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Marylanders defeat Philadelphia: yellow fever updated.

Those strategic points which influence this amateur historian to declare a victory for Baltimore and Maryland over Philadelphia are: I. Based upon clinical and epidemiological data, two Marylanders, Potter and Davidge, were among the first to contest Rush and his contagion theory; they told him so and published their views. To prove this point, Potter went to the extreme of inoculating himself with presumedly infected material. Stubbins Ffirth, a young University of Pennsylvania medical student, did the same four years later. To Rush's credit was ultimate abandonment of his originally held views. II. John Crawford, of Baltimore, although not the originator of the insect concept of transmission of infectious agents, published his concepts in 1811. III. Henry Rose Carter, a Maryland graduate, clearly delineated, in 1898, that after identification of an index case of yellow fever an extrinsic incubation period was necessary before the evolution of secondary cases. IV. James Carroll, another University of Maryland graduate, who worked as Deputy under Walter Reed with Lazear and Agramonte, helped prove Finlay's original concept that the Aedes aegypti mosquito was the natural vector of yellow fever. Carroll himself was the first experimentally induced case. V. Studies in primates provide new approaches for management of yellow fever. Nutritional support and treatment with specific anti-viral agents may be useful for therapy of human yellow fever. Maryland members of the Climatological are mindful of Philadelphia's rich medical heritage and of the many battles won in the City of Brotherly Love. Physicians in colonial and early America experienced The best and worst of times, theirs was an age of foolishness and belief, of incredulity and light, of darkness, despair and hope. This tale of two cities ends in peace.

Animals↗

[Philadelphia chromosome-negative chronic myelogenous leukemia with trisomy 13].

Trisomy 13, as a sole karyotypic abnormality in acute leukemia, has been reported in several cases. However, in chronic myelogenous leukemia (CML), only two cases with this abnormality were reported so far. We describe herein a 68-year-old case with Philadelphia chromosome-negative CML and trisomy 13. Leukocytosis was pointed out during the treatment for other diseases. After 7 months, abrupt increase in leukocyte count (108,000/microliters) and splenomegaly developed. Decreased neutrophil alkaline phosphatase activity and morphological features fulfilled the diagnostic terms for CML. However, the karyotypic analysis revealed trisomy 13 instead of Philadelphia chromosome, and the BCR gene rearrangement was not detected. In cases with acute leukemia accompanied by trisomy 13, malignant transformation of an immature hematopoietic precursor cell has been suggested by the expression of antigens characteristic of both the myeloid and lymphoid lineage. In a few cases with myelodysplastic syndrome, a multipotent stem cell disorder, trisomy 13 has also been reported. From these standpoints, there might be a possibility that trisomy 13 as a sole abnormality in hematologic disorders would be related to tumorigenesis in the levels of multipotent stem cells.

Aged↗

Molecular analysis of a case of Philadelphia chromosome-positive acute myeloid leukemia.

This report describes a precise molecular analysis of a rare case of Philadelphia chromosome (Ph) positive acute myeloid leukemia (AML) (FAB classification M2). Phenotypic markers were positive for cells of the myeloid lineage, but negative for B cell and T cell lineage. The leukemic cells carried a Philadelphia chromosome. Major breakpoint cluster region (M-BCR) rearrangement was detected by the Southern blot analysis. Reverse transcriptase polymerase chain reaction analysis revealed the presence of b3a2 BCR/ABL mRNA transcripts. The patient achieved complete remission by conventional remission induction therapy for acute myeloid leukemia. M-BCR rearrangement could not be detected during complete remission. After hematological remission of an 8-month duration, the patient relapsed and died of respiratory distress due to pneumonia. Our case indicate Ph-positive AML with M-BCR rearrangement actually exists. Ph-positive AML carries either M-BCR rearrangement expressing the P210 BCR-ABL or minor breakpoint cluster region (m-BCR) rearrangement producing the P190 BCR-ABL. Therefore, additional other factor (s) apart from the Ph chromosome must be responsible for the acute malignant transformation.

