[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Although the survival of children and adolescents with malignant germ-cell tumours has improved greatly in recent years, the outcome remains poor for those with refractory or recurrent malignant germ-cell tumours. We aimed to determine whether objective tumour response could be achieved in patients with refractory or recurrent malignant germ-cell tumours with PEI-regional deep hyperthermia as salvage treatment.
METHODS: Patients with refractory or recurrent non-testicular malignant germ-cell tumours after standard cisplatin-based chemotherapy were treated prospectively with PEI chemotherapy (cisplatin 40 mg/m2, delivered intravenously on days 1 and 4; etoposide 100 mg/m2, intravenously on days 1-4; and ifosfamide 1800 mg/m2, intravenously on days 1-4) plus simultaneous 1-h regional deep hyperthermia (41-43°C) on days 1 and 4. Patients received three to four treatment courses at 21-day intervals until residual tumour resection was possible; they subsequently received one or two additional courses of PEI-regional deep hyperthermia. Local radiotherapy was given for incompletely resected tumours. Chemotherapy and hyperthermia toxic effects were assessed using WHO grading. The primary endpoint was the proportion of patients who had an objective response as assessed with Response Evaluation Criteria in Solid Tumors version 1.0 guidelines. Secondary endpoints were the event-free survival and overall survival after 5 years. This ongoing PEI-regional deep hyperthermia study (Hyper-PEI protocol) is registered at the German Cancer Society, number 50-2732.
FINDINGS: 44 patients aged 7 months to 21 years (median 2 years 7 months) with refractory or recurrent malignant germ-cell tumours (nine patients with poor response, 23 patients with first relapse, 12 patients with multiple relapses) were included in this study. We identified 34 yolk sac tumours, eight embryonal carcinomas, one choriocarcinoma, and one dysgerminoma by histology analysis. Of the 35 patients who had sufficient clinical and radiographical data available for response assessment, 30 (86%) had an objective response to treatment (16 patients had complete remission and 14 had partial remission). 5-year event-free survival was 62% (95% CI 45-75), and 5-year overall survival was 72% (95% CI 55-83). The median follow-up of surviving patients was 82 months (range 9-195). WHO grade 3-4 neutropenia and thrombocytopenia occurred in all 181 chemotherapy cycles. Granulocytopenic fever, which required intercurrent hospital admission, was noted in 29 (66%) of 44 patients after 53 (29%) of 181 courses. Five patients experienced treatment-related grade-3 acute renal toxic effects.
INTERPRETATION: A multimodal strategy integrating PEI-regional deep hyperthermia and tumour resection with or without radiation can successfully treat children and adolescents with refractory or recurrent malignant non-testicular germ-cell tumours. The long-term prognosis of patients with poor response or after first relapse was almost similar to those receiving first-line treatment. This strategy merits further investigation.
FUNDING: Deutsche Krebshilfe eV, Bonn, Elterninitiative Kinderkrebsklinik Düsseldorf eV, the Barbara and Hubertus-Trettnerstiftung, and the Marie Quendt Fund.
The Lancet Oncology 06/2013; · 25.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Current follow-up- and outcome-evaluations of Legg-Calvé-Perthes disease (LCPD) are based on subjective measures of function, clinical and radiological parameters. The objective of this study was to evaluate the sagittal plane kinematics and the effect on hip joint loading on the affected hip in children with LCPD.
Computerized gait analysis was performed in 49 LCPD patients aged ≥ 5 years with unilateral hip involvement. Sagittal plane kinematics and kinetics were compared to a group of healthy children (n=30).
Kinematics: a significantly increased anterior tilt and range of motion (ROM) of the pelvis combined with a marked reduction of the extension of the involved hip joint compared to the control group was observed. The increased ROM of the contralateral hip results from increased maximum flexion. Power generation: overall significantly decreased on the involved side during florid stage. Global hip function: significantly reduced hip flexor index of the involved hip; 46.2% of the patients in advanced stage, although having no significant changes in kinematics - except increased anterior pelvic tilt - had a pathologic HFI.
