Objective: Improve the care of patients followed for acute leukemia in the Oncohematology department of the National Hospital of Niamey. Methods: This was a prospective study, over a period of 2 years from January 1, ...Objective: Improve the care of patients followed for acute leukemia in the Oncohematology department of the National Hospital of Niamey. Methods: This was a prospective study, over a period of 2 years from January 1, 2018 to December 31, 2019, in patients with acute leukemia in the Oncohematology department of the National Hospital of Niamey (HNN), whose diagnosis was made on a blood smear associated with a myelogram and immunophenotyping and who were consenting. Results: We collected 25 cases of acute leukemia confirmed by myelogram and immunophenotyping. The mean age of the patients was 31.32 years, with a predominance of women, a sex ratio of 0.92. Pupils and students were in the majority with 40% and most came from the Niamey region, i.e. 68%. Anemic syndrome was the most common clinical sign in 96%. ALL predominated in 64% of cases. On the blood count, the hyperleukocytosis was more marked in AML (mean white count: 197256.6 elts/mm3) than in ALL (137891.6 elts/mm3), it was the same for thrombocytopenia which is more marked in AML (75588.89/mm3) than in ALL (52156.25/mm3). Therapeutically, 52% of patients received chemotherapy. The mean overall survival was 16.223 ± 3.191 months, including a mean survival for AML of 6.853 ± 1200 months compared to 21.720 ± 5.920 months for ALL. Conclusion: Acute leukemia still remains a major problem in our context, due to the precariousness of limited financial, diagnostic and therapeutic resources. Thus reflecting in our results, the increasing number of cases, the diagnostic delay and the guarded prognosis. This is the reality in several other countries in the sub-region and even in certain developed countries.展开更多
The evolution of bone marrow morphology is necessary in Acute Mye-loid Leukemia(AML)prediction.It takes an enormous number of times to ana-lyze with the standardization and inter-observer variability.Here,we proposed ...The evolution of bone marrow morphology is necessary in Acute Mye-loid Leukemia(AML)prediction.It takes an enormous number of times to ana-lyze with the standardization and inter-observer variability.Here,we proposed a novel AML detection model using a Deep Convolutional Neural Network(D-CNN).The proposed Faster R-CNN(Faster Region-Based CNN)models are trained with Morphological Dataset.The proposed Faster R-CNN model is trained using the augmented dataset.For overcoming the Imbalanced Data problem,data augmentation techniques are imposed.The Faster R-CNN performance was com-pared with existing transfer learning techniques.The results show that the Faster R-CNN performance was significant than other techniques.The number of images in each class is different.For example,the Neutrophil(segmented)class consists of 8,486 images,and Lymphocyte(atypical)class consists of eleven images.The dataset is used to train the CNN for single-cell morphology classification.The proposed work implies the high-class performance server called Nvidia Tesla V100 GPU(Graphics processing unit).展开更多
<strong>Background:</strong> Acute Myeloid leukemia (AML) is the most prominent acute leukemia in adults. In the United States, we experience over 20,000 cases per year. Over the past decade, improvements ...<strong>Background:</strong> Acute Myeloid leukemia (AML) is the most prominent acute leukemia in adults. In the United States, we experience over 20,000 cases per year. Over the past decade, improvements in the diagnosis of subtypes of AML and advances in therapeutic approaches have improved the outlook for patients with AML. However, despite these advancements, the survival rate among patients who are less than 65 years of age is only 40 percent. <strong>Purpose:</strong> The purpose of the paper is to study if there exists any significant difference in the survival probabilities of male and female AML patients. Also, we want to investigate if there is any parametric probability distribution that best fits the male and female patient survival and compare the survival probabilities with the non-parametric Kaplan-Meier (KM) method. <strong>Methods:</strong> We used both parametric and non-parametric statistical methods to perform the survival analysis to assess the survival probabilities of 2015 patients diagnosed with AML.<strong> Results:</strong> We found evidence of a statistically significant difference between the mean survival time of male and female patients diagnosed with AML. We performed parametric survival analysis and found a Generalized Extreme Value (GEV) distribution best fitting the data of the survival time for male and female patients. We then estimated the survival probabilities and compared them with the frequently used non-parametric Kaplan-Meier (KM) survival method. <strong>Conclusion:</strong> The comparison between the survival probability estimates of the two methods revealed a better survival probability estimate by the parametric method than the Kaplan-Meier. We also compared the median survival time of male and female patients individually with descriptive, parametric, and non-parametric methods of analysis. The parametric survival analysis is more robust and efficient because it is based on a well-defined parametric probabilistic distribution, hence preferred over the non-parametric Kaplan-Meier estimate. This study offers therapeutic significance for further enhancement to treat patients with Acute Myeloid Leukemia.展开更多