Aged↗

Allogeneic bone marrow transplantation for Philadelphia chromosome-positive chronic myelogenous leukemia in childhood.

Allogeneic bone marrow transplantation (BMT) offers the only potential for long-term control of chronic myelogenous leukemia. From November 1992 to August 1994, we prospectively studied five pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia, a unique finding in Taiwan, who were treated with allogeneic BMT at different stages of the disease. Their ages at diagnosis ranged from 2 to 10 years. Four donors were HLA-matched siblings and the other was an HLA-matched unrelated donor. All patients received busulfan (4 mg/kg/day for 4 days) followed by cyclophosphamide (60 mg/kg/day for 2 successive days) as the conditioning regimen. Engraftment was documented within 22 days after transplantation in all five patients. Two out of the four patients in the sibling donor group, both of whom had BMT in the first chronic phase, achieved event-free survival after follow-up for 41 months and 17 months. The other two patients, who had BMT in the second lymphoblastic crisis and the second chronic phase, died within 6 months after transplantation due to lymphoid blastic crisis and complication of cytomegaloviral pneumonitis, respectively. The patient who received marrow from the unrelated donor underwent BMT in the accelerated phase and died within 6 months after transplantation due to myeloid blastic crisis. In conclusion, allogeneic BMT performed in the first chronic phase of childhood Philadelphia chromosome-positive chronic myelogenous leukemia seems to have better results than BMT after the first chronic phase.

Bone Marrow Transplantation↗

Frontline therapies for adult patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia: a systematic literature review.

OBJECTIVES: Philadelphia (Ph) chromosome-negative B-cell acute lymphoblastic leukemia (B-ALL) is the most common ALL in adults. Overall survival (OS) with frontline chemotherapy remains poor. Blinatumomab is currently the only targeted agent approved for frontline treatment. METHODS: We systematically reviewed 96 studies (43 interventional, 53 observational) between 2012-2026 evaluating frontline pharmacologic therapy in adults with Ph- B-ALL. RESULTS: Across chemotherapy studies, nearly half of patients relapsed within 3 years, and only 49%-69% survived beyond 3 years. Blinatumomab demonstrated robust and consistent efficacy in first complete response (CR1), supported by 2 randomized controlled trials (RCT) and 16 single-arm trials (SAT). In one RCT, blinatumomab reduced the risk of death by 59% versus chemotherapy alone (HR 0.41) when added to frontline consolidation in minimal residual disease (MRD) negative patients. Median OS reached 41.2 months in a SAT where blinatumomab monotherapy was administered to patients in MRD-positive CR1. SATs showed consistent efficacy outcomes regardless of age, MRD status, or chemotherapy backbone. DISCUSSION: Additional targeted therapies still under investigation have shown mixed results. CONCLUSION: Frontline inotuzumab (±blinatumomab) plus chemotherapy showed promise in older populations, while the efficacy benefit of rituximab was inconclusive. No new safety signals were identified in the frontline setting for targeted therapies.

Humans↗

Overweight among young children in the Philadelphia health care centers: incidence and prevalence.

OBJECTIVES: To estimate the prevalence and incidence of overweight among low-income, inner-city children aged 3 to 7 years and to determine predictors of changes in body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) percentile. DESIGN: Retrospective cohort study using administrative and medical records. SETTING: The Philadelphia Health Care Centers, 1996 through 2003. PARTICIPANTS: Three hundred eighty-six patients who had at least 2 well-child visits between the ages of 3 and 7 years, had at least 1 visit between September 2001 and 2003, and were between the ages of 5 and 7 years at the most recent visit. Mean follow-up time was 2.4 years. MAIN EXPOSURES: Age, sex, race/ethnicity, and BMI percentile at baseline. MAIN OUTCOME MEASURES: Prevalence and incidence of overweight and at risk of overweight and change in BMI percentile. RESULTS: Prevalence of overweight at the initial visit was 18%, with 16% at risk of overweight. At the last visit, the prevalence of overweight was 19%, with 15% at risk of overweight. Based on maximum BMI percentile, 29% were overweight at some point and an additional 19% were at risk of overweight at least once. Annualized incidence of overweight among those not overweight at baseline was 5% per year: 2% per year for normal-weight children and 14% per year for children in the at-risk category. The outcomes were not associated with sex, race/ethnicity, or age at first or last visit. Incident overweight was positively associated with BMI percentile at baseline. CONCLUSION: The early onset and frequent persistence of overweight demonstrated herein underline the need to prevent overweight among very young children.