Sagittal plane hip function is significantly impaired in florid and advanced LCPD. The results of this study will lead to further investigations into whether this development can be prevented by conservative or operative treatment thus improving function and long-term prognosis.
[Show abstract][Hide abstract] ABSTRACT: To determine whether MR bone marrow findings in Gaucher patients may help to identify patients at high risk of developing severe Gaucher bone complications exemplified by avascular necrosis (AVN) of the femoral head.
MR images were obtained in 63 Type I Gaucher patients through a standard protocol using coronal T 1 and T 2-weighted sequences of the lower extremities. The location and extent of infiltrated marrow was established using a semi-quantitative MRI scoring method (Düsseldorf Gaucher score, DGS) and the morphological pattern of bone marrow involvement determined (whether homogeneous type A or non-homogeneous type B). The active marrow process with bone edema and AVN of the femoral head were also analyzed.
Bone marrow involvement was observed in femoral sites more than in tibial sites. A high DGS was significantly correlated with type B morphology and femoral AVN (both p < 0.0001). Splenectomized patients showed a significantly higher Düsseldorf Gaucher score and type B morphology than non-splenectomized patients (both p < 0.05). AVN was seen in 46 % of patients with type B morphology versus 3 % in type A morphology (p < 0.0001). DGS and morphology of bone marrow involvement were not significantly correlated with active marrow processes.
Type B marrow morphology and extensive marrow packing were significantly associated with AVN of the femoral head (both p < 0.0001). These patterns are considered predictive and may be employed in a disease management context to alert physicians to the need for urgent therapeutic measures.
RöFo - Fortschritte auf dem Gebiet der R 11/2010; 182(11):979-85. · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of the study was to investigate the adequacy of palliative radiation treatment in end-stage cancer patients.
Of 216 patients referred for palliative radiotherapy, 33 died within 30 days and constitute the population of the study. Symptoms, Karnofsky Performance Status (KPS), laboratory tests, and survival estimates were obtained. Treatment course was evaluated by medical records. Univariate analyses were performed by using the 2-sided chi-square test. With significant variables, multiple regression analysis was performed.
Median age was 65 years, and median survival was 15 days. Prevailing primary cancer types were lung (39%) and breast (18%). Metastases were present in 94% of patients, brain (36%), bone (24%) and lung (18%). In 91%, KPS was < 0%. KPS, lactate dehydrogenase, dyspnea, leucocytosis, and brain metastases conveyed a poor prognosis. From 85 survival estimates, only 16% were correct, but 21% expected more than 6 months. Radiotherapy was delivered to 91% of patients. In 90% of radiation treatments, regimens of at least 30 Gy with fractions of 2-3 Gy were applied. Half of the patients spent greater than 60% of their remaining lifespan on therapy. In only 58% of patients was radiotherapy completed. Progressive complaints were noted in 52% and palliation in 26%.
Radiotherapy was not appropriately customized to these patients considering the median treatment time, which resembles the median survival time. About half of the patients did not benefit despite spending most of their remaining lives on therapy. Prolonged irradiation schedules probably reflect overly optimistic prognoses and unrealistic concerns about late radiation damage. Single-fraction radiotherapy was too seldom used.
Cancer 07/2010; 116(13):3251-6. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Incidental irradiation of the prostate may affect serum prostate-specific antigen (PSA). However, scarce data exist on PSA changes after irradiation of noncancerous prostatic tissue. This is an update of a study on PSA after pelvic irradiation.
From 1997 to 2007, blood samples of 33 men were examined who had undergone pelvic irradiation for rectal or anal cancer. The planning target volume included the prostate in all cases. No patient had clinical evidence of prostatic disease. Radiotherapy was applied in fractions of 1.8-2 Gy up to 40-50 Gy (n = 3), 50-60 Gy (n = 21), and 60-65 Gy (n = 2). Seven patients received 5 x 5 Gy. Serum PSA was measured before, during, and after radiotherapy periodically. Median log (PSA) changes were calculated according to elapsed time from starting radiotherapy. The significance was tested with chi(2)-test.