Sunitinib is an orally administered, multi-target tyrosine kinase inhibitor that has been approved by the FDA for the treatment of renal cell carcinoma and imatinib resistant gastro-intestinal tumors. Anti-leukemic ac...Sunitinib is an orally administered, multi-target tyrosine kinase inhibitor that has been approved by the FDA for the treatment of renal cell carcinoma and imatinib resistant gastro-intestinal tumors. Anti-leukemic activity of sunitinib has been examined in early clinical trials with limited success. However, recent trials on acute myeloid leukemia (AML) patients carrying FLT3 mutations have shown promising results. Effects of sunitinib on leukemic clonogenic cells and potential leukemic stem cells have not been examined so far. We analyzed the anti-proliferative and apoptotic properties of sunitinib on AML-derived cell lines. We also tested the effect of sunitinib on AML patient derived clonogenic cells (AML-CFC), as well as flow-sorted potential leukemic progenitors. Peripheral blood or bone marrow samples were obtained from newly diagnosed AML patients and flow sorted for CD34+ CD133+ or ALDH+ cells. Umbilical cord blood derived CD34+ cells were used as normal controls. Sunitinib induced growth arrest and apoptosis in AML derived cell lines. In addition, 7 μM sunitinib induced 75% reduction of AML-CFC as compared to DMSO treated control (±6.79%;n = 4). In contrast, 7 μM sunitinib treatment of umbilical cord blood derived normal CD34+ cells showed 29% reduction in AML-CFC (±6.77%;n = 5). Treatment of ALDH+ cells sorted from 2 AML cases and CD34+ CD133+ cells from one patient showed reduction of AML-CFC on treatment with sunitinib. Our study highlighted a potent anti-proliferative and proapoptotic effect of sunitinib on AML cell lines, AML patient derived clonogenic cells and potential leukemic stem cells.展开更多
Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of res...Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.展开更多
Cutaneous presentation revealing acute myeloid leukemia (AML) is rare, and the prognosis is poor. We report a case of an 11-month-old male who presented with cutaneous lesions present as diffuse purplish papulo-nodula...Cutaneous presentation revealing acute myeloid leukemia (AML) is rare, and the prognosis is poor. We report a case of an 11-month-old male who presented with cutaneous lesions present as diffuse purplish papulo-nodular lesions, revealing M5 acute myeloid leukemia. Skin biopsy and immunohistochemical examination, combined with routine blood analysis and bone marrow examination, contributed to early diagnosis. However, despite intensive chemotherapy treatment, the prognosis was poor and death occurred during the first months of treatment.展开更多
Myeloid sarcoma(MS)is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia(AML).This neoplasm can also be an initial manifestation of relapse in a previously treated A...Myeloid sarcoma(MS)is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia(AML).This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission.A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010.After one month,bone marrow biopsy and aspiration confirmed the diagnosis of AML.Allogeneic mobilization peripheral blood stem cell transplantation was performed,with the sister of the patient as donor,after complete remission(CR)was achieved by chemotherapy.Five months after treatment,an adrenal mass was detected by positron emission tomography-computed tomography(PET-CT).Radiotherapy was performed for the localized mass after a multidisciplinary team(MDT)discussion.The patient is still alive as of May 2013,with no evidence of recurrent MS or leukemia.展开更多
Objective: To evaluate the therapeutic effect of the fludarabine and cytarabine (FA) regimen on acute myeloid leukemia (AML) at different phases during treatment. Methods: A total of 185 patients with AML were divided...Objective: To evaluate the therapeutic effect of the fludarabine and cytarabine (FA) regimen on acute myeloid leukemia (AML) at different phases during treatment. Methods: A total of 185 patients with AML were divided into 4 groups based on the outcome of previous treatments. Patients in Group 1 had no remission after the first course of induction chemotherapy (n = 55). Patients in Group 2 had no remission after no less than two courses of induction chemotherapy (n = 41). Patients in Group 3 had early relapse (n = 40). Patients in Group 4 had late relapse (n = 49). Patients in groups 2, 3 and 4 had refractory AML or AML with relapse. We assessed the efficacy and toxicity of FA combination chemotherapy in each of these 4 groups. Results: The complete remission (CR) rates of Groups 1, 2, 3 and 4 were 74.5% (41/55), 45.9% (19/41), 17.5% (7/40) and 38.8% (19/49), respectively. The CR rate was higher in Group 1 than in the other 3 groups (34.6%, 45/130) (P = 0.000). A significant correlation was found between CR rate and the number of chemotherapeutic courses (P = 0.023). The main adverse reactions included bone marrow suppression and secondary infection. Conclusion: FA regimen is a good choice for patients with AML, especially those who have failed to achieve CR after the first course of induction chemotherapy.展开更多