Body Mass Index↗

A survey of the health of homeless children in Philadelphia shelters.

We conducted a random-sample survey of homeless children and their mothers residing in Philadelphia (Pa) shelters. One hundred forty-six families were included in the final sample, resulting in an 80% response rate. The aims of the survey were to characterize the child's current and past health status, to determine access to and use of medical services, and to determine the serum erythrocyte protoporphyrin levels and tuberculin skin test status of the children. In addition, psychological tests were administered to both child and parent to assess developmental level and psychological problems. Finally, detailed questions were asked concerning the reasons for the homeless condition. The important reasons for homelessness cited in the survey included physical abuse, substance abuse, disagreements with landlords, and poor living conditions. The children's health problems included a high incidence of reported accidents and injuries, burns, and lead toxicity; the parents suffered from depression, physical abuse, and substance abuse. School-aged children tended to have low scores on tests of expressive vocabulary and word decoding, and preschoolers seemed to be below age expectations in receptive vocabulary and visual motor skills. The findings of this study suggest that homeless children tend to score poorly on developmental and psychological tests and tend to sustain serious burns and accidents. Policy implications of the survey include suggestions for health screening, rehabilitation, and education.

Accidents↗

Craniosynostosis, Philadelphia type: a new autosomal dominant syndrome with sagittal craniosynostosis and syndactyly of the fingers and toes.

The acrocephalosyndactyly syndromes (ACS) are a group of clinically similar disorders that share the manifestations of craniosynostosis and a variety of hand and foot anomalies. Here we report on a 5-generation kindred segregating sagittal craniosynostosis and syndactyly of the fingers and the toes in an autosomal dominant manner. The anomalies seen in this kindred comprise a syndrome distinct from other craniosynostosis syndromes. For this novel syndrome, we propose the name craniosynostosis, Philadelphia type.

Acrocephalosyndactylia↗

Unusual expression of mRNA typical of Philadelphia positive acute lymphoblastic leukemia detected in chronic myeloid leukemia.

The Philadelphia chromosome (Ph) is found in both chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The Ph translocation, t(9;22)(q34;q11), can disrupt the BCR gene on chromosome 22 in one to two areas called the major (Mbcr1) and minor (mbcr1) breakpoint cluster regions. In CML the breakpoint has been mapped almost exclusively to Mbcr1, whereas in Ph positive ALL both Mbcr1 and the upstream mbcr1 breakpoints have been described. In this communication we describe an unusual patient with typical chronic phase Ph positive CML and evidence of the uncharacteristic mbcr1 breakpoint, predicting expression of the ALL-type p190 fusion protein. Fluorescence in situ hybridization demonstrated BCR gene rearrangement, the reverse transcription polymerase chain reaction detected the BCR-ABL fusion mRNA characteristic of the mbcr1 breakpoint, and failed to detect BCR-ABL mRNA characteristic of the Mbcr1 breakpoint. Southern blot analysis revealed no rearrangement in Mbcr1, and direct sequencing of the PCR product confirmed it to be the ALL-type mbcr1 fusion mRNA with the first exon of the BCR gene fused to ABL exon a2. This case differs from the previously reported cases of "p190" CML in that the patient presented without abnormal hematopoietic features other than those found in typical CML and provides further evidence that the p190 mRNA is not sufficient to cause an acute rather than chronic leukemia.

Base Sequence↗

Cutaneous sarcoidosis in a patient with Philadelphia-positive chronic myelogenous leukemia treated with interferon-alpha.