18 patients died during follow-up. For 15 patients, long-term PSA data with a median follow-up of 9 years (2,546-3,528 days) are available. PSA levels rose during the first weeks of irradiation peaking at 2-4 weeks with a significant 2.7-fold increase (p < 0.01). 1 year after radiation therapy, PSA declined below (90%) the preirradiation level, but this difference was not significant (p = 0.36). On further follow-up PSA did not change up to 8.9 years after radiotherapy (p = 0.36).
Irradiation of the prostate causes transient increase of serum PSA. By 1 year, PSA has returned near the preirradiation value and stays there for at least 9 years. A major interference with prostate cancer screening or surveillance after radiotherapy is therefore unlikely.
Strahlentherapie und Onkologie 10/2008; 184(10):526-9. · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Until recently, gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) has increasingly replaced iodinated contrast agent examinations in dialysis patients, although only limited data existed about the clinical safety of Gd contrast agents in these patients. Specific clinical adverse events (AEs), including nephrogenic systemic fibrosis, were linked to Gd exposure in dialysis patients. An inflammatory reaction or transmetallation may be involved.
Secondary analysis of a 5-day observational study in a parent cardiovascular study with repetitive cardiac MRI (32 patients) and patients undergoing Gd-enhanced MRI for clinical indications (6 patients). Clinical information and samples were obtained according to parent protocol.
Dialysis patients at a university-based dialysis unit.
Gd-chelate complex. 37 of 38 patients underwent 64 MRI studies with Gd-diethylenetriamine penta-acetic acid (Gd-DTPA). 25 of these patients underwent additional MRI studies with gadobutrol (n = 10), 0.9% saline (n = 7), or both (n = 8), and 1 patient received gadobutrol only.
Clinical adverse events; C-reactive protein (CRP) levels on days 1, 3, and 5 after MRI; Gd levels in blood and urine after MRI.
CRP levels increased 10-fold on day 3 after MRI in 87% of MRI studies with Gd-DTPA (+59.3 +/- 57.9 mg/L [P < 0.001] versus -0.9 +/- 3.7 mg/L with gadobutrol versus -0.9 +/- 8.5 mg/L with 0.9% saline). 77 mild to moderate and 3 serious AEs were observed in 24 patients. CRP levels and adverse events did not correlate with Gd blood concentrations. CRP level increase or AEs were not observed after MRI with gadobutrol or 0.9% saline.
Observational study without randomization, risk of bias because of multiple MRI studies in a limited patient cohort.
Gd-DTPA, but not gadobutrol, induces an acute-phase reaction and clinical AEs in dialysis patients. Additional investigations have to analyze the underlying pathomechanism.
American Journal of Kidney Diseases 06/2008; 51(6):976-86. · 5.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Due to PSA screening and increased awareness, prostate cancer (PCa) is identified earlier resulting in smaller diagnostic samples on prostate needle biopsy. Because Gleason grading plays a critical role in treatment planning, we undertook a controlled study to evaluate interobserver variability among German pathologists to grade small PCas using a series of tissue microarray (TMA) images.
We have previously demonstrated excellent agreement in Gleason grading using TMAs among expert genitourinary pathologists. In the current study, we identified 331 TMA images (95% PCa and 5% benign) to be evaluated by an expert PCa pathologist and subsequently by practicing pathologists throughout Germany. The images were presented using the Bacus Webslide Browser on a CD-ROM. Evaluations were kept anonymous and participant's scoring was compared to the expert's results.
A total of 29 German pathologists analysed an average of 278 images. Mean percentage of TMA images which had been assigned the same Gleason score (GS) as done by the expert was 45.7%. GSs differed by no more than one point (+/-1) in 83.5% of the TMA samples evaluated. The respondents were able to correctly assign a GS into clinically relevant categories (i.e. <7, 7, >7) in 68.3% of cases. A total of 75.9% respondents under-graded the TMA images. Gleason grading agreement with the expert reviewer correlated with the number of biopsies evaluated by the pathologist per week. Years of diagnostic experience, self-description as a urologic pathologist or affiliation with a university hospital did not correlate with the pathologist's performance.
The vast majority of participants under-graded the small tumors. Clinically relevant GS categories were correctly assigned in 68% of cases. This raises a potentially significant problem for pathologists, who have not had as much experience evaluating small PCas.
