Association Between Cancer Cachexia and Prognosis in Patients with Head and Neck Squamous Cell Carcinoma Who Received Chemoradiotherapy

doi:10.21203/rs.3.rs-695263/v1

Objectives: This retrospective observational study is conducted to evaluate the association between cancer cachexia and prognosis in head and neck cancer patients treated with chemoradiotherapy using skeletal muscle mass index at the level of the third lumbar vertebra with computed tomography.

Methods: Two hundred forty-two patients were enrolled and categorized into the following four groups based on cancer cachexia criteria and treatment setting: definitive chemoradiotherapy with cachexia, definitive chemoradiotherapy without cachexia, adjuvant chemoradiotherapy with cachexia, and adjuvant chemoradiotherapy without cachexia. Progression-free survival (PFS) and overall survival (OS) between cachexia and non-cachexia groups were compared by treatment setting using the long-rank test. Prognostic factors were evaluated using the Cox proportional hazards model.

Results: Fifty patients were diagnosed with cancer cachexia (20.7%). In the definitive setting, both PFS and OS were significantly shorter in the cachexia group (median PFS, 15.5 months vs. not reached, p < 0.01; median OS, 48.4 months vs. not reached. p < 0.01). Conversely, there was no significant difference between the two groups in the adjuvant setting. UICC Stage IV, base of albumin of <4, and cachexia were significant poor prognostic factors in the definitive setting. However, no prognostic factors were detected in the adjuvant setting.

Conclusion: Cancer cachexia was negatively related with prognosis in patients with head and neck squamous cell carcinoma who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients. Further research is warranted.

Oncology

cancer cachexia

prognosis

chemoradiotherapy

UICC Stage IV

albumin

Head and neck cancer (HNC) was the seventh most common cancer worldwide in 2018, accounting for 3% of all cancer types[1].

Although risk factors for HNC are not completely understood, several different factors such as smoking, alcohol, diet, and chronic viral infection, including human papillomavirus-associated oropharyngeal carcinoma, have been reported to increase its risk [2][3][4]. Conversely, several factors, such as improvement in lifestyle, reduce the risk of cancer.

Sarcopenia has been recognized to be an important prognostic factor in various types of cancer[5]. It is characterized as an age-related decline in muscle mass and strength, as opposed to increased muscle fat infiltration associated with frailty or poor physical function[6][7][5]. Sarcopenia is associated with negative outcomes such as higher risk for falls, loss of independence, hospitalization, and death[5]. It has also been associated with poor prognosis or severe toxicity in cancer patients with chemotherapy[8], and has no universal treatment[9]. However, both resistance treatment and aerobic exercise can increase muscle strength and reduce negative outcomes in general[10].

Patients with cancer also have a risk of decline of skeletal muscle mass via cachexia—a multifactorial disease in which skeletal muscle mass declines owing to systemic inflammation[11]; cachexia has also been recognized to be associated with hippocratic facies[12][13]. It is caused by the activation of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IF- γ)[14], leading to a decline in protein synthesis and increase in proteolysis and lipolysis, frequently occurring in solid tumors, particularly gastric, pancreatic, lung, and HNC cancers[15]. Cachexia is often present in patients with head and neck squamous cell carcinoma (HNSCC) and progresses during chemoradiotherapy, which is administered for a few months. Diagnosis is based on one of the following criteria: 1) weight loss of > 5% in 6 months (in the absence of simple starvation); 2) body mass index (BMI) of < 20 and weight loss of > 2%; 3) sarcopenia and weight loss of > 2%[11]. Thus, cachexia can be considered sarcopenia plus malnutrition.

Although cachexia can reflect conditions other than sarcopenia in patients with cancer, few reports associated with cachexia and prognosis. In this study, we evaluated the association between cachexia and prognosis in patients with HNSCC who received chemoradiotherapy.

