukemia. In both humans 1 and mice, the disease is usually rapidly fatal, with only short remissions sometimes produced by steroid or antifolic acid therapy. In the mouse, however, treatment with cortisone in the preleukemic phase of the disease has been shown to decrease the incidence of leukemia induced by x-ray 2 and

The following conclusions can be made concerning the cause of anemia in patients with untreated chronic lymphatic leukemia excluding the rare case with an autoimmune hemolytic anemia: 1. Early in the natural history of the disease there is a normal amount of erythroblastic tissue which produces red cells at a normal rate. The rate of red cell destruction is also normal. 2. With progression of the disease the erythroblastic tissue is gradually replaced by lymphatic tissue, leading to a decrease in red cell production. The rate of red cell destruction is still normal. 3. Only late in the disease may decreased rate of red cell production be aggravated by an increased rate of red cell destruction.

The clinical course of ninety-five cases of lymphomas and leukemias following therapy with methyl bis β-chloroethyl amine hydrochloride has been reviewed. These included fifty-seven cases of Hodgkin's disease, ten cases each of lymphosarcoma and chronic lymphatic leukemia, five cases of follicular lymphoblastoma, six cases of chronic myeloid leukemia and nine cases of other related diseases. The response of each case is classified according to criteria based on the period of amelioration of symptoms and duration of effective nitrogen mustard therapy. The clinical improvement and marked palliation in cases, even those responding only briefly, indicates the value of this method of therapy in Hodgkin's disease, lymphosarcoma and chronic lymphatic leukemia. The survival of forty patients with Hodgkin's disease averaged 40 months with a response to nitrogen mustard of twelve months. The seventeen patients still alive have responded 22.4 months and have an average duration of 65 months. This compares well with the best results reported for x-ray therapy and is especially encouraging in view of the terminal status of 50 per cent of the patients at the onset of nitrogen mustard therapy. Roentgen-resistant cases survived slightly longer but had a shorter response to nitrogen mustard than when irradiation was interrupted. Irradiation should be continued as long as feasible in controlling local tumor masses, with nitrogen mustard as adjunctive therapy in suppressing multicentric dissemination of the disease. Nitrogen mustard cannot be recommended as the sole therapeutic agent in lymphomas. As a rule the patient who responds well to irradiation will also respond well to nitrogen mustard. Toxic manifestations of nitrogen mustard therapy were of significance only in five terminal cases which developed anemia, leukopenia and purpura. However, these symptoms as the presenting toxic features of lymphoma prior to nitrogen mustard therapy were frequently controlled for considerable periods. The response of lymphosarcoma and chronic lymphatic leukemia is of sufficient promise to suggest continued use of nitrogen mustard therapy in cases selected according to certain clinical features.

SummaryOpossums were thymectomized when lymphatic tissue had developed in some lymph nodes but not in the spleen. They were sacrificed 2 weeks later. Lymph nodes were grossly deficient in small and medium lymphocytes and lymphatic tissue did not appear in the spleen. Myeloid tissue not only persisted but was found greatly increased in amount at a time when it would have normally decreased. Maturation and proliferation of this tissue was abnormal, being characterized by maturation arrest and ineffective erythropoiesis. These findings indicate that the thymus influences the origin of lymphatic tissue, at least in the spleen, maintenance of lymphatic tissue in lymph nodes, and suppression of myeloid tissue in lymph nodes and spleen.

The effect of a MLD of total body irradiation on the "embryonic" thymus of the opossum was analyzed. The destructive effect depended on cell types in the thymus when irradiated. Small lymphocytes immediately after formation were more sensitive to irradiation than older small lymphocytes. Hassall's corpuscles and epithelial cells were most resistant to the destructive effect of irradiation. Mitoses were most suppressed at 16 hours after irradiation. The suppressive effect was greatest when the thymus was filled with small lymphocytes at the time of irradiation. "Embryos" irradiated when the mitotic index was highest had an elevated mitotic index. Irradiation of epithelial thymus delayed first appearance of lymphocytes about 2 days. The sequence of appearance of lymphocytes in the "embryonic" thymus after irradiation recapitulated normal embryogenesis. Regeneration of lymphocytes in older "embryos" was modified because of the persistence of small lymphocytes after irradiation. These cells eventually disappe...

