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Hindawi Sarcoma Volume 2020, Article ID 8260730, 9 pages https://doi.org/10.1155/2020/8260730 Clinical Study Long-Term Follow-up of a Randomized Study of Oral Etoposide versus Viscum album Fermentatum Pini as Maintenance Therapy in Osteosarcoma Patients in Complete Surgical Remission after Second Relapse 1 1 2 3 Alessandra Longhi , Marilena Cesari, Massimo Serra, and Erminia Mariani Chemotherapy Division, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Immunoreumathology and Tissue Regeneration Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Correspondence should be addressed to Alessandra Longhi; alessandra.longhi@ior.it Received 26 January 2020; Accepted 20 March 2020; Published 27 April 2020 Academic Editor: Manish Agarwal Copyright © 2020 Alessandra Longhi et al. $is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. In relapsed osteosarcoma, the 5-yr postrelapse disease-free survival (PRDFS) rate after the second relapse is<20%. In June 2007, a randomized study was started comparing oral etoposide vs Viscum album fermentatum Pini (an extract derived from the parasitic plant Viscum album L., European mistletoe) as maintenance therapy in patients with metastatic osteosarcoma in complete surgical remission after the second relapse. $e primary endpoint was the PRDFS rate at 12 months (compared to the historical control rate). $is is a long-term updated result. Patients and Methods. 10 patients received oral etoposide 50 mg/m daily for 21 days every 28 days for 6 months, and 9 patients received Viscum album fermentatum Pini 3 times/wk subcutaneously for 1 year. $e study closed early in July 2011 due to insufficient recruitment. Lymphocyte subpopulations were analyzed at T0, T3, T6, T9, and T12 months. Results. On 30 June 2019, at a median follow-up ITTof 83 months (range 3–144 ms), a median PRDFS of 106 ms (2–144) was observed in the Viscum arm with 5/9 patients who never relapse vs a PRDFS of 7 months (3–134) in the etoposide arm (all patients in the Etoposide arm relapsed) (hazard ratio HR � 0.287, 95% CI: 0.076–0.884, p � 0.03). Model forecast 10-yr overall survival rates as 64% in the Viscum arm and 33% in the etoposide arm. Lymphocyte subpopulation counts (CD3, CD4, and CD56) showed an increase in the Viscum arm while a decrease was observed in the etoposide arm during treatment. Conclusions. After 12 years from the start of the trial, the patients in the Viscum arm continue to show a considerably longer PRDFS compared to oral etoposide, and a trend for an advantage in OS is evident even if the number of treated patients is too small to draw conclusions. Viscum as maintenance treatment after complete surgical remission in relapsed osteosarcoma should be further investigated and compared with other drugs. bone), the time to progression (>24 months vs shorter 1. Introduction periods), and the number of lung metastases (1–3 vs more Overall survival of patients with relapsed osteosarcoma than 3 nodules) [3]. Relapse mainly affects the lungs, and remained unsatisfactory and unchanged over the last three patients achieving complete surgical remission after relapse decades, as well as the efforts to develop novel active agents have a prolonged 5-year postrelapse survival [1]. Subsequent have generally yielded disappointing results [1,2]. Main repeated relapses decrease further the chance of cure. In our prognostic factors for the survival of relapsed patients in- previous study, 235 relapsed osteosarcoma patients had a 5- clude the location of relapse (better prognosis for the lung vs yr PRDFS of 29%, and only 14 out of 120 (11.6%) patients 2 Sarcoma Viscum album extracts appear to interfere with tumor an- who had a second relapse never relapsed for the third time [1]. $e COSS study published in 2009 on 249 osteosarcoma giogenesis [15]. Recently, xenograft models showed the activity of a patients after a second relapse showed that the five-year overall and event-free survival rates were 16% and 9%, re- Viscum extract in osteosarcoma [16] and in Ewing sarcoma spectively [2]. A more recent paper (2017) [4] on 60 Italian both in in vitro and in vivo conditions [17]. In analogy to patients with relapsed osteosarcoma followed from 2003 to previous studies on other tumors, it was shown that Viscum 2013 showed that the median postrelapse disease-free sur- extracts have proapoptotic