Patients

We retrospectively analyzed prospectively collected data from consecutive patients with HNSCC who were initiated with concurrent chemoradiotherapy (CCRT) with cisplatin at the Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR) between January 2015 and December 2018. Patients’ data included the following characteristics: age, sex, height, weight, smoking status, Eastern Cooperative Oncology Group performance status (PS, ECOG PS), location of the primary tumor, histological diagnosis (including p16 protein expression), clinical stage (based on UICC TNM classification), base of albumin, total dose of cisplatin, radiation details, and pretreatment computed tomography (CT) findings. These factors were categorized for analysis as follows: age: <65 year or ≥ 65 years; sex: male or female; ECOG PS: 0 or ≥ 1; smoking: current/former or never; primary tumor site: nasopharynx, oropharynx, or other; clinical stage: 1–3 or 4; and base of albumin: <4 or ≥ 4. Cachexia was diagnosed as previously described[16]. We analyzed CT images, including the CT component of whole-body PET-CT scans, at the level of the third lumbar vertebra (L3). Skeletal muscle mass area was calculated using the Volume Analyzer SYNAPSE VINCENT image analysis system (Fujifilm Medical, Tokyo, Japan)[17]. Abdominal skeletal muscle includes the psoas major, paraspinals (erector spinae and quadratus lumborum), and muscles of the abdominal wall (transversus abdominus, external and internal obliques, and rectus abdominus). The skeletal muscle mass index (SMI) which normalizes skeletal muscle area adjusted by height was used as an indicator of sarcopenia[8]. The cross-sectional area of skeletal muscle at L3 was measured using the SYNAPSE VINCENT with Hounsfield unit thresholds of − 30 to + 150. After segmentation, minor manual measurements were performed as required. Sarcopenia was diagnosed with reference to Martin’s cut-off value: SMI of < 43 cm²/m² for men with BMI < 25 kg/m² or < 53 cm²/m² for men with BMI ≥ 25 kg/m² and < 41 cm²/m² for women[18].

Cisplatin was administered at a dose of 80 mg/m² (from 2012 to August 2015) or 100 mg/m² (from August 2015 to 2018) every 3 weeks for a total of three cycles. Elderly patients and those with reduced organ function received a reduced cisplatin dose according to the discretion of their physician. If one or more severe adverse events were observed during the CCRT, a skip, delay, or dose reduction of the second or third cisplatin cycle was permitted. Radiotherapy was performed as 3-dimensional conformal radiotherapy (3D‑CRT) or intensity‑modified radiotherapy (IMRT) with the conventional fraction, 2–2.12 Gy per fraction, once per day, five times per week. Prophylactic percutaneous endoscopic gastrostomy was performed unless particular reasons forbid it (such as refusal by the patient or past history of gastrectomy). Follow-up examinations using enhanced CT and measurements of blood biochemistry and serum tumor markers were performed approximately every 3 months after CCRT.

Statistical analysis

Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and log-rank test. Data were censored on January 31, 2021. Patients who were lost to follow-up were censored at the date of last contact or follow-up. PFS was calculated from the date of radiation initiation to the date of disease relapse, disease progression or death from any cause. OS was calculated from the date of radiation initiation to the date of death from any cause. Patients who were alive on January 31, 2021 were censored for OS analysis. We estimated survival curves by definitive or adjuvant CCRT using the Kaplan–Meier method and log-rank test. We performed univariate and multivariate analyses to estimate factors potentially prognostic for PFS and OS by calculating hazard ratios (HRs) using the Cox proportional hazards model. The level of significance was set at p value of < 0.1 for univariate analysis and of < 0.05 for multivariate analysis, which was two-sided. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a modified interface for R software (www.r-project.org)[19].