A patient with Philadelphia-positive (Ph+) chronic myelogenous leukemia (CML) was diagnosed with cutaneous sarcoidosis after treatment with interferon-alpha (IFN-alpha). Following IFN-alpha dose reduction, the skin lesions disappeared. Few cases of sarcoidosis associated with IFN treatment have been reported, and only in one patient with pre-existing CML. Our patient was unique in that (1) the sarcoidosis was induced by the IFN-alpha treatment alone, (2) it developed de novo, and (3) it was confined to the skin.

Female↗

Role of granulocyte-macrophage colony-stimulating factor in Philadelphia (Ph1)-positive acute lymphoblastic leukemia: studies on two newly established Ph1-positive acute lymphoblastic leukemia cell lines (Z-119 and Z-181).

Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) is a malignant disorder characterized by a poor prognosis. In recent years hematopoietic growth factors have been used to recruit myeloid leukemia blasts into the proliferative phase of the cell cycle and as supportive agents, both with cytotoxic regimens and in the setting of bone marrow transplantation. This approach prompted us to investigate whether myeloid growth factors have a role in Ph1 positive ALL. To do this, we utilized two newly established Ph1-positive cell lines, Z-119 and Z-181. Both lines have L2 morphology, ultrastructural characteristics of lymphoblasts and typical B-lineage surface markers identical to those observed in the two Ph1-positive ALL patients from whom they were derived. In addition, a single rearranged immunoglobulin heavy-chain gene (JH) band was found in both cell lines by Southern blot analysis, confirming B-cell clonality. Cytogenetic analysis of the two lines revealed t(9;22). Polymerase chain reaction (PCR) amplified cDNA from both Z-119 and Z-181 cells revealed an e1--a2 BCR-ABL junction, and p190BCR-ABL protein was detected in them by the immune complex kinase assay. Both cell lines produce interleukin (IL)-1 beta, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), but neither IL-1 beta, G-CSF, their corresponding antibodies and inhibitory molecules, nor GM-CSF, affected the cell lines' growth. However, GM-CSF neutralizing antibodies inhibited Z-181 but not Z-119 colony formation in a dose-dependent fashion by up to 77% and addition of GM-SCF reversed this inhibitory effect. Receptor studies with radiolabeled GM-CSF demonstrated specific binding to Z-181 but not to Z-119 cells, and Scatchard analysis revealed that Z-181 cells express high-affinity GM-CSF receptors. Furthermore, PCR analysis showed that Z-181 but not Z-119 bears the transcript for the GM-CSF receptor. Finally, studies using PH1-positive ALL patients' marrow cells revealed similar data. In 3 of 8 samples we detected significant concentrations of GM-CSF (7.5-13 pg/2 x 10(7) cells) and in 2 of 3 cases GM-CSF significantly stimulated Ph1-positive ALL colony proliferation. These data suggest that Ph1-positive ALL cells may produce GM-CSF, express GM-CSF receptors and thus show a proliferative response to this cytokine.

Adult↗

Dendritic cells generated from blood precursors of chronic myelogenous leukemia patients carry the Philadelphia translocation and can induce a CML-specific primary cytotoxic T-cell response.

Dendritic cells (DC) are professional antigen-presenting cells specialized in the initiation of primary immune responses. We were interested to know whether mature DC can be grown in vitro from peripheral blood mononuclear cells (PBMC) of patients with chronic myelogenous leukemia (CML), and whether they carry the Philadelphia (Ph) translocation. Using a method recently described, DC were generated from PBMC precursors of 12 patients with CML using GM-CSF, IL-4, and monocyte-conditioned medium. DC exhibited the typical morphology with thin cytoplasmatic processes and expressed high levels of MHC class II, CD86, and CD83 typical for mature DC. After sorting with the monoclonal antibody CD83, a cell population of more than 95% CD83 positive cells was obtained. The presence of the Ph translocation was analyzed in these cells, in PBMC, lymphoblastoid cell lines (LCL), and in phytohemagglutinin (PHA)-induced T blasts from the same patients by fluorescence in situ hybridization (FISH). In contrast to all other cells analyzed, the vast majority of DC (95.9 +/- 0.7%) displayed the Ph translocation, irrespective of disease stage or therapy. PBMC were predominantly positive for the Ph chromosome (67.6 +/- 7.3%), whereas only 11.4 +/- 1% of the B cells and 4.4 +/- 1.1% of the PHA blasts carried the Ph translocation. Using such leukemic DC as antigen-presenting cells, a primary CML-directed cytotoxic immune response in vitro was obtained, as shown by the specific recognition of Ph chromosome positive cells. We conclude that DC can be generated from blood progenitors of CML patients in vitro and exhibit, to a large extent, the Ph translocation. Such DC, which in a preliminary experiment have been able to induce a primary CML-directed cytotoxic immune response in vitro, might be ideal candidates for adoptive immunotherapy either by direct transfer of DC for in vivo generation of a T-cell response or by in vitro generation of CML-specific cytotoxic autologous or HLA-matched normal T-cell clones for use in vivo.