activity on osteosarcoma cells, via vival (PRDFS) after the second relapse was 6 months (range caspase activation, and also it displayed a synergistic activity 42 days to 44 months). $e majority of patients (84%) re- with chemotherapeutic drugs usually employed in osteo- sarcoma therapy (doxorubicin, ifosfamide, and etoposide) lapsed less than 12 months after the second complete sur- gical remission. $e 5-year postsecond relapse survival rate [16]. A further preclinical study demonstrated the cytotoxic activity of Viscum Species in different pediatric cancer cells was 22%. Lung recurrence as a unique site correlated with a better 5-year survival (33.6%) compared to other sites of [18]. Other in vitro studies demonstrated different activation recurrence (5%; p � 0.008) [4]. Patients who relapse with operable metastases are usually operated. Postoperative of dendritic cells and promotion of $1 immune response adjuvant chemotherapy is usually not a standard after re- according to different species of Viscum [19]. lapse because there is no evidence of an advantage that Some therapeutic protocols for osteosarcoma would outweigh the chemotherapeutic toxicity, and most employed etoposide (topoisomerase II inhibitor) mainly effective drugs are employed in the adjuvant phase. Che- IV in combination with ifosfamide at relapse. Yet, oral motherapy in a relapsed patient is usually administered in administration is used as well, and in clinical practice, usually in recurrent disease. A recent report [20] on 28 advanced or inoperable diseases. Tumors have immuno- suppressive capacities through secretion of various cytokines metastatic osteosarcoma patients showed that the use of etoposide 25 mg t.i.d induced 15% partial remission. $e favoring an escape from the immune response [5]. $era- peutic strategies to counteract the tumor-induced immu- median PFS was 3.7 months, and the median overall survival was 7.4 months. nosuppressive effect are employed by blocking immune checkpoints (CTLA-4, PD-L1, or PD-1) on T cells with Hematologic toxicity is one of the main limiting char- specific antibodies and thereby restoring the cytotoxic ca- acteristics of etoposide with an increased risk of secondary pacity of these cells [6]. Immunotherapy in bone sarcoma malignancy either after IV [21] or after oral administration was first applied by Coley who injected a mixture of [22–24]. streptococcal bacteria into unresectable bone sarcomas in In a previous paper [23], we presented the results of a 1891, achieving an immunological reaction and tumor re- randomized study of a Viscum album extract or oral eto- poside administration in osteosarcoma patients in complete gression [7]. Few studies are available on immunotherapies in osteosarcoma with limited results [8]. Interferon proved surgical remission after second relapse. In which, PRDFS rates, quality of life, and tolerability of each therapy after 12 to be unsatisfactory in improving the overall survival in adjuvant setting in localized osteosarcoma in the EUR- months of treatment were reported [25]. AMOS 1 trial [9]. Muramyl tripeptide (MTP), a BCG-de- In the present paper, we report updated results on rived drug, which activates macrophages, administrated PRDFS and on overall survival (OS) of those study pop- together with ifosfamide, improved 6 years of OS from 70% ulation after a follow-up period of 12 years from the opening to 78% (p � 0.03) in patients with localized osteosarcoma in of the study. adjuvant setting [10]. MTP has been licensed in European countries for the adjuvant treatment of localized 2. Materials and Methods osteosarcoma. Immunotherapy with anti-PD-L1 showed promising $is monoinstitutional, prospective, randomized, open-la- cure advantages in some cancers other than osteosarcoma. bel study approved by the Ethic Committee of the Istituto Less than 20% of osteosarcoma patients are PD-L1 positive. Ortopedico Rizzoli (IOR), Bologna, was registered in the in A recent report of pembrolizumab (an anti-PD-L1) the EU clinical trials register (EudraCT number 2006- employed in a 12 advanced osteosarcoma patients series 002676-18) and conducted according to the Declaration of produced unsatisfactory results [11]. Helsinki. Patients in complete surgical remission after the Viscum album extracts (European mistletoe) is part of second relapse for osteosarcoma were enrolled starting in integrative