Patients’ characteristics

Three hundred and thirty-four patients were included. Of all the patients, 102 were excluded because presence or absence of cachexia could not be evaluated owing to the lack of abdominal CT imaging before treatment. Overall, 242-patient cohort comprised 50 (20.7%) with cachexia patients and 192 (79.3%) without cachexia patients with a median age of 61 years (range, 20–80 years). The median observation time was 37.1 months (range, 2.3-68.9 months) after the initiation of CCRT. Among these, 54 patients could not complete CCRT because of toxicity. The median radiation dose was 66 Gy and the median cisplatin dose was 280 mg, which differed between 2015 and 2016–2018 (240 mg and 300 mg, respectively) owing to alteration of the standard dose. At the time of censoring, 57 patients (23.5%) had died from the primary disease. The-242 patients were divided into definitive CCRT (n = 174) and adjuvant CCRT (n = 68) groups. For data analysis, the two groups were categorized into the following four: 1) definitive CCRT with cachexia, 2) definitive CCRT without cachexia, 3) adjuvant CCRT with cachexia, and 4) adjuvant CCRT without cachexia (Fig. 1). The characteristics of the 242 patients classified into four groups are shown in Table 1. The median interval between CT imaging and initial chemotherapy was 34 days (range: 1–235). In the definitive CCRT setting, the groups with cachexia and without cachexia significantly differed in PS and base of albumin. In the adjuvant CCRT setting, the two groups showed no difference.

Long-term outcomes

Fig. 2 shows PFS and OS stratified by cachexia and CCRT setting. There were significant differences for definitive CCRT between cachexia and non-cachexia groups: PFS (15.5 months vs. NA; HR, 2.75; 95%CI, 1.52–4.98; p < 0.01) and OS (48.4 months vs. NA; HR, 3.80; 95%CI, 1.88–7.63; p < 0.01). Three-year survival rate and local recurrence rate were significantly higher in the cachexia group (53.3% vs. 25.0%; p < 0.01 and 36.4% vs. 8.3%, p < 0.01). In the adjuvant CCRT setting, there were no significant differences between the two groups for PFS (NA vs. 23.7 months; HR, 0.86; 95%CI, 0.40–1.87; p = 0.92) or OS (NA vs. NA; HR, 1.07; 95%CI, 0.46–2.52; p = 0.87). Three-year survival rate and local recurrence rate were not significantly different between the two groups (45.0% vs. 50.0%, p = 0.79 and 25.0% vs. 25.0%, p = 1.00).

Risk factor of prognosis

In the definitive CCRT setting, multivariate Cox proportional hazard analysis indicated that the stage (HR, 2.33; 95%CI, 1.25–4.36; p < 0.01*), base of albumin (HR, 3.11; 95%CI, 1.77–5.49; p < 0.01*), and cachexia (HR, 2.52; 95%CI, 1.35–4.72; p < 0.01*) were independent risk factors for PFS. Independent risk factors for poor OS were stage (HR, 2.58; 95%CI, 1.14–5.80; p = 0.02*), base of albumin (HR, 4.18; 95%CI, 2.05–8.53; p < 0.01*), and cachexia (HR, 3.30; 95%CI, 1.54–7.05; p < 0.01*). Analysis by adjuvant CCRT setting revealed no independent predictive factors (Table 2, Table 3).

Adverse events

The frequency of grade 3–4 adverse events is presented in Table 3. In definitive CCRT, all adverse events were strongly associated with cachexia. Among the grade 3–4 adverse events, the frequency of anemia and leukopenia had significant difference between the two groups (20% and 1.4%, p < 0.01, 60% and 34.7%, p < 0.01, respectively). In the adjuvant CCRT setting, there were no significant differences in the frequency of severe adverse events.

We investigated the association between cancer cachexia and prognosis in patients with HNSCC who received chemoradiotherapy. The results demonstrated that cachexia was an independent predictor of poor prognosis, particularly in the definitive setting. Grade 3–4 adverse events occurred more frequently in patients with cachexia.

As mentioned above, skeletal muscle mass may decrease in patients with cancer via two mechanisms: sarcopenia and cachexia. Sarcopenia has also been previously reported as an indicator of poor prognosis of HNC[20][21]. Sarcopenia is related to age, and reports show that aerobic exercise may be a feasible and effective therapy [22][10]. Conversely, cachexia results from inflammation and malnutrition due to cancer. In patients with HNSCC receiving definitive CCRT, decreased oral nutrition may result from complex factors, including tumor site and toxicity owing to chemoradiotherapy, which may lead to cachexia. The prevalence of cachexia is high in HNC, and its prevention is important for patients with HNC who received chemoradiotherapy.