Journal of Cancer Research and Clinical Oncology 04/2008; 134(10):1071-8. · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heat shock proteins (HSPs) play an important role in the cellular response to environmental stress and exert a cytoprotective effect. Especially HSP70 is an effective inhibitor of apoptosis, suggesting a role of HSP70 in carcinogenesis and tumor progression. To explore the relevance of HSP70 in renal cell carcinomas (RCCs), we analyzed nuclear and cytoplasmic HSP70 protein expression in formalin-fixed tissue from 145 clear cell RCCs by immunohistochemistry as well as Western blot analysis. Nuclear HSP70 expression was found in all RCCs and 75% of the tumors also exhibited a cytoplasmic HSP70 staining. Importantly, RCCs showed significantly reduced cytoplasmic (p=0.001) and combined nuclear/cytoplasmic (p=0.0022) HSP70 expression when compared with their cells of origin. A significant (p=0.0176) decrease of nuclear HSP70 expression became evident from well to poorly differentiated clear cell RCCs. Quite similarly, a trend (p=0.0558) for reduced combined nuclear/cytoplasmic HSP70 expression was shown from early (pT1) to advanced (pT3) tumor stages. Nevertheless, no correlation between HSP70 expression and patients survival became evident. In conclusion, our investigation demonstrates a significant decrease of antiapoptotic HSP70 protein expression during carcinogenesis and during progression from well (G1) to poorly (G3) differentiated clear cell RCCs. Our results suggest that HSP70-mediated inhibition of apoptosis seems to be of minor importance for carcinogenesis and tumor progression in RCCs.
Histology and histopathology 11/2007; 22(10):1099-107. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Impaired apoptosis, mediated by members of the inhibitor of apoptosis proteins (IAP) family such as survivin, is thought to contribute to leukemic cell survival. In contrast to low expression of survivin in normal differentiated adult tissues, very high levels of survivin have been described in a number of different tumors. Overexpression of survivin was found to correlate with poor prognosis in a variety of cancers including hematologic malignancies. To date, however, there is no information available on the prognostic role of survivin in pediatric precursor B-cell acute lymphocytic leukemia (BCP-ALL), the most frequent malignancy in childhood.
In a retrospective study including 66 pediatric patients we analyzed the impact of survivin protein levels on outcome in BCP-ALL.
Survivin overexpression, with an up to ten-fold increase of the normal level, was detected in 65% of the leukemic samples in contrast to negligible expression in non-malignant hematopoietic cells. Despite considerable variety of expression levels in ALL cells, there was no association of survivin levels with established risk factors. However, patients suffering relapse of disease or death had significantly higher survivin expression than those with a favorable outcome. Overexpression of survivin is a significant prognostic marker for 3 year relapse free, event-free and overall survival, again independent of the established prognostic factors in ALL, such as age and leukocyte count at diagnosis as assessed in multivariate analysis.
Overexpression of survivin in BCP-ALL identifies patients with a high risk of early relapse. Upon confirmation in a prospective analysis, survivin expression may, in the future, serve to further refine treatment stratification with intensification of therapy in those patients prone to relapse.
[Show abstract][Hide abstract] ABSTRACT: To study how survival of palliative cancer patients relates to subjective prediction of survival, objective prognostic factors (PFs), and individual psychological coping.
Survival was estimated according to three categories (< 1 month, 1 to 6 months, and > 6 months) by two physicians (A and B) and the institutional tumor board (C) for 216 patients recently referred for palliative radiotherapy. After 6 months, the accuracy of these estimates was assessed. The prognostic relevance of clinical symptoms, performance status, laboratory tests, and self-reported emotional distress (Hospital Anxiety and Depression Scale) was investigated.