medicine, and its usage is popular among cancer June 2007, and 18 out of 20 patients had lung meta- patients in German-speaking countries [12,13]. Viscum al- stasectomy for their second relapse; lung metastases were bum extracts contain a variety of immunoactive compounds 1–3 nodule each and were all resected in our institute from that include lectins, viscotoxins, oligosaccharides and the same team of surgeon, and margins were considered polysaccharides, flavonoids, and triterpene acids [14]. $e wide if occurred in normal lung tissue. Two patients had antitumor activity of Viscum lectins has been demonstrated bone metastases, and their margins were wide. both in in vitro and in vivo, and it has been supposed to be Study characteristics are presented in summarized form related to the activation of monocytes/macrophages, gran- only. For a detailed description of the whole study and of ulocytes, natural killer cells, Tcells, and dendritic cells and to patients’ inclusion criteria, sample size, and patients’ ran- the induction of a variety of cytokines [5]. Furthermore, domization see Longhi et al. [25]. Sarcoma 3 2.1. Treatment. Etoposide was administered orally in doses 3. Results of 50 mg/m2 per day for 21 days every 28 days for 6 cycles. From June 2007 to July 2011, twenty patients were ran- Viscum album fermentatum Pini (manufactured as “Iscador domized. Eleven patients were randomly assigned to the P” by Iscador AG, Switzerland) was administered subcu- etoposide arm and nine to the Viscum arm. One patient taneously 3 times a week for 12 months. $e Viscum album enrolled in the etoposide arm refused to accept etoposide extract was injected subcutaneously (abdominal) 3 times/ after randomization, and he has withdrawn from the trial; he week. $e starting dose was 2 boxes of Series 0 for 14 vials was analyzed as assigned to etoposide following the inten- (each box contains 2 vials of 0.01 mg, 2 vials of 0.1 mg, and 3 tion-to-treat approach. vials of 1 mg), followed by 2 boxes of series I for 14 vials (2 Due to inadequate recruitment compared to what it vials of 0.1 mg, 2 vials of 1 mg, and 3 vials of 10 mg) vials, and was planned (36 patients in three years, 18 each arm), the subsequent treatment with series II (1, 10, and 20 mg) was th study was terminated early after 48 months by protocol carried out continuously until the 12 month [25]. amendment after the inclusion of 20 patients (11 etoposide and 9 Viscum). Data updated in July 2013 were already published [25]. Patients were continued to be followed 2.2. Clinical Assessment. Clinical and radiological assess- periodically. $e analysis presented here has been updated ment was done at the screening visit and after 3, 6, 9, and on June 30, 2019, 12 years after the start of the study and at 12 months [25] of treatment, and then if no progression a median follow-up of 106 months (range 3–144) of 19 was registered, it was done every 4 months until 3 years, th treated patients or 83 months (3–144) considering in- then every six months until the 5 year, and then every tention-to-treat (ITT) analysis on 20 randomized patients. year for at least until the tenth year. All patients were also Males were 11 and females 9; mean age at baseline was 33.9 planned to undergo blood test for the evaluation years (range 11–65). Arms were well balanced for risk of lymphocyte subpopulations at T0, T3, T6, T9, and T12 factors such as site of relapse, number of lesions at the months. Phenotype characterization of the second relapse and intervals from the end of chemotherapy different lymphocyte subpopulations was performed by and the first and second relapse, and percentage of necrosis specific monoclonal antibodies (CD3 � panT, of primary tumor (necrosis >90% � good responders; CD4 � helper, CD8 � suppressor, CD56 and CD16 � na- necrosis ≤90% � poor responder) (Table 1). ABCB1 tural killer, and CD19 � panB). P-glycoprotein positivity was also evaluated on a meta- static specimen resected previously to treatment as a negative prognostic factor in osteosarcoma [26]. ABCB1 2.3. Statistical Methods. For the long-term evaluation presented here, PRDFS and OS have been statistically positivity was revealed in metastatic tissue in 2 out of 4 patients in the Viscum arm (the other 2 were PgP negative) compared between treatment arms using the log-rank test. and in 1 out of 4 patients in the etoposide arm. $e one- Hazard