To our knowledge, this is the first study with a large sample size to evaluate the influence of cachexia in patients with HNSCC who received chemoradiotherapy. Our findings showed that cachexia is an important prognostic factor regardless of stage and that ongoing nutritional intervention before CCRT may improve prognosis.

Recently, in Japan, anamorelin—a high-affinity, selective agonist of the ghrelin receptor—was approved for the treatment of cachexia in patients with non–small-cell lung carcinoma, gastric cancer, pancreatic cancer, and colorectal cancer but not in those with HNC[23]. Thus, nutritional intervention may be one of the most effective approaches for the early stage of cachexia in HNSCC. However, several reports that evaluated the effects of nutritional intervention have failed to show any improvement for survival in HNSCC as setting of both definitive and adjuvant chemotherapy[24]. Although nutritional status appears to improve with dietary counseling, megestrol acetate, and prophylactic enteral tube feeding, there is no evidence that nutritional intervention can improve prognosis of patients with HNC[25][26][27]. However, these studies include few patients treated with chemotherapy; the results are limited; thus, further study in this area is warranted. Our data, at least, support the potential of a nutrition-based approach.

In this study, unlike several previous reports, we separately analyzed definitive and adjuvant CCRT settings. As the standard treatment for HNSCC is surgery plus adjuvant CCRT (in cases at high risk for recurrence) or definitive CCRT, several studies included both groups in their analysis.

Our study showed that cachexia was an independent prognostic factor in patients who received definitive CCRT. This may be because definitive CCRT has a wide range of radiation, including cervical lymph nodes, causing patients to experience loss of oral intake.

Evaluation of cachexia in the adjuvant CCRT setting was difficult because its presence or absence was determined using preoperative abdominal CT imaging findings. Postoperative imaging would have been more accurate; however, it provides no clinical benefit.

In sarcopenia, owing to reduced age-related changes in body composition, polar drugs that are mainly water-soluble tend to have smaller volumes of distribution, resulting in higher serum levels in sarcopenia.

Poor prognosis in elderly patients with cachexia may result from dose reduction owing to anticancer drug therapy[28]. In the same study, the frequency of grade 3-4 adverse events was high in cachexia. In our data, frequency of grade 3-4 some hematotoxicity were observed highly in cachexia, especially in definitive CCRT. The frequency of other adverse events was low to begin with, so it was considered that there was no difference. It has been reported that cisplatin may improve prognosis at a total dose of ≥200 mg [29][30]. Owing to dose reduction or poor PS, the median cisplatin total dose was 240 mg in cachexia; however, renal failure did not occur. The change in standard dose for cisplatin made in 2015 did not affect the distribution of cachexia. Cachexia was a significant poor prognostic factor, regardless of cisplatin dose.

Sarcopenia has also been associated with poor prognosis. It is normally diagnosed based on skeletal mass index at L3 using one of the two cut-off value methods (Prado or Martin)[8][18]; we used Martin’s. These cut-off values derived from Western studies are unsuitable for Asian patients with BMI of <25. An Asian sarcopenia working group proposed using dual energy X-ray absorptiometry or bioimpedance (BIA)[31] measurements. However, these are not performed routinely in clinical practice, therefore retrospective analysis is difficult.

Our study has several limitations in being retrospective, based on data from a single-institution with potential selection bias and short follow-up duration. Manual skeletal mass measurement was sometimes necessary. However, in contrast to that in abdominal cavity cancer such as gastric cancer or pancreatic cancer, abdominal CT imaging is not routinely performed. Finally, because our electric medical records changed in 2018, we could not collect adverse events associated with nutrition, such as appetite loss or nausea. However, we consider our results meaningful.

We have retrospectively evaluated the association between cancer cachexia and prognosis in patients with HNSCC who received CCRT. Cachexia was an independent poor prognostic factor in patients with HNSCC who received definitive CCRT. Ongoing nutritional intervention before CCRT can help improve survival. Further study is warranted.

