Follow-up Reality for Breast Cancer Patients - Standardised Survey of Patients and Physicians and Analysis of Treatment Data.

Introduction: Currently, about 360 000 breast cancer patients who could, after completion of their primary therapy, take advantage of follow-up options are living in Germany. Up to now very little is known about the extent to which the available options are used and as to how the follow-up reality is experienced and evaluated. Thus, an explorative examination among the patients and their physicians was undertaken. Patients and Methods: All patients who underwent surgery in a certified breast centre between 2007 and 2013 received a standardised questionnaire; at the same time the physicians responsible for the follow-up were invited to answer a standardised questionnaire. Results: 920 patients (response rate: 61 %) with a median age of 65 years (32-95) could be analysed. 99 % of the participants stated that they regularly attended follow-ups. The personal contact with the physician (mean value: 4.4) and the reassurance that the cancer disease had not recurred (mean value: 4.5) were described on a scale of 0 to 5 to be two of the most important factors of the follow-up. Deficits were expressed with regard to psychosocial care (70 %) and the perception and treatment of physical complaints (55 %). In addition, 105 physicians returned completed questionnaires (response rate: 12 %). For asymptomatic patients the physicians performed the following examinations most frequently: anamnesis (92 %), physical examination (87 %) as well as laboratory tests (63 %) and tumour marker determinations (40 %). Conclusion: On the whole it became clear that the vast majority of the patients took advantage of the follow-up options. From the patient's perspective the importance of the follow-up lies in contact to the physician and the comforting assurance that the breast cancer has not relapsed. Deficits are seen in the psychosocial care and the perception and treatment of physical impairments. Not recommended examinations were employed by a significant proportion of the surveyed physicians.

[Immunoglobulin substitution in patients with indolent non-Hodgkin's lymphoma]. / Immunglobulin-Substitution bei Patienten mit indolenten Non-Hodgkin-Lymphomen.

BACKGROUND: Infections are major complications in chronic lymphoproliferative disorders, among them indolent non-Hodgkin's lymphoma (iNHL) including chronic lymphocytic leukemia, follicular lymphoma and multiple myeloma.We report on a retrospective cohort analysis of outpatients with indolent non-Hodgkin's lymphoma who were treated in an oncology / hematology group practice and received intravenous polyvalent immunoglobulin G (IVIG) as supportive care. The aim was to describe the treated iNHL population, the course of therapy and the effects of IVIG administrations on the levels of immunoglobulin G (IgG), the incidence of infections and the survival time. PATIENTS AND METHOD: 57 patients with secondary iNHL antibody deficiencies (n = 46) or IgG subclass deficiencies (n = 11) who received IVIG substitution were included. Patients received median 11 IVIG doses with a mean dose of 28 g over a period of median 9.5 months. RESULTS: Mean IgG levels increased with IVIG substitution at about twice and then remained within the normal range. The incidence of infections decreased in 46 % of treated patients. Effects on survival could not be observed. Median overall survival was in the group of substituted patients 124 months (range 7-124), the control group had a median survival time of 96 months (range 3-129) (p = 0.537). CONCLUSION: IgG levels should be reviewed during IVIG substitution on a regular basis and dosage and intervals should be adjusted individually.

Evaluation of psychosocial distress in patients treated in a community-based oncology group practice in Germany.

BACKGROUND: Systematic evaluation of psychosocial distress in oncology outpatients is an important issue. We assessed feasibility and benefit of standardized routine screening using the Distress Thermometer (DT) and Problem List (PL) in all patients of our community-based hematooncology group practice. PATIENTS AND METHODS: One thousand four hundred forty-six patients were screened between July 2008 and September 2008. Five hundred randomly selected patients were sent a feedback form. RESULTS: The average distress level was 4.7, with 37% indicating a distress level >5. Patients with nonmalignant diseases (81% autoimmune diseases or hereditary hemochromatosis) showed the highest distress level of 5.2. Most distressed were patients who just learned about relapse or metastases (6.4), patients receiving best supportive care (5.4) and patients receiving adjuvant antihormonal therapy (5.4). Ninety-seven percent of patients appreciated to speak to their doctor about their distress. Fifty-six percent felt better than usual after this consultation. CONCLUSION: DT and PL are feasible instruments to measure distress in hematooncology outpatients receiving routine care. DT and PL are able to improve doctor-patient communication and thus should be implemented in routine patient care. The study shows that distress is distributed differently between individuals, disease groups and treatment phases.