In 61%, 55%, and 63% of the patients, prognoses were correctly estimated by A, B, and C, respectively. kappa statistic showed fair agreement of the estimates, which proved to be overly optimistic. Accuracy of the three estimates did not improve with increasing professional experience. In particular, the survival of 96%, 71%, and 87% of patients who died in less than 1 month was overestimated by A, B, and C, respectively. On univariate analysis, 11 of 27 parameters significantly affected survival, namely performance status, primary cancer, fatigue, dyspnea, use of strong analgesics, brain metastases, leukocytosis, lactate dehydrogenase (LDH), depression, and anxiety. On multivariate analysis, colorectal and breast cancer had a favorable prognosis, whereas brain metastases, Karnofsky performance status less than 50%, strong analgesics, dyspnea, LDH, and leukocytosis were associated with a poor prognosis.
This study revealed that physicians' survival estimates were unreliable, especially in the case of patients near death. Self-reported emotional distress and objective PFs may improve the accuracy of survival estimates.
Journal of Clinical Oncology 08/2007; 25(22):3313-20. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rac proteins of the Rho-like GTPase family, including the ubiquitous Rac1, the hematopoiesis-specific Rac2, and the least-characterized Rac3 play a major role in oncogenic transformation, tumor invasion and metastasis. However, the prognostic relevance of Rac expression in human tumors has not been investigated yet. In the present study, Rac protein expression was analyzed in benign secretory epithelium, high-grade prostatic intraepithelium neoplasia (HG-PIN), and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Thus, Rac proteins were significantly strongly expressed in HG-PIN (P < 0.001) and prostate carcinomas (P < 0.001) when compared with benign secretory epithelium. Accordingly, all tumor tissues analyzed by isoform-specific real-time PCR (n = 7) exhibited significantly higher RNA expression levels of Rac (i.e. sum of Rac1 and Rac3 expression levels) than the respective benign counterparts (P = 0.018) and this appeared to result mainly from increased expression of the Rac3 isoform as verified by immunoblotting. Univariate analyses showed statistically significant associations of increased Rac protein expression in prostate cancer (P = 0.045), preoperative prostate-specific antigen levels (P = 0.044), pT stage (P = 0.002), and Gleason score (P = 0.001) with decreased disease-free survival (DFS). This prognostic effect of increased protein expression of Rac remained significant even in a multivariate analysis including all these four factors (relative risk = 3.22, 95% confidence interval = 1.04-10.00; P = 0.043). In conclusion, our data suggest that increased Rac protein expression in prostate cancer relative to the corresponding benign secretory epithelium is an independent predictor of decreased DFS and appears to result mainly from increased expression of the Rac3 isoform.
Endocrine Related Cancer 07/2007; 14(2):245-56. · 5.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this prospective, randomized, double-blind trial we investigated the use of stimulating catheters in patients during and after shoulder surgery; functional improvement being the primary outcome measurement.
After eliciting an adequate muscular twitch at < or =0.5 mA nerve stimulation output, the perineural catheter was advanced either blindly (conventional catheter = CC group, n = 20) or guided by stimulation via the catheter (stimulating catheter = SC group, n = 20). A bolus of 40 mL prilocaine 1% and 10 mL ropivacaine 0.75% was injected, followed by a patient-controlled infusion of ropivacaine 0.2% (8 mL/h infusion rate, bolus 2 mL, lockout time 20 min).
Onset of motor block was faster in the SC group, whereas sensory block did not differ between groups. Median pain scores on two postoperative days were equal. Improvement of the objective shoulder function score (Constant Murley Score) 6 wk postoperatively was enhanced to a clinically relevant extent in the SC group compared to the CC group (P < 0.01).
We conclude that the use of a stimulating catheter results in a faster onset of motor block, unaltered postoperative pain, and a significantly improved functional outcome 6 wk after shoulder surgery.