rates and 95% confidence intervals (CI) have been year PRDFS and OS were already reported: only the 1-year derived from a corresponding Cox proportional hazard PRDFS rate of the Viscum arm differed significantly from regression with the treatment arm as the only independent the historical 12% rate (p � 0.004) [23]. After the end of factor. Forecasts of 10-year OS rates have been estimated study participation, two patients of the Viscum arm using parametric proportional hazard regression models continued to use Viscum either for 12 months or at a 6- with lognormal, exponential, log-logistic, or Weibull month on/off schedule, respectively. One patient of the distribution of the survival times (Klein and Moesch- berger, 1997). $e lognormal model fitted the data best etoposide arm after resection of lung metastases as the third relapse crossed over to Viscum and continued for 3 (smallest value for −2∗log-likelihood); therefore, these estimates are shown. Due to the decrease in sample size years spontaneously, and he is alive, free from disease. One patient in the etoposide arm after a third relapse of os- from 18 to 10 per study arm, no other adjustments were teosarcoma (lung metastases, resected) developed a second done, especially the global alpha error level of 5% remained cancer one year after (GIST of stomach) which was unchanged in order to not violate the validity of the resected. $e patient is alive and free of both cancer in June statistical testing procedure and its interpretation. Due to 2019. $e 5-years PRDFS rate in the Viscum arm was 55.5% the decrease in sample size from 18 to 10 per study arm, the (95% CI 21–86%) and 9% (95% CI 0, 2–43%) in the eto- power of the single-arm binomial test for superiority of a poside arm. $e 5-yr OS was 66.7% (95% CI: 28.2–87.8) in given treatment over the historical PRDFS rate of 12% the Viscum arm vs 40% (95% CI: 12.3–67) in the etoposide dropped from 81% to 61.8%. However, once a statistically significant difference (here, the superiority of 55.6% arm. On 30 June 2019, five out of nine enrolled patients in the Viscum arm never relapsed since the start of protocol, PRDFS rate of the Viscum arm at 1 yr over the historical 12% rate) has been found, the power of the (planned) test while all patients in the etoposide arm relapsed; the me- dian PRDFS was 106 months (range 2–144) in the Viscum becomes irrelevant (i.e., statistically significant difference arm versus a median PRDFS of 7 months (range 1–84 is valid independent on sample size). With regard to months) in the etoposide arm (hazard ratio HR � 0.287, etoposide, the 1-yr PRDFS was 27.3% compared with the 95% CI: 0.076–0.884, χ expected rate of 35% which is not statistically significant. � 4.714, p � 0.0299) (Figure 1). In the etoposide arm, 4 out of 11 patients were alive and Anyway, the long-term follow-up revealed a PRDF totally rd free of disease after a 3 relapse, median OS 43 months significant for Viscum over the etoposide arm. 4 Sarcoma Table 1: Patients characteristics. T. PgP on OS Status PTS Start TX Age Sex Arm Site/N PRDFS Outcome necrosis Met. (ms) 30.6.19 08/06/ 1 48 F Viscum P Lung one NA NE 144 144 NED NED 03/09/ 2 18 F Viscum P Lung two PR Pos 134 134 NED NED 02/10/ 3 28 M Viscum P Lung two GR Pos 140 140 NED NED 21/04/ 4 29 M Viscum P Lung one GR NA 3 17 R Dead 19/09/ 5 30 F Viscum P Lung two PR NE 121 121 NED NED Lung 23/09/ 6 21 F Viscum P PR Neg 6 120 R NED1 08 three 02/04/ 7 20 F Viscum P Bone one PR Neg 106 106 NED NED 23/07/ 8 41 M Viscum P Lung one GR NE 2 24 R Dead 30/06/ 9 22 M Viscum P Lung one GR Neg 11 36 R Dead 12/06/ 10 28 M Etoposide Bone one PR NA 3 5 R Dead 17/01/ 11 62 F Etoposide Lung one GR NA 12 128 R NED 1 17/01/ 12 48 M Etoposide Lung one PR NE 6 134 R NED 1 17/03/ 13 16 F Etoposide Lung one GR Neg 3 5 R Dead 07/01/ 14 11 M Etoposide Lung two GR Neg 1 3 R Dead 10/07/ 15 35 F Etoposide Lung one NA Neg 9 118 R NED 1 28/05/ 16 65 M Etoposide Lung two NA Neg 84 119 R NED 1 11/02/ 17 17 M Etoposide Lung two PR Pos 4 25 R Dead 11/05/ 18 63 M Etoposide Lung one NA Pos 42 60 R Dead 08/07/ 19 17 F Etoposide Lung two PR Neg 8 23 R Dead 08/08/ Etop never started ITT NA 20 67 M NE Dead ITT 11 43 nd Site/N � site of the 2 metastase, N of lesions; tumor necrosis: necrosis on primary tumor; GR � good responder> 90% and PR � poor responder≤ 90%; PgP on metastases: pos � Positive, Neg � Negative; NA � not available