Background: Multiparameter flow cytometry is the most important method for the lineage assignment and maturational analysis of acute leukemias (AL) cells. The multi parametric immunophenotyping analysis allows the det...Background: Multiparameter flow cytometry is the most important method for the lineage assignment and maturational analysis of acute leukemias (AL) cells. The multi parametric immunophenotyping analysis allows the detection of aberrant antigen expression and the analysis of heterogeneity and clonality of malignant cells in AL. The aim of the work is to study the immunophenotypes of blasts from patients with AL and determine the frequency of aberrant markers. Subjects and Methods: Retrospective study to analyze immunophenotypic data of de novo 144 AL patients who were diagnosed in Clinical Pathology Department, Sohag University. Results: We found that 61.8% of AL patients were classified as acute myeloblastic leukemia (AML) while 38.9% classified as acute lymphoblastic leukemia (ALL). The commonest FAB subtype in AML group was AML-M2 (31.8%) followed by M4-M5 27.3%. As regard ALL, there were 85.7% with B-ALL and 14.3% with T-ALL. The aberrancy expressions were found in 66 of AL cases (45.8%), CD7 was the most commonly expressed lymphoid antigen in AML (25%), CD13 was the most commonly expressed myeloid antigen in ALL (39.3%). Conclusion: The multi parametric immunophenotyping analysis of AL is sufficient for diagnosis and classification of leukemia. The frequencies of展开更多
Acute leukemia is the most common childhood cancer and accounts for 31% of all cancers in children. There are two main types of acute leukemia. The most common is ALL （acute lymphoblastic leukemia） affecting the lym...Acute leukemia is the most common childhood cancer and accounts for 31% of all cancers in children. There are two main types of acute leukemia. The most common is ALL （acute lymphoblastic leukemia） affecting the lymphoid lineage, and the more rare AML （acute myeloid leukemia） affecting the myeloid linage. The intention of this thesis is to follow the course of treatment from the admission to the hospital until the last check up and also see how a child will react to the treatment and side effects in later life. We studied literature and my own case records from the period when I was treated for ALL. From the literature and my case records, we can see that children tolerate treatment quite well. Due to rapid diagnostics and the possibility to give high doses chemotherapy, the overall prognosis appears to be very good. Today, acute leukemias of paediatric patients have a really favourable prognosis. The overall survival rate for ALL is higher than 80% and for AML 65%. So the results are good, but there is still a long way to go before we can be satisfied. To date we do not have a contingency program for children treated for acute leukemia after 18 years of age （neither in Norway or Slovakia） so perhaps this should be a focus point in the future. It could be extended to follow up patients in adulthood in order to monitor late effects that may occur in later life after many years of treatment.展开更多
文摘Objective: Improve the care of patients followed for acute leukemia in the Oncohematology department of the National Hospital of Niamey. Methods: This was a prospective study, over a period of 2 years from January 1, 2018 to December 31, 2019, in patients with acute leukemia in the Oncohematology department of the National Hospital of Niamey (HNN), whose diagnosis was made on a blood smear associated with a myelogram and immunophenotyping and who were consenting. Results: We collected 25 cases of acute leukemia confirmed by myelogram and immunophenotyping. The mean age of the patients was 31.32 years, with a predominance of women, a sex ratio of 0.92. Pupils and students were in the majority with 40% and most came from the Niamey region, i.e. 68%. Anemic syndrome was the most common clinical sign in 96%. ALL predominated in 64% of cases. On the blood count, the hyperleukocytosis was more marked in AML (mean white count: 197256.6 elts/mm3) than in ALL (137891.6 elts/mm3), it was the same for thrombocytopenia which is more marked in AML (75588.89/mm3) than in ALL (52156.25/mm3). Therapeutically, 52% of patients received chemotherapy. The mean overall survival was 16.223 ± 3.191 months, including a mean survival for AML of 6.853 ± 1200 months compared to 21.720 ± 5.920 months for ALL. Conclusion: Acute leukemia still remains a major problem in our context, due to the precariousness of limited financial, diagnostic and therapeutic resources. Thus reflecting in our results, the increasing number of cases, the diagnostic delay and the guarded prognosis. This is the reality in several other countries in the sub-region and even in certain developed countries.