The impact of new treatment options for advanced colorectal cancer on routine care: results of a retrospective analysis of 206 consecutive patients treated in a community-based oncology group practice in Germany.

Due to necessary selection criteria, the results obtained in clinical trials may not reflect the actual impact of current treatment options for unselected general populations. We analysed the treatment modalities and the outcome in 206 consecutive patients with advanced colorectal cancer who started treatment between 1/1999 and 11/2004. The median age of this cohort was 66 years (range 30-87) and 39 patients (19%) were ≥ 75 years old. First-line treatment consisted of low-dose bolus 5-fluorouracil and folinic acid regimens in 68 patients (33%), weekly 24-h 5-fluorouracil infusion and folinic acid in 36 patients (17%), weekly 24-h 5-fluorouracil infusion plus oxaliplatin or irinotecan in 60 patients (29%), capecitabine regimens in 22 patients (11%), monotherapy with oxaliplatin or irinotecan in six patients (3%) and other regimens in 14 patients (7%). A total of 166 patients (81%) received a second-line treatment and third-line chemotherapy was given to 122/206 patients (59%). With a minimum follow-up of 18 months, the median survival of the cohort is 21 months (range 1-85) and 17 months (range 3-57) for patients ≥ 75 years. We conclude that the increased survival seen in prospective studies can be transferred to routine care for unselected patients with advanced colorectal cancer.

Platinum sensitivity in a BRCA1 mutation carrier with advanced breast cancer.

Although BRCA1-associated breast carcinomas are frequently detected in nodal-negative stage, they typically present with an aggressive histopathological phenotype that is reflected by a poor prognosis and an increased risk for distant metastatic spread. Recent in vitro data suggest a high sensitivity of BRCA1-associated carcinomas to platinum-based chemotherapy and a lower sensitivity to anthracyclines and taxanes. This is explained by the key role of BRCA1 in DNA double-strand repair via homologous recombination, thereby leading to a higher sensitivity to DNA intercalating agents, such as platinum. Here we present the case of a woman suffering from BRCA1-associated metastatic breast carcinoma that was resistant to docetaxel, but responded strongly to cisplatin-containing chemotherapy. This supports the rationale of ongoing clinical studies.

[Lymphomas: new therapeutic options]. / Lymphomverdacht. Wie gehen Sie vor, welche Chancen hat ihr Patient?

Malignant lymphomas are differentiated clinically, morphologically and molecular-biologically, into aggressive (formerly high-grade malignant) and indolent (formerly low-grade malignant) lymphomas. In the meantime, virtually all patients can be diagnosed and treated on an ambulatory basis. The introduction of the monoclonal antibody rituximab (R) in combination with chemotherapeutic agents, has led to the development of highly potent forms of chemoimmunotherapy. In the case of aggressive lymphomas, R-CHOP has been shown to be significantly superior to CHOP alone, both in elderly and younger patients. In stage III and IV indolent (follicular) lymphomas, rituximab/chemotherapy combinations achieve response rates in excess of 90%, and prolonged progression-free survival rates which, for the first time hold out hope of a cure. Monoclonal antibodies that can be coupled to radioisotopes open up new possibilities for potent radioimmunotherapy which look promising for effecting a cure or long-lasting palliation in additional proportion of the patients.

Outpatient therapy in metastatic breast cancer. A retrospective study of 90 patients treated in an oncology group practice.

BACKGROUND: Whenever possible, treatment of breast cancer should be performed in an outpatient setting, but only few data about patients being treated exclusively on an outpatient basis are available. PATIENTS AND METHODS: A retrospective analysis was performed in 90 unselected patients who were treated consecutively in our oncology group practice between 6/95 and 8/99. RESULTS: Median age at detection of metastases was 55 years (30-90) and performance status ranged from 0 to 2. 83 patients (92.2%) received chemotherapy, 7 (7.8%) received endocrine therapy only. CMF was used in 27.7%, anthracyclines in 71.1% and taxanes in 43.3%. 855 chemotherapy cycles were performed and the observed toxicity was mild. Reversible grade 3 and 4 hematotoxicity was seen after 27 cycles (3.2%). Neurotoxicity or mucositis grade 3 and 4 were seen in 6 patients (6.6%). Therapy-associated hospitalization occurred in 1 patient thrice due to febrile neutropenia. Complete remissions were seen in 5 patients (5.6%) during first-line therapy. Median survival of the whole cohort until the end of the follow-up period (2/03) was 28 months (2-259). Overall survival after 1, 2, 3 and 5 years was 83, 56, 33 and 18% respectively. 50% could die at home. CONCLUSIONS: Treatment of metastatic breast cancer can be performed with minimal toxicity and a high patient acceptance in the outpatient setting. Overall survival and median survival are comparable to historical results achieved in specialized academic hospitals. Hospitalization could be avoided in the majority of patients and half of them could die at home.