and NE � not evaluable; NED � nonevidence of disease after enrollment: NED1 � nonevidence of disease after treatment for a third relapse; R � relapse; ITT �intention-to-treat; PRDFS: postrelapse disease-free survival; OS: overall survival. (range 3–134), while 6 out of 9 patients in the Viscum arm showed an increase in CD3, CD4, and NK after 6 ms of were alive with a median OS of 120 months (range 14–144). Viscum therapy, while a net decrease of these lymphocyte A parametric proportional hazard regression model time subpopulations was observed in the first 3 months of forecasts 10-year OS rates for the Viscum and etoposide arms treatment in the etoposide group (Figures 3 and 4). $e of 64% and 33%, respectively, assuming a lognormal dis- correlation between changes of each of the three T-lym- tribution of survival (Figure 2). phocytes subpopulations (CD3, CD4, and NK) demon- On 30 June 2019, the PRDFS of the five long-term strated a consensual modification in the Viscum arm, while on the contrary, they had a disorganized pattern in the survivors in the Viscum arm were 144, 140, 134, 121, and 106 months, respectively. etoposide arm (Table 2). Patients after 12 months of study $e count of lymphocyte subpopulations was performed were continued to be followed with simple blood count in 7 patients in the Viscum arm (5 of whom had full test until regularly every visit, not with lymphocyte subpopulation T12 months) and 7 patients in the etoposide arm (4 until T12 count, and no abnormal changes were reported in total white months) at T0, T3 ms, T6 ms, T9 ms, and T12 ms, and they blood cells or total lymphocytes in the following controls. Sarcoma 5 1.0 Viscum album fermentatum has a long history being Hazard ratio 10 yrs PRDFS 0.9 HR = 0.287 used for over 80 years as a complementary integrative 55, 6 in Viscum arm CI = (0.087 – 0.944) 0% in Etoposide medicine, and it is safe with limited toxicity; it has been 0.8 p = 0.0399 arm employed in several studies with some benefit reported on 0.7 survival [28] and QOL, but many of these studies have 0.6 methodologic flaws. Viscum has been employed intravenous 0.5 [29], intratumoral [30], and also intravenously in pediatric 0.4 10-year 5-year cancer case reports. A recent case series from Essen pediatric PRDFS 0.3 PRDFS oncology reported some benefit in heavily pretreated ad- 0.2 vanced pediatric cancer patients treated with intravenous 0.1 Viscum (4/10 patients reported a partial response and 2/10 Trial Follow-up 0.0 stable disease), and side effects requested hospitalization 024 68 10 [31]. Years since randomization Twelve years after the start of our study, the patients Treatment arm treated with Viscum album fermentatum Pini continue to Etoposide Censored have a considerably and statistically significant longer Viscum PRDFS compared to the oral etoposide arm. Also, side Figure 1: Postrelapse disease-free survival. effects and quality of life measured with EORTC QOL30 were favorable to the Viscum arm as previously reported [25]. Viscum can be administrated safely subcutaneously 1.0 for years without serious side effects, while prolonged use 10-years forecast overall 0.9 survival of etoposide can increase the risk of second cancer. $is Viscum arm 64% 0.8 Etoposide arm 33% study has the limitation of the small sample size. Patients 0.7 were oligometastatic mainly to the lungs, so it was a fa- 0.6 vorable set of patients, but they were well balanced in the 0.5 two arms, and the differences were significant. $e 5-yr PRDSF results (55.5% in the Viscum arm) of this small 0.4 study is better than previously reported [2, 4]. In fact, if we 0.3 10-year compare results from another report by Tirtei et al. [4], in OS 0.2 which patients with lung metastases only have a 5-yrs post- 0.1 second relapse DFS of 33.6% and those with one lung Trial Follow-up 0.0 nodule only had a 5-yr PRDFS of 42% lower than the 02468 10 results of our study. Years since randomization Also, the results of 10-year overall survival forecast are Treatment arm encouraging (64% for Viscum vs 33% for etoposide). $ose Etoposide Censored patients who could reach a third complete surgical remission VA-E after the third relapse had an improved OS in both arms Figure 2: Overall survival. underling the importance of surgical resection of metastases to reach a longer survival. $e analysis of lymphocyte subpopulation changes during time in the