Ethics approval and consent to participate

The requirement for informed consent was waived because data were reported anonymously. The study was approved by the Institutional Review Board of The Cancer Institute Hospital of JFCR (2021-1037). All procedures were performed in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and subsequent versions.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of interest: All of the authors, except 5, report they have no conflict of interest to disclose. NH reports personal fees from TAIHO Pharmaceutical Co., Ltd. YS reports personal fees from ONO Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, MSD K.K., and TAIHO Pharmaceutical Co., Ltd. NF reports personal fees from Eisai. JT reports personal fees from Eisai. ST reports grants and personal fees from ONO Pharmaceutical Co., Ltd., Bristol-Myers Squibb, MSD, AstraZeneca, Chugai, and BAYER.

Data availability: The datasets generated and analyzed in this study are available from the corresponding author upon reasonable request

Authors’ contributions Conception and design: NH, YS. Development of methodology: NH, YS. Data acquisition: NH, YS, YF, NF, XW and KN. Analysis and interpretation of data: NH. Draft writing, review, and/or revision of the manuscript: NH, YS and ST. Final approval of the manuscript: YS, YF, NF, XW, KN, TU, AO, MO, JT, YS, HM, TT and ST. All authors read and approved the final manuscript.

Acknowledgments

We thank the medical staff of the Department of Head and Neck Surgery, and Radiation Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research for their support during this study. We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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Table 1. Patients’ characteristics

		Definitive CCRT							Adjuvant CCRT
		Cachexia n=30			Without cachexia n=144			P value	Cachexia n=20			Without cachexia n=48		P value
		n		(%)	n		(%)		n		(%)	n	(%)
Age	Median(range)	57.5 (37-73)			61.0(36-80)			0.18	64(43-72)			59.5(20-76)		0.11
Sex	Male	24	(80.0)		118	(81.9)		0.79	16	(80.0)		46	(95.8)	0.06
	Female	6	(20.0)		26	(22.8)			4	(20.0)		2	(4.6)
PS	0	21	(70.0)		131	(91.0)		＜0.01	13	(65.0)		39	(81.2)	0.21
	≥1	9	(30.0)		13	(9.0)			7	(35.0)		9	(18.8)
Smoking	Yes	23	(76.7)		114	(79.2)		0.81	15	(75.0)		37	(77.1)	1.00
	No	7	(23.3)		30	(20.8)			5	(25.0)		11	(22.9)
Primary site	Naso/oropharynx	13	(43.3)		74	(51.4)		0.54	2	(10.0)		6	(12.5)	1.00
	Other	17	(56.7)		70	(48.6)			18	(90.0)		42	(87.5)
P16	Positive	14	(46.7)		73	(50.7)		0.81	14	(70.0)		29	(60.4)	0.70
	Negative	8	(26.7)		51	(35.4)			2	(10.0)		7	(14.6)
	Unknown	8	(26.7)		20	(13.9)			4	(20.0)		12	(25.0)
Stage	I-III	15	(50.0)		103	(71.5)		0.03	6	(30.0)		19	(39.6)	0.58
	IV	15	(50.0)		41	(28.5)			14	(70.0)		29	(60.4)
Base of albumin	Median	4.1(2.5-4.5)			4.2(3.2-4.9)			＜0.01	4.1(3.5-4.7)			4.1(2.1-4.7)		0.77
CCRT dose	Median	240			280			0.33	240			290		0.15
RT dose	Median	66 (60-66)			66 (60-70)			0.76	66 (60-70)			66 (46-70)		0.92

PS: performance status; CCRT: concurrent chemoradiotherapy; RT: radiation therapy