[Organisation of studies]. / Organisation von Studienteilnahmen in der hämatoonkologischen Praxis.

Haemato-oncological studies in private practices for haematology and oncology have been identified as an important instrument for quality assurance in the treatment of haemato-oncological patients. As the organisational structures of private practices for haematology and oncology are usually highly complex the inclusion into studies needs a high motivation and binds resources. Workflow was observed in four private practices for haematology and oncology. With this data, suggestions for a common workflow model for study inclusion in private practices were elaborated and are discussed in this article. A common workflow-model of study inclusion for private practices is illustrated in two flow charts. If patients are to be successfully included in studies, additional structures and resources have to be implemented. Beyond this the necessary steps for study inclusion must be incorporated into the everyday routine of the practices.

[Severe lead poisoning due to Ayurvedic indian plant medicine]. / Chronische Bleivergiftung durch ayurvedische Heilpillen.

HISTORY AND CLINICAL FINDINGS: A 39-year-old woman with a history of slowly progressive muscular dystrophia was transferred to us for further evaluations of a hypochromic, microcytic anaemia. The patient complained about progressive muscle weakness, loss of appetite and constipation, sleep disorders as well as muscle and back pain. Clinical examination revealed a tetraparesis without any detectable muscle reflexes and atrophic muscles of the extremities. A bilateral radial paresis was found with a loss of power. INVESTIGATIONS: She presented with a hypochromic, microcytic anaemia with a haemoglobin of 7.9 g/dl. Re-evaluation of her peripheral blood smear showed basophilic stippling of the erythrocytes. Bone marrow biopsy revealed a marked dyserythropoiesis with 50% ring sideroblasts. After the examination of the bone marrow, the blood lead level was found to be grossly elevated up to 880 microg/l. DIAGNOSIS: Re-evaluation of the patient's history revealed that she had been to India for an Ayurvedic treatment approach to improve her muscle dystrophia. She had taken regularly 4 different natural plant pills which she had bought in an Ayurvedic health centre. Toxicologic analysis of these pills revealed one to have a lead concentration of 50.4 mg/g. TREATMENT AND COURSE: The patient was treated with 16 infusions of sodium-EDTA followed by a 4-week treatment with dimercaptopropionic acid orally. Her neurological condition improved and the radial paresis resolved gradually so that she could return to work. Her haematological parameters normalized. CONCLUSION: This case report underscores the importance, while asking patients for their drug history, to ask additionally if natural plant medicine is taken or applied regularly. The report reveals that Ayurvedic pills from India may have a high concentration of lead and may cause severe poisoning.

Successful long-term treatment of systemic lupus erythematosus with rituximab maintenance therapy.

Systemic lupus erythematosus (SLE) is a chronic, inflammatory autoimmune disease that may involve multiple organ systems. Treatment consists of immunosuppression, cytotoxic treatment, plasmapheresis and immunoglobuline therapy. Treatment of patients refractory to standard treatment approaches is difficult and results are poor. We describe a 39-year old patient with SLE suffering from grand mal epilepsy due to cerebral vasculopathy with positive lupus anticoagulant, who was refractory to standard treatment modalities. The patient was treated with the anti-CD20 monoclonal antibody rituximab (375 mg/m2 x 4, repeated at weekly intervals). Rituximab applications were delivered in October 2000, March 2001 and October 2001. Since March 2002 she has received maintenance therapy with rituximab 375 mg/m2 every three months. A second female with refractory SLE was treated successfully in April 2002 and receives maintenance therapy every three months. Both patients responded well to rituximab therapy. The first patient showed a major improvement of her clinical condition, and 30 months after the beginning of the rituximab therapy she is free of any symptoms. Inflammation parameters, ANA and lupus anticoagulant declined significantly after the treatment. The clinical condition of the second patient improved dramatically, all inflammation parameters normalized and her circulating immunocomplexes disappeared. In conclusion, rituximab maintenance treatment may be a new effective therapy in SLE.