文摘The evolution of bone marrow morphology is necessary in Acute Mye-loid Leukemia(AML)prediction.It takes an enormous number of times to ana-lyze with the standardization and inter-observer variability.Here,we proposed a novel AML detection model using a Deep Convolutional Neural Network(D-CNN).The proposed Faster R-CNN(Faster Region-Based CNN)models are trained with Morphological Dataset.The proposed Faster R-CNN model is trained using the augmented dataset.For overcoming the Imbalanced Data problem,data augmentation techniques are imposed.The Faster R-CNN performance was com-pared with existing transfer learning techniques.The results show that the Faster R-CNN performance was significant than other techniques.The number of images in each class is different.For example,the Neutrophil(segmented)class consists of 8,486 images,and Lymphocyte(atypical)class consists of eleven images.The dataset is used to train the CNN for single-cell morphology classification.The proposed work implies the high-class performance server called Nvidia Tesla V100 GPU(Graphics processing unit).
文摘<strong>Background:</strong> Acute Myeloid leukemia (AML) is the most prominent acute leukemia in adults. In the United States, we experience over 20,000 cases per year. Over the past decade, improvements in the diagnosis of subtypes of AML and advances in therapeutic approaches have improved the outlook for patients with AML. However, despite these advancements, the survival rate among patients who are less than 65 years of age is only 40 percent. <strong>Purpose:</strong> The purpose of the paper is to study if there exists any significant difference in the survival probabilities of male and female AML patients. Also, we want to investigate if there is any parametric probability distribution that best fits the male and female patient survival and compare the survival probabilities with the non-parametric Kaplan-Meier (KM) method. <strong>Methods:</strong> We used both parametric and non-parametric statistical methods to perform the survival analysis to assess the survival probabilities of 2015 patients diagnosed with AML.<strong> Results:</strong> We found evidence of a statistically significant difference between the mean survival time of male and female patients diagnosed with AML. We performed parametric survival analysis and found a Generalized Extreme Value (GEV) distribution best fitting the data of the survival time for male and female patients. We then estimated the survival probabilities and compared them with the frequently used non-parametric Kaplan-Meier (KM) survival method. <strong>Conclusion:</strong> The comparison between the survival probability estimates of the two methods revealed a better survival probability estimate by the parametric method than the Kaplan-Meier. We also compared the median survival time of male and female patients individually with descriptive, parametric, and non-parametric methods of analysis. The parametric survival analysis is more robust and efficient because it is based on a well-defined parametric probabilistic distribution, hence preferred over the non-parametric Kaplan-Meier estimate. This study offers therapeutic significance for further enhancement to treat patients with Acute Myeloid Leukemia.
文摘Sunitinib is an orally administered, multi-target tyrosine kinase inhibitor that has been approved by the FDA for the treatment of renal cell carcinoma and imatinib resistant gastro-intestinal tumors. Anti-leukemic activity of sunitinib has been examined in early clinical trials with limited success. However, recent trials on acute myeloid leukemia (AML) patients carrying FLT3 mutations have shown promising results. Effects of sunitinib on leukemic clonogenic cells and potential leukemic stem cells have not been examined so far. We analyzed the anti-proliferative and apoptotic properties of sunitinib on AML-derived cell lines. We also tested the effect of sunitinib on AML patient derived clonogenic cells (AML-CFC), as well as flow-sorted potential leukemic progenitors. Peripheral blood or bone marrow samples were obtained from newly diagnosed AML patients and flow sorted for CD34+ CD133+ or ALDH+ cells. Umbilical cord blood derived CD34+ cells were used as normal controls. Sunitinib induced growth arrest and apoptosis in AML derived cell lines. In addition, 7 μM sunitinib induced 75% reduction of AML-CFC as compared to DMSO treated control (±6.79%;n = 4). In contrast, 7 μM sunitinib treatment of umbilical cord blood derived normal CD34+ cells showed 29% reduction in AML-CFC (±6.77%;n = 5). Treatment of ALDH+ cells sorted from 2 AML cases and CD34+ CD133+ cells from one patient showed reduction of AML-CFC on treatment with sunitinib. Our study highlighted a potent anti-proliferative and proapoptotic effect of sunitinib on AML cell lines, AML patient derived clonogenic cells and potential leukemic stem cells.
基金supported by grants from the National Natural Science Foundation of China(Nos.81370660,81170524)
文摘Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.