Sarcoid is a generalized disease with fairly characteristic but nonspecific, noncaseating granulomas found most frequently in the hematopoietic tissues. Clinically it is usually manifested by a chronic course with fever and various combinations of lymphadenopathy, splenomegaly, and hepatomegaly. Leukopenia and reversal of the protein albumin-globulin ratio are frequent. A fairly characteristic diffuse lesion in the lung fields, hilar lymphadenopathy, and, less frequently, osteolytic lesions of the small bones of the hands and feet may be found on x-ray examination. A negative tuberculin reaction, even with old tuberculin in 1:10 dilution, and a positive Kveim reaction occur in almost all patients. Since numerous diseases may mimic sarcoid in one or more of these respects, it is necessary that one demonstrate as many of these phenomena as possible in order to make a definite diagnosis. More important and usually more difficult is the demonstration of the non-caseating granuloma. The usual method is

The production of agglutinins to Salmonella typhi was studied in the opossum embryo in the period immediately before and after the development of thymic and lymph node lymphoid tissue. Antibody was found only in embryos older than 8 days which corresponds to an 8- to 10-week human embryo in terms of organogenesis and is the earliest stage at which antibody production has been recorded.

Four hundred seventy-one adult patients and ten adult prisoner volunteers received 2,099 intravenous (IV) injections of iron dextran (Imferon), usually 250 to 500 mg at less than 100 mg/min. Intravenous iron supplies enough iron to permit RBC formation greater than 50 mL/day and repletion of tissue iron. Tissue iron did not always supply iron at an optimal rate. Hemoglobin production was higher after IV than oral or intramuscular iron if the hemoglobin level was less than 9 g/dL. Three life-threatening immediate anaphylactoid and eight severe delayed reactions were observed. There were no deaths. Delayed reactions were more frequent in women and collagen-vascular diseases and less frequent in pregnancy. Because anaphylactoid reactions are serious and unpredictable, IV iron dextran should be used only when iron deficiency anemia cannot be treated adequately with oral iron. ( JAMA 243:1726-1731, 1980)

Introduction It has been known since 1903 1 that clinical and hematologic remissions in chronic myelogenous leukemia, a generalized disease, follow irradiation therapy localized to the spleen. 2,3 The white count will fall and the hemoglobin rises. It has also been apparent that the beneficial effects of irradiation persist for some time after the cessation of therapy. 4-5 In an attempt to understand this phenomenon, studies of the sternal bone marrow have been made in these patients following splenic irradiation. Early observers reported contradictory results. 5-9 In more recent work, a decrease in marrow granulocytic tissue 10 and a decrease in the number of mitotic figures in the marrow 11 were observed following splenic irradiation. All of these studies, however, have short-comings in that (1) reliance was placed upon study of bone marrow smears which do not portray accurately the structure of the marrow, 12,13 and (2) patients were not

Excerpt An early and major role in development of immunologic capacity is played by the thymus, which induces development of extrathymic lymphatic tissue and of immunologically competent cells in t...

Excerpt Blood formation may be analyzed in terms of kinetics (the rate of production of cells) and maturation (elaboration of specific morphologic and functional features characteristic of a cell; ...

Transfusion of banked autologous blood was used for intraoperative and postoperative blood replacement in 178 patients. Up to 4 units of blood can safely be drawn within ten days before operation. Each phlebotomy was followed by the intravenous administration of 250 mg of iron dextran injection (Imferon) to furnish the bone marrow with adequate iron for red blood cell replacement. All patients came to surgery with hemoglobin levels greater than 10 gm/100 ml and hematocrit values greater than 30%. None showed clinical evidence of blood volume depletion. Autologous transfusion avoids almost all of the problems associated with homologous transfusion; most importantly, it avoids transmission of hepatitis.

A review of the literature on polycythemia vera reveals that only 10 cases have been described in the Negro race. If all of these cases were valid examples of polycythemia vera, the following patient would be the 11th case to be reported. Report of Case History.— A 48-year-old Negro woman was first seen in the Hematology Clinic of Colorado General Hospital on May 16, 1958. The patient complained of mild occipital headache, dizziness, and bleeding gums of two years' duration. Two years prior to admission she had bled excessively after tooth extraction. In August, 1957, she was hospitalized because of an acute swelling of the right leg, presumably a thrombophlebitis. At this time she was told that she had too much blood, and during the following few months a pint of blood was removed on two occasions. After this procedure, she received an unknown medication for several months. The only

One of us (M.H.B.) had observed that the number of erythroblasts is increased in the marrow of patients with chronic myelocytic (granulocytic) leukemia who have bled chronically. This erythroblastic hyperplasia, in patients with a malignant proliferation of granulocytes, has considerable theoretical significance. In three cases of chronic myelocytic leukemia increased red blood cell production and erythroblastic hyperplasia resulted from chronic bleeding. In one case the bleeding was spontaneous; in the other two cases repeated phlebotomies were done to stimulate erythropoiesis. Materials and Methods One unit of whole blood (500 ml) was removed each week from two patients (cases 1 and 2) unless hemoglobin level was considerably lower than the previous week, or unless it was below 11.0 gm/100 ml. The iron lost at each phlebotomy was replaced intravenously with 5 ml of iron dextran injection (Imferon) containing 250 mg of elemental iron. We occasionally gave iron dextran injection even when