Cell Line, Transformed↗

A de novo philadelphia chromosome-positive acute mixed-lineage leukemia with both major and minor BCR/ABL mRNA transcripts.

A patient with a Philadelphia chromosome (Ph)-positive acute mixed-lineage leukemia (AMLL) expressing both major and minor BCR/ABL mRNA transcripts is described. Phenotypic analysis of the leukemic blasts revealed positivity for both myeloid and B-cell lineages. Southern blot analysis showed a rearrangement of the immunoglobulin heavy chain (IgH) gene. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed the expression of both major and minor BCR/ABL mRNA transcripts. To our knowledge, this is the first report of AMLL expressing both major and minor BCR/ABL mRNA transcripts and rearrangement of the IgH gene.

Adult↗

Clinical and prognostic features of patients with Philadelphia chromosome-positive chronic myelogenous leukemia and extramedullary disease.

Twenty-four patients who developed extramedullary disease during the course of Philadelphia chromosome-positive chronic myelogenous leukemia are described. The most frequent sites of extramedullary disease were lymph nodes (54%), bone (37%), and skin and soft tissue (29%). The appearance of extramedullary disease was associated with a high incidence of other features of accelerated disease (37%) and with cytogenetic clonal evolution (62.5%). The median time from extramedullary disease to blastic crisis was 4 months, and the median survival was 5 months. At the time of analysis, 23 patients have died, 16 after evolving into blastic crisis, and 7 from progressive disease without satisfying the criteria of medullary blastic crisis. This study confirms the importance of extramedullary disease as a sign of poor prognosis in chronic myelogenous leukemia, and the need for alternate therapies when such an event develops.

Bone Neoplasms↗

CD34 antigen expression in children with Philadelphia chromosome-positive acute lymphoblastic leukemia.

One characteristic of Philadelphia chromosome (Ph')-positive acute leukemia is the occasional presence of both lymphoid and myeloid features in the same leukemia. This phenomenon supports the theory that this subtype of acute leukemia arises from lymphoid-myeloid stem cell, pluripotent progenitors. Very few reports, however, describe the immunophenotype, especially CD34 antigen, of Ph'-positive acute lymphoblastic leukemia (ALL). It has been shown that CD34, the human progenitor cell antigen, is found on 1% or less of normal human bone marrow cells, approximately 30% of acute leukemias, and multipotent progenitor cells; CD34 is not found on normal peripheral blood cells. A high frequency of CD34 expression was found in children with Ph'-positive ALL: CD34 was positive for all six patients tested, and one had an acute mixed-lineage leukemia. These findings suggest the involvement of a pluripotent stem cell in Ph'-positive ALL.

Antigens, CD↗

Intensive combination chemotherapy and autologous bone marrow transplantation leads to the reappearance of Philadelphia chromosome-negative cells in chronic myelogenous leukemia.