Anesthesia and analgesia 03/2007; 104(2):442-7. · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Rac-specific guanine nucleotide exchange factor, Tiam1, plays a major role in oncogenicity, tumour invasion and metastasis but its usefulness as a prognostic marker in human cancer has not been tested yet. In the present study, Tiam1 expression was analysed in benign secretory epithelium, pre-neoplastic high-grade prostatic intraepithelium neoplasia (HG-PIN) and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Tiam1 proved significantly overexpressed in both HG-PIN (P<0.001) and prostate carcinomas (P<0.001) when compared to benign secretory epithelium. Strong Tiam1 overexpression (i.e. > or =3.5-fold) in prostate carcinomas relative to the respective benign prostatic epithelium was statistically significantly associated with disease recurrence (P=0.016), the presence of lymph vessel invasion (P=0.031) and high Gleason scores (GS) (i.e. > or =7) (P=0.044). Univariate analysis showed a statistically significant association of strong Tiam1 overexpression with decreased disease-free survival (DFS) (P=0.03). This prognostic effect of strong Tiam1 overexpression remained significant in multivariate analysis including preoperative prostate-specific antigen levels, pT stage, and GS (relative risk= 3.75, 95% confidence interval=1.06-13.16; P=0.04). Together, our data suggest that strong Tiam1 overexpression relative to the corresponding benign epithelial cells is a new and independent predictor of decreased DFS for patients with prostate cancer.
British Journal of Cancer 10/2006; 95(8):1081-6. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In children with locally advanced or recurrent malignant tumours, prognosis can be improved by regional deep hyperthermia (RHT) in combination with platin-based chemotherapy. However, because of the increasing number of patients that achieve long-time remission with this therapy, it is necessary to evaluate long-term sequelae of thermochemotherapy. During the years 1993-2004 one has observed avascular osteonecrosis (AON) of the femoral head after RHT in seven children with pelvic germ cell tumours or rhabdomyosarcomas.
Although AON may develop in patients with malignancies treated with chemo- or radiotherapy alone, RHT might nevertheless contribute to the occurrence of AON. In order to determine potential risk factors for AON after RHT, this study analysed the relationship of AON to the patient's age, medical history and treatment parameters such as thermal dose equivalent and power output.
In the present study AON was associated with young age as well as intensity of hyperthermia indicated by high power levels that exceed 20 W per kg body weight and/or application of eight or more heat sessions as well as additional radiotherapy. Based on this observation, it was assumed that an optimized three dimensional thermal field modelling may be helpful to avoid hazardous temperatures in the femoral heads during RHT treatment and to reduce AON of the femoral heads.
International Journal of Hyperthermia 10/2006; 22(6):451-61. · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our aim was to investigate the relationship between urinary excretion of deoxypyridinoline (DPD) as a marker of bone resorption, and Perthes' disease. There were 39 children with Perthes' disease in the florid stage who collected first-morning urine samples at regular intervals of at least three months. The level of urinary DPD was analysed by chemiluminescence immunoassay and was correlated with the radiological stage of the disease as classified by Waldenström, and the severity of epiphyseal involvement according to the classification systems of Catterall and Herring. The urinary DPD levels of a group of 44 healthy children were used as a control. The median urinary DPD/creatinine (CREA) ratio was significantly reduced (p < 0.0001) in the condensation stage and increased to slightly elevated values at the final stage (p = 0.05) when compared with that of the control group. Herring-C patients showed significantly lower median DPD/CREA ratios than Herring-B patients (p = 0.03). The significantly decreased median DPD/CREA ratio in early Perthes' disease indicated a reduced bone turnover and supports the theory of a systemic aetiology. Urinary levels of DPD may therefore be used to monitor the course of Perthes' disease.
Journal of Bone and Joint Surgery - British Volume 08/2006; 88(7):967-71. · 2.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The C8- subunit of the eighth component of complement was analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and immunoblotting in sera from 68 normal individuals, 12C8β-deficient patients (from seven unrelated families), and 10 of the parents of the latter. Three different forms of the C8- subunit were observed: 34/68 normal individuals were found to have a C8- triple band (termed C8-1, C8-2, C8-3 variants), 23/68 the C8-2 and C8-3 variants, and 11/68 the CS-1 and C8-3 variants. In contrast, all C8β-deficient patients had detectable C8-2 and C8-3 variants but lacked the C8-1 variant in addition to the C80 subunit. Three out often parents of the C8β-deficient patients were found to have the C8- triple band, whereas 7/10, like their children, had the C8-2 and C8-3 variants only. We conclude that there is a linkage between the C8- pattern and C8β deficiency. These data may support earlier findings that in humans the genes encoding for C8- and C8β are closely linked on chromosome 1.