two treatment 4. Discussion arms, indicating a different lymphocyte distribution between the two treatments, and at 6 months, it was almost opposite $e treatment of relapsed osteosarcoma patients remains unsatisfactory especially after a second and further relapse, (p< 0, 05) (Figure 3) with an increase of T subpopulations (CD3, CD4, and NK) in the Viscum arm, while a net decrease and surgery is the best treatment when feasible and can prolong PRDFS (1, 2, and 3). Chemotherapy treatment in is observed in the etoposide arm (Figures 4(a) and 4(b)). Viscum could be used in patients free from disease at high absence of measurable disease after complete surgical re- risk of recurrence as maintenance therapy and compared in mission in relapsed patients is usually nonstandard. Few a randomized trial with other drugs or biologic response studies were published on maintenance therapy in osteo- modifiers. If we consider that so far cytotoxic maintenance sarcoma. A randomized study on metronomic chemother- therapy has not proved effective in osteosarcoma, an in- apy as maintenance therapy in localized osteosarcoma was expensive maintenance treatment like Viscum should be published in 2016. 298 patients with localized osteosarcoma encouraged to be further evaluated in postrelapsed were randomized to receive metronomic chemotherapy with osteosarcoma. oral cyclophosphamide + methotrexate for 73 weeks as maintenance therapy vs no therapy after usual neoadjuvant So far, the scientific community and pharmaceutical companies showed no interest in randomized trials with chemotherapy with MAP: no benefit on disease-free survival Viscum compared to other conventional therapies. We hope or overall survival was reported [27]. It is relevant that 35% that the results of this study will encourage future multi- of those patients randomized to receive metronomic che- center, international studies. motherapy refused it. Probability of OS Probability of PRDFS 6 Sarcoma Lymphocyte concentration changes –100 –200 -300 –400 –500 Viscum album Etoposide Treatment Baseline 3-month delta 6-month delta 9-month delta 12-month delta Viscum album 0 9.14 ± 240.32 138.43 ± 518.60 278.60 ± 429.52 –85.60 ± 409.01 Etoposide 0 403.25 ± 249.35 56.500 ± 392.45 15.000 ± 169.50 119.250 ± 248.97 Results are expressed as means ± standard deviation. Comparison between treatments were performad by Mann–Whitney U test: p < 0.01 between treatments at 3 month delta. Figure 3: Total Lymphocyte count in Viscum- and Etoposide-treated patients at T0, T3, T6, T9, and T12. Viscum album –50 –100 –150 036 9 12 3 3 CD3 (mm ) CD19 (mm ) 3 3 CD56 (mm ) CD8 (mm ) CD4 (mm ) Phenotype Baseline 3-month delta 6-month delta 9-month delta 12-month delta CD3 0 –19.08 ± 251.16 85.25 ± 271.96 208.66 ± 298.28 –35.13 ± 209.23 CD4 0 14.27 ± 144.53 26.45 ± 170.78 84.38 ± 149.58 –39.82 ± 102.51 CD8 0 2.48 ± 80.14 54.33 ± 96.95 86.22 ± 131.97 –20.38 ± 101.57 CD56 0 20.72 ± 102.48 29.17 ± 193.47 31.41 ± 190.36 –24.59 ± 180.06 CD19 0 14.07 ± 42.64 22.85 ± 85.37 36.11 ± 72.69 –18.63 ± 40.76 Results are expressed as means ± standard deviation. Comparison between treatments were performad by Mann–Whitney U test: signicant treatments at 3 month delta between treatments for CD56, p < 0.05 and for CD20. p < 0.001. (a) Figure 4: Continued. Lymphocytes (mm ) Lymphocytes (mm ) Sarcoma 7 Etoposide –50 –100 –150 036 9 12 3 3 CD3 (mm ) CD19 (mm ) 3 3 CD56 (mm ) CD8 (mm ) CD4 (mm ) Phenotype Baseline 3-month delta 6-month delta 9-month delta 12-month delta CD3 0 –33.23 ± 297.59 –73.60 ± 263.76 61.09 ± 167.88 –37.88 ± 276.81 CD4 0 –73.17 ± 116.24 9.30 ± 179.02 60.17 ± 30.15 26.62 ± 121.35 CD8 0 –83.18 ± 162.19 –25.40 ± 125.45 –55.40 ± 115.40 –32.52 ± 102.56 CD56 0 –139.40 ± 128.30 –64.17 ± 61.27 –52.20 ± 37.94 17.45 ± 84.27 CD19 0 –120.87 ± 64.90 –20.61 ± 106.95 14.31 ± 29.19 72.34 ± 87.55 Results are expressed as means ± standard deviation. Comparison between treatments were performad by Mann–Whitney U test: signicant treatments at 3 month delta between treatments for CD56, p < 0.05 and for CD20. p < 0.001. (b) Figure 4: Lymphocyte subgroup count in (a) Viscum and (b) etoposide. Table 2: Correlation between variations of cell population at different time points. 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Sarcoma – Hindawi Publishing Corporation
Published: Apr 27, 2020
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