Table 2. Univariate and multivariate analysis for PFS

	Definitive CCRT						Adjuvant CCRT
	Univariate			Multivariate			Univariate
	HR	95%CI	P value	HR	95%CI	P value	HR	95%CI	P value
Age, ≥65	1.29	0.74-2.25	0.35	1.17	0.66-2.06	0.57	0.86	0.41-1.79	0.69
Sex, Male	1.30	0.61-2.77	0.48	1.25	0.56-2.77	0.58	0.88	0.26-2.90	0.83
PS, ≥1	2.35	1.20-4.58	0.01	1.23	0.60-2.49	0.56	1.47	0.70-3.09	0.30
Smoking, Current/former	0.98	0.50-1.91	0.95				0.66	0.30-1.43	0.30
Primary site, Naso/oropharynx	0.41	0.22-0.71	＜0.01	0.61	0.31-1.17	0.14	1.01	0.35-2.88	0.97
Stage, IV	3.67	2.11-6.37	＜0.01	2.33	1.25-4.36-	＜0.01	2.16	0.97-4.79	0.06
Base of albumin, ＜4	3.44	0.16-0.50	＜0.01	3.11	1.77-5.49	＜0.01	0.96	0.48-1.92	0.92
Cachexia	2.75	1.52-4.98	＜0.01	2.52	1.35-4.72	＜0.01	0.86	0.40-1.87	0.92

PS: performance status; CCRT: concurrent chemoradiotherapy

Table 3. Univariate and multivariate analyses for OS

	Definitive CCRT						Adjuvant CCRT
	Univariate			Multivariate			Univariate
	HR	95%CI	P value	HR	95%CI	P value	HR	95%CI	P value
Age, ≥65	1.44	0.72-2.87	0.30	1.33	0.64-2.75	0.43	0.61	0.25-1.48	0.27
Sex, Male	1.32	0.51-3.42	0.57	1.45	0.50-4.21	0.49	1.17	0.28-5.01	0.82
PS, ≥1	3.05	1.37-6.78	＜0.01	1.55	0.67-3.57	0.29	0.87	0.34-2.21	0.78
Smoking, Current/former	0.65	0.30-1.41	0.28				0.95	0.35-2.56	0.93
Primary site, Naso/oropharynx	0.44	0.21-0.92	0.03	0.84	0.35-2.00	0.70	1.47	0.73-2.96	0.27
Stage, IV	4.10	2.02-8.34	＜0.01	2.58	1.14-5.80-	0.02	1.00	0.30-3.38	0.99
Base of albumin, ＜4	2.42	1.44-4.08	＜0.01	4.18	2.05-8.53	＜0.01	0.72	0.31-1.65	0.44
Cachexia	3.80	1.88-7.63	＜0.01	3.30	1.54-7.05	＜0.01	1.07	0.46-2.52	0.87

PS: performance status; CCRT: concurrent chemoradiotherapy

Table 4. Frequency of adverse events of more than grade 3

	Definitive CCRT							Adjuvant CCRT
	Cachexia n=30			Without cachexia n=144			P value	Cachexia n=20		Without cachexia n=48		P value
	n		(%)	n		(%)		n	(%)	n	(%)
anemia	6	(20)		2	(1.4)		＜0.01	0	(0.0)	4	(8.3)	0.31
Leukopenia	18	(60)		50	(34.7)		＜0.01	10	(50.0)	19	(39.6)	0.59
Neutropenia	9	(30)		20	(20.8)		0.33	8	(40.0)	18	(37.5)	1.00
Thrombocytopenia	2	(6.7)		1	(0.7)		0.07	0	(0.0)	1	(2.1)	1.00
Liver failure	1	(3.3)		0	(0.0)		0.17	1	(5.0)	1	(2.1)	0.50
Renal failure	0	(0.0)		0	(0.0)		1.00	0	(0.0)	0	(0.0)	1.00

CCRT: concurrent chemoradiotherapy

Competing interest reported. All of the authors, except 5, report they have no conflict of interest to disclose. NH reports personal fees from TAIHO Pharmaceutical Co., Ltd. YS reports personal fees from ONO Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, MSD K.K., and TAIHO Pharmaceutical Co., Ltd. NF reports personal fees from Eisai. JT reports personal fees from Eisai. ST reports grants and personal fees from ONO Pharmaceutical Co., Ltd., Bristol-Myers Squibb, MSD, AstraZeneca, Chugai, and BAYER.

Association Between Cancer Cachexia and Prognosis in Patients with Head and Neck Squamous Cell Carcinoma Who Received Chemoradiotherapy

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Abstract

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Introduction

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Patients

Statistical analysis

Results

Discussion

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Additional Declarations

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