Dose reduction of steroid premedication for paclitaxel: no increase of hypersensitivity reactions.

BACKGROUND: Premedication with dexamethasone, ranitidine and clemastine is mandatory for patients receiving paclitaxel to avoid hypersensitivity reactions. The proposed dexamethasone dose is 20 mg orally 12 and 6 h prior to paclitaxel infusion. With this premedication severe hypersensitivity reactions are reduced to 1-2% of the treated patients. Besides this oral schedule a single dose of dexamethasone, 40 mg given i.v., just prior to paclitaxel has been shown to be equally effective. In an attempt to reduce steroid-induced side effects, especially for patients receiving weekly paclitaxel protocols, we reduced the dexamethasone dose. PATIENTS AND METHODS: A total of 132 patients were treated on an outpatient basis with paclitaxel-containing protocols. Paclitaxel was given in doses of 135-175 mg/m(2) once every 3 weeks in 76 patients and/or with 100 mg/m(2) weekly in 70 patients. Dexamethasone premedication was given in a single dose (40, 20, 10 mg) as an infusion directly before paclitaxel. RESULTS: 0/46 patients receiving 40 mg dexamethasone premedication in 235 cycles and 0/48 patients receiving 20 mg dexamethasone premedication in 186 cycles experienced a severe hypersensitivity reaction. 1/52 patients receiving 10 mg dexamethasone in 480 applications developed a severe hypersensitivity reaction with bronchospasm, hypotension and supraventricular tachycardia shortly after her first paclitaxel infusion started. CONCLUSION: No increase of severe hypersensitivity reactions is seen when dexamethasone premedication is reduced to doses of 20 or even 10 mg prior to paclitaxel infusion.

The polyneuropathy associated with Waldenström's macroglobulinaemia can be treated effectively with chemotherapy and the anti-CD20 monoclonal antibody rituximab.

A 50-year-old male developed headache, impaired balance, visual defects and severe deafness. Ten months later he presented with markedly reduced power and tremor of his right arm. Waldenström's macroglobulinaemia (WM) with accompanying polyneuropathy was diagnosed. The patient received chemotherapy, which resulted in a partial improvement of the arm tremor. Subsequently, he was treated with rituximab (4 x 375 mg/m2), leading to complete resolution of the tremor and the paresis of his arm. Additionally, his headache and imbalance disappeared. Fifteen months after rituximab therapy he remained free of any neurological symptoms. This is the first report showing that WM-associated polyneuropathy can be treated effectively with a combination of chemotherapy and the anti-CD20 monoclonal antibody rituximab.

Induction of complete haematological remission after monotherapy with anti-CD20 monoclonal antibody (RITUXIMAB) in a patient with alkylating agent resistant Waldenström's macroglobulinaemia.

Response of Waldenström's macroglobulinaemia to chemotherapy with alkylating agents is usually only transient. We report a case with marked bone marrow involvement and resistance to chemotherapy with alkylating agents. The patient was red cell and platelet transfusion dependent. Three weeks after rituximab-monotherapy, he achieved a complete haematological remission which is continuing 6 months after the end of therapy. Our case demonstrates that treatment with the unconjugated anti-CD20-monoclonal antibody (rituximab) may be a new powerful tool for a better treatment of Waldenström's macroglobulinaemia.

Cutaneous monoblastic leukemia as a first sign of relapse six years after autologous bone marrow transplantation for acute leukemia.

A patient with acute monoblastic leukemia (AML, M5A) was treated successfully in December 1987. In 1993 after 6 years in complete remission, she presented with an intracutaneous nodular mass on her right upper arm which was resected in toto and shown to be undifferentiated monoblastic leukemia. Two further chloroma lesions were excised in July 1994 and March 1995 respectively. Bone marrow cytology and histology always showed a continuing complete remission with no evidence of leukemia relapse. In July 1995 she presented with a disseminated skin infiltrate and a relapse with 80% monoblasts in the bone marrow. After one course of chemotherapy (Idarubicin/Ara-C), a second complete remission was achieved and her leukemic skin infiltrate disappeared completely. This case illustrates that chloromas of the skin can occur as late as 6 years after treatment for AML and also emphasizes that the occurrence of a chloroma does not necessarily mean immediate leukemia relapse. It also stresses that a second complete remission can be achieved with standard AML-induction therapy despite widespread leukemic skin infiltrates in such patients.