文摘Cutaneous presentation revealing acute myeloid leukemia (AML) is rare, and the prognosis is poor. We report a case of an 11-month-old male who presented with cutaneous lesions present as diffuse purplish papulo-nodular lesions, revealing M5 acute myeloid leukemia. Skin biopsy and immunohistochemical examination, combined with routine blood analysis and bone marrow examination, contributed to early diagnosis. However, despite intensive chemotherapy treatment, the prognosis was poor and death occurred during the first months of treatment.
文摘Myeloid sarcoma(MS)is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia(AML).This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission.A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010.After one month,bone marrow biopsy and aspiration confirmed the diagnosis of AML.Allogeneic mobilization peripheral blood stem cell transplantation was performed,with the sister of the patient as donor,after complete remission(CR)was achieved by chemotherapy.Five months after treatment,an adrenal mass was detected by positron emission tomography-computed tomography(PET-CT).Radiotherapy was performed for the localized mass after a multidisciplinary team(MDT)discussion.The patient is still alive as of May 2013,with no evidence of recurrent MS or leukemia.
基金Supported by a grant from the Planned Science and Technology Project of Guangzhou (No. 2006Z3-E0401)
文摘Objective: To evaluate the therapeutic effect of the fludarabine and cytarabine (FA) regimen on acute myeloid leukemia (AML) at different phases during treatment. Methods: A total of 185 patients with AML were divided into 4 groups based on the outcome of previous treatments. Patients in Group 1 had no remission after the first course of induction chemotherapy (n = 55). Patients in Group 2 had no remission after no less than two courses of induction chemotherapy (n = 41). Patients in Group 3 had early relapse (n = 40). Patients in Group 4 had late relapse (n = 49). Patients in groups 2, 3 and 4 had refractory AML or AML with relapse. We assessed the efficacy and toxicity of FA combination chemotherapy in each of these 4 groups. Results: The complete remission (CR) rates of Groups 1, 2, 3 and 4 were 74.5% (41/55), 45.9% (19/41), 17.5% (7/40) and 38.8% (19/49), respectively. The CR rate was higher in Group 1 than in the other 3 groups (34.6%, 45/130) (P = 0.000). A significant correlation was found between CR rate and the number of chemotherapeutic courses (P = 0.023). The main adverse reactions included bone marrow suppression and secondary infection. Conclusion: FA regimen is a good choice for patients with AML, especially those who have failed to achieve CR after the first course of induction chemotherapy.
文摘Background: Multiparameter flow cytometry is the most important method for the lineage assignment and maturational analysis of acute leukemias (AL) cells. The multi parametric immunophenotyping analysis allows the detection of aberrant antigen expression and the analysis of heterogeneity and clonality of malignant cells in AL. The aim of the work is to study the immunophenotypes of blasts from patients with AL and determine the frequency of aberrant markers. Subjects and Methods: Retrospective study to analyze immunophenotypic data of de novo 144 AL patients who were diagnosed in Clinical Pathology Department, Sohag University. Results: We found that 61.8% of AL patients were classified as acute myeloblastic leukemia (AML) while 38.9% classified as acute lymphoblastic leukemia (ALL). The commonest FAB subtype in AML group was AML-M2 (31.8%) followed by M4-M5 27.3%. As regard ALL, there were 85.7% with B-ALL and 14.3% with T-ALL. The aberrancy expressions were found in 66 of AL cases (45.8%), CD7 was the most commonly expressed lymphoid antigen in AML (25%), CD13 was the most commonly expressed myeloid antigen in ALL (39.3%). Conclusion: The multi parametric immunophenotyping analysis of AL is sufficient for diagnosis and classification of leukemia. The frequencies of
文摘Acute leukemia is the most common childhood cancer and accounts for 31% of all cancers in children. There are two main types of acute leukemia. The most common is ALL （acute lymphoblastic leukemia） affecting the lymphoid lineage, and the more rare AML （acute myeloid leukemia） affecting the myeloid linage. The intention of this thesis is to follow the course of treatment from the admission to the hospital until the last check up and also see how a child will react to the treatment and side effects in later life. We studied literature and my own case records from the period when I was treated for ALL. From the literature and my case records, we can see that children tolerate treatment quite well. Due to rapid diagnostics and the possibility to give high doses chemotherapy, the overall prognosis appears to be very good. Today, acute leukemias of paediatric patients have a really favourable prognosis. The overall survival rate for ALL is higher than 80% and for AML 65%. So the results are good, but there is still a long way to go before we can be satisfied. To date we do not have a contingency program for children treated for acute leukemia after 18 years of age （neither in Norway or Slovakia） so perhaps this should be a focus point in the future. It could be extended to follow up patients in adulthood in order to monitor late effects that may occur in later life after many years of treatment.