Fifteen patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who were ineligible for allogeneic bone marrow transplantation (BMT) or alpha-interferon therapy were included in this study. Eight patients were in the first late chronic phase, five were in the second chronic phase, one was in the accelerated phase, and one was in the blastic phase. Autologous bone marrow cells (median, 2.5 x 10(8) nucleated cells/kg) were stored at a median of 30 months after diagnosis. Patients were treated with cyclophosphamide (1.5 g/m2 daily for 4 days), carmustine (BCNU) (300 mg/m2), and etoposide (VP-16) (250 mg/m2 daily for 3 days) (CBV), followed by reinfusion of autologous bone marrow. Hematopoietic recovery was rapid, and toxicity was mild to moderate in 14 patients. One patient died of cytomegalovirus pneumonitis. Eight of 15 patients showed Ph suppression to less than 90% Ph-positive metaphases after autologous BMT. Major cytogenetic responses (Ph suppression to less than 35% Ph-positive metaphases) developed in four patients. Cytogenetic responses were observed in 4 of 11 patients infused with 100% Ph-positive marrows, and in all 4 patients infused with Ph-mosaic marrows (mixture of diploid and Ph-positive cells). Better results were observed when autologous BMT was performed in the chronic phase compared with the advanced phases. The major cytogenetic responses have lasted for 3, 4, 12, and 15+ months, whereas minor cytogenetic responses lasted for only a short time (less than 2 months). Three of seven patients (43%) in the chronic phase with previous resistance to alpha-interferon therapy became sensitive to alpha-interferon therapy after autologous BMT. The authors concluded that intensive chemotherapy followed by autologous BMT produced cytogenetic remissions in patients with Ph-positive CML and reinduced disease sensitivity to alpha-interferon therapy in patients previously resistant to it. This is particularly useful when treatment is given during the chronic phase and stem cells are collected at a time of previous cytogenetic remission.

Adult↗

Extramedullary blast crisis in chronic myelogenous leukemia. Demonstration of T-cell lineage and Philadelphia chromosome in a paraspinal tumor.

A case of chronic myelogenous leukemia (CML) with penetrance of the Ph1 molecular alteration into the T-cell lineage of a paraspinal tumor is reported. The T-cell nature of the paraspinal tumor was documented by immunochemical study and genotyping. The Philadelphia chromosome was also detected by genotyping in the same tumor cell population. To the authors' knowledge, this is the first case of extramedullary T-cell blast crisis in CML demonstrated in an extranodal tumor. The clinical significance of detecting extramedullary blast crisis, and the theories for the scarcity of T-cell transformation in CML are discussed.

Blast Crisis↗

The role of molecular techniques in the clinical management of leukemia. Lessons from the Philadelphia chromosome.

The Philadelphia chromosome (Ph1) was the first genetic change to be associated consistently with leukemia, and it is one of the best understood on the molecular level. Because of this, it is an excellent model to investigate the application of molecular techniques to the clinical setting. These techniques are reviewed as are their clinical use in chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and transplantation. The Ph1 is caused by the fusion of two genes on chromosomes 9 and 22, resulting in the BCR-ABL fusion gene. This new gene is believed to be the cause of these Ph1-positive leukemias. The ability to detect the BCR-ABL fusion gene evolved from cytogenetic detection to Southern blot analysis, and now includes sophisticated techniques such as polymerase chain reaction (PCR) methods and pulsed-field gels. Diagnosis of the BCR-ABL fusion gene by Southern blot detection of bcr genetic rearrangements is the prototype of molecular cancer diagnosis. The sensitivity and clinical uses of this test are reviewed, especially its application to monitoring the response to treatment. PCR methods enable the researcher to detect 1 CML cell in a population of 10(5) cells. Clinical experience with PCR, especially in transplantation medicine, is providing a better understanding of the meaning of the terms "remission" and "cure." Newer techniques using fluorescent in situ hybridization have considerable potential for BCR-ABL detection, but no clinical experience has been gained with these techniques currently. The diagnosis of the BCR-ABL fusion gene in ALL has important clinical implications because it is the most common molecular genetic change in adult ALL and is associated with short remissions and poor outcome in all age groups. Diagnosis of the BCR-ABL fusion in ALL is difficult because the molecular findings are more heterogeneous than they are in CML. The methods available and their accuracy and sensitivity are compared. A review of their clinical impact is included.

Fusion Proteins, bcr-abl↗