Storage of noncryopreserved periphered blood stem cells for transplantation.

Mobilized peripheral blood stem cells (PBSC) were collected in autologous plasma and acid-citrate-dextrose formula A (ACD-A) by leukaphereses using the CS3000 cell separator (Baxter) and stored at 4 degrees C in a refrigerator for 8 days. We have looked at the viability of the nucleated cells with the trypan blue test and the proliferation and differentiation capacity using a standardized progenitor cell cloning assay. The changes in viability, granulocyte-macrophage colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), and mixed-lineage colony-forming units (CFU-GEMM) were determined daily during the storage period. Viability was 90.8% (SD 8%) at day 0 and declined to a mean of 69.5% (SD 15.5%) at day 8. CFU-GM decreased to 47% (SD 28.7%), CFU-GEMM to 48% (SD 42.2%), and BFU-E to 40.1% (SD 18.4%) after 6 days. After 5 days of storage the mean viability was 79.7% (SD 17.8%), whereas the mean CFU-GM were 65.3% (SD 28.4%) the mean CFU-GEMM were 61.8% (SD 30.4%) and the mean BFU-E were 55.1% (SD 18.2%). At day 4 viability was still 82.5% (SD 17.0%), recovery of CFU-GM was 78.5% (SD 28.8%), recovery of CFU-GEMM was 70.7% (SD 40.4%) and recovery of BFU-E was 65.0% (SD 17.5%). These data show, that PBSC can be stored safely over at least 5 days at 4 degrees C while the patient receives high-dose chemotherapy.

[Integrative concept on the treatment of highly malignant non-Hodgkin lymphomas]. / Integratives Konzept zur Behandlung Hochmaligner Non-Hodgkin-Lymphome (NHL).

With CHOP, the standard protocol for the treatment of high-grade non-Hodgkin's lymphomas, about 40% of long term survival has been reported. A recent randomized comparison of CHOP vs. ProMACE-Cyta-BOM vs. m-BACOD vs. MACOP-B showed no advantage of these third generation protocols. The analysis of prognostic factors in several controlled trials and the results of the International Non-Hodgkin's Lymphoma Prognostic Factors Project identified stage, LDH, performance status and number of extranodal sites as the most important pretreatment factors. Already the pretreatment LDH-level (normal vs. enhanced) defines accurately cohorts of patients with low or high risk. Based on these results two cooperative trials were initiated: In trial A we are currently evaluating in a randomised fashion the concept of high dose chemotherapy (BEAM) with autologous stemcell rescue vs. a standard treatment for high risk patients < 60 years. In trial B low risk patients or high risk patients > 60 years are randomised to receive either CHOP or CHOEP at two or three weeks intervals.

Limited sampling models for reliable estimation of etoposide area under the curve.

Limited sampling models are able to estimate the area under the concentration-time curve (AUC) from plasma concentrations measured at only a few time points. The purpose of this study was to establish a model estimating etoposide AUC independently of specific chemotherapy protocols, underlying malignancies, concomitant diseases and age. Pharmacokinetic parameters were measured in 30 patients treated with polychemotherapy including etoposide (80-150 mg/m2). Etoposide analysis was performed by thin layer chromatography and consecutive quantitative sample detection by 252Cf-plasma desorption mass spectrometry. Data from the first 15 patients formed the training set. Based on the training data, five different models were generated, with the multiple regression coefficient r ranging from 0.91 to 0.96. The following model was selected as "most accurate": AUC = 343 (min)C4h(micrograms/ml) + 650(min)C8h(micrograms/ml) + 1252 (min micrograms/mol), where C4h is the plasma concentration of etoposide at 4 h after the end of infusion and C8h at 8 h. This model was validated on the test set, comprising the data of the remaining 15 patients. The mean predictive error (MPE) was -0.2% and the root mean square predictive error (RMSE) was 4.7%. When used for a large number of patients, this practicable and simple model is an instrument for use in prospective studies, to measure a correlation between drug dosage and efficacy or toxicity of the drug.

The role of decreased retinoblastoma protein expression in acute myelomonocytic and monoblastic leukemias.

The results of different investigators show that lack of p105 expression is relatively common in human myeloid leukemias, especially in monocytic leukemias. This suggests that loss of p105 expression could contribute to the altered growth control of these cells. So far no clear data exist which show that low p105 levels in AML blasts predict a poor therapy outcome. Therefore it is not very likely that p105 expression will become a strong prognostic factor for the different treatment strategies in AML.

Thrombocytopenia-adapted in vitro bleeding test assesses platelet function in thrombocytopenic patients.

Platelet counts do not always reflect the true bleeding risk in chronically thrombocytopenic patients, and the posttransfusion platelet increments do not necessarily demonstrate that therapeutic efficacy. There are no easy and reliable tests yet permitting the determination of platelet function in thrombocytopenic patients. The in-vitro bleeding test (IVBT) with the Thrombostat 4000 proved to be a very sensitive and specific test for the detection of platelet disorders. In order to become suitable for the investigation of thrombocytopenic blood with platelet count between 5 x 10(9)/L and 50 x 10(9)/L, special modifications were necessary. We report on the evaluation of two thrombocytopenia-adapted modifications (TP-IVBT 150/120), first with blood of healthy donors made thrombocytopenic (three experiments with six blood samples each of different platelet concentrations and identical hematocrit) and then in a clinical study on 77 thrombocytopenic patients (69 with bone marrow hypoplasia, eight with autoimmune thrombocytopenia) receiving 267 platelet transfusions. The patients were followed over 15 days on average (1-67 days) by daily examinations (total 1,285 observation days). Most TP-IVBT measurements were carried out in triplicate, using the modification with the 120-microns filter (TP-IVBT 120) because it proved to be superior to the other modification. Additionally, cell counts, hematocrit, body temperature, platelet volume, platelet distribution width, expression of CD 36, 41a, 42b on platelets, Simplate bleeding time, and detailed analysis of bleeding signs were performed for the calculation of a bleeding score. There was a close correlation between TP-IVBT and platelet counts with thrombocytopenic normal blood (r2 = 0.81-0.94). This indicated the suitability of this test modification to examine platelet function in thrombocytopenic patients. The clinical study showed that the TP-IVBT helped at least to determine the platelet-related bleeding risk in thrombocytopenic patients. It allowed differentiation between hypoplastic and autoimmune thrombocytopenia in most cases. In addition, significant differences in platelet function of various diseases and of different bone marrow regeneration could be demonstrated. The TP-IVBT is well-suited for the control of platelet transfusion efficacy and may replace the in-vivo bleeding time in most cases. On the other hand, the test still shows too much of a variation and involves too much labor and cost for routine application.

Ultrasound evaluation of hepatic and splenic microabscesses in the immunocompromised patient: sonographic patterns, differential diagnosis, and follow-up.

High-dose chemotherapy, especially for bone marrow transplantation, causes a great degree of immunosuppression, and thus carries the risk for invasive fungal infections. Although hepatic and splenic involvement in disseminated candidiasis is frequent, involvement of these organs is rarely appreciated antemortem. During the last decade, focal hepatosplenic candidiasis has been recognized increasingly by ultrasound. We report the sonographic and clinical findings of 6 patients: 3 AML (acute myeloid leukemia), 2 NHL (non-Hodgkin's lymphoma), and 1 HD (Hodgkin's disease) who demonstrated multiple, small-nodule, hypoechoic lesions in spleen and/or liver after high-dose chemotherapy. All patients were in complete hematologic remission when the study was performed. Septic fever was unresponsive to antibiotic therapy. Granulocytopenia (< or = 1000/mm3) was seen for at least 10 days. However, the manifestation of hepatolienal microabscesses became apparent by ultrasound only after the neutrophil count returned to normal in all but 1 patient. Microabscesses decreased or disappeared on follow-up examination after antifungal treatment. Systemic candida infection was confirmed serologically. Sonographic-guided abscess biopsy (n = 3) revealed necrosis/abscess. Structural inhomogeneity of parenchymal organs was seen for several months after therapy.