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== 结论 (Results) ==

=== 心电图学 (Electrocardiography) ===

DOX 治疗组中有 24 只 （38%） 在初次就诊时进行了心电图检查，18 只 （75%） 观察到异常，包括加速的脑室心律 （n = 8）、室性早产复合体 （n = 7）、窦性心动过速 （n = 3）、室性心动过速 （n = 2） 和房室传导阻滞 （n = 1）。CTL 组中有 39 只狗 （51%） 在就诊时进行了心电图检查，29 只狗 （74%） 注意到异常，包括加速的脑室节律 （n = 12）、室性早产复合体 （n = 11）、窦性心动过速 （n = 5）、室性心动过速 （n = 2）、电交替 （n = 3） 和窦性心律失常 （n = 2）。

Twenty-four dogs (38%) in the DOX-treated group had an ECG performed at initial presentation and 18 (75%) had abnormalities noted, including accelerated idioventricular rhythm (n = 8), ventricular premature complexes (n = 7), sinus tachycardia (n = 3), ventricular tachycardia (n = 2) and atrioventricular block (n = 1). Thirty-nine dogs (51%) in the CTL group had an ECG performed at presentation and 29 dogs (74%) had abnormalities noted, including accelerated idioventricular rhythm (n = 12), ventricular premature complexes (n = 11), sinus tachycardia (n = 5), ventricular tachycardia (n = 2), electrical alternans (n = 3) and sinus arrhythmia (n = 2).

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=== 超声心动图 (Echocardiography) ===

所有 140 只狗都至少进行了一次超声心动图检查。DOX治疗组进行的超声心动图的中位数为4次（范围为1-10）。DOX 治疗组中有 58 只狗 （91%） 在就诊时有心包填塞的超声心动图证据。肿块位于32只狗的右耳/心耳（50%），28只狗的右心房（44%），2只狗的右心室流出道（3%）和2只狗的右房室沟（3%）。DOX治疗组的55只狗（86%）进行了肿瘤测量，平均最长直径为3.7厘米（中位数为3.25;范围为2-8厘米）。CTL组的超声心动图中位数为2（范围为1-7）。CTL 组中有 71 只狗 （93%） 在就诊时有心包填塞的超声心动图证据。肿块位于36只狗的右心房（47%），25只狗的右耳/心耳（31%），5只狗的右房室沟（6%），4只狗的主动脉和左心房之间（5%），3只狗的三尖瓣（4%），3只狗的右心房和主动脉之间（4%），1只狗的左心室无壁（1%）。CTL组中有59只狗（78%）的肿瘤测量值，平均最长直径为3.4厘米（中位数为3.5;范围为1-8厘米）。

All 140 dogs had at least one echocardiogram performed. The median number of echocardiograms performed in the DOX-treated group was four (range, 1–10). Fifty-eight dogs (91%) in the DOX-treated group had echocardiographic evidence of tamponade at presentation. The mass was located in the right auricle/atrial appendage in 32 dogs (50%), right atrium in 28 dogs (44%), right ventricular outflow tract in 2 dogs (3%) and right atrioventricular groove in 2 dogs (3%). Tumour measurements were available for 55 dogs (86%) in the DOX-treated group, and the mean longest diameter was 3.7 cm (median, 3.25; range, 2–8 cm). The median number of echocardiograms in the CTL group was 2 (range, 1–7). Seventy-one dogs (93%) in the CTL group had echocardiographic evidence of tamponade at presentation. The mass was located in the right atrium in 36 dogs (47%), right auricle/atrial appendage in 25 dogs (31%), right atrioventricular groove in 5 dogs (6%), between the aorta and left atrium in 4 dogs (5%), tricuspid valve in 3 dogs (4%), between the right atrium and aorta in 3 dogs (4%), and in the left ventricular-free wall in 1 dog (1%). Tumour measurements were available for 59 dogs (78%) in the CTL group, and the mean longest diameter was 3.4 cm (median, 3.5; range, 1–8 cm).


在DOX治疗组的58只狗（91%）中进行了心包穿刺术。该组的平均心包穿刺次数为 2 例（中位数为 1;范围为 0-8）。CTL组对69只狗（91%）进行了心包穿刺术。该组的平均心包穿刺次数为1例（中位数为1;范围为0-3）。

Pericardiocentesis was performed in 58 dogs (91%) in the DOX-treated group. Mean number of pericardiocenteses for this group was 2 (median, 1; range, 0–8). Pericardiocentesis was performed in 69 dogs (91%) in the CTL group. Mean number of pericardiocenteses for this group was 1 (median, 1; range, 0–3).

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=== 治疗 (Treatment) ===

'''DOX 方案 (DOX protocol)'''

在DOX治疗组中，总共对64只狗施用了232剂DOX。每只狗的平均DOX剂量为4（中位数为4;范围为1-9）。九只狗接受了超过 5 剂的 DOX，最大剂量为 9 剂。58 只 （91%） 狗以 30 mg/m^2 剂量治疗，6 只狗 （9%） 以 1 mg/kg 剂量治疗。56 只狗 （88%） 每 2 周接受治疗一次，6 只狗 （9%） 每 3 周接受治疗;没有 2 只狗的治疗时间表信息。

A total of 232 doses of DOX were administered to 64 dogs in the DOX-treated group. The mean number of DOX doses per dog was 4 (median, 4; range, 1–9). Nine dogs received more than 5 doses of DOX and the maximum number of doses administered was 9. Fifty-eight (91%) dogs were treated at the 30 mg m−2 dose and 6 dogs (9%) were treated at 1 mg kg−1. Fifty-six dogs (88%) received treatment every 2 weeks and six dogs (9%) were treated every 3 weeks; treatment schedule information was not available for 2 dogs.


'''响应者的并发和后续协议 (Concurrent and subsequent protocols for responders)'''

11 只狗 （17%） 开始同时进行节拍化疗，包括环磷酰胺（12.5-15 mg/m^2 PO q/24）和非甾体抗炎药在 DOX 方案的前三个周期的某个时间点。14 只狗 （22%） 在完成 DOX 方案或至少四个 DOX 周期后接受节拍化疗。一只狗在完成 DOX 治疗后每周接受长春新碱（0.5 mg/m^2 IV）和标准剂量环磷酰胺（250 mg/m^2 PO，分 3 天）维持治疗。

Eleven dogs (17%) began concurrent metronomic chemotherapy, consisting of cyclophosphamide (12.5–15 mg/m^2 PO q per 24) and a non-steroidal anti-inflammatory drug at some point during the first three cycles of DOX protocol. Fourteen dogs (22%) were treated with metronomic chemotherapy after the completion of their DOX protocols or following at least four cycles of DOX. One dog underwent maintenance treatment with vincristine (0.5 mg m−2 IV), and standard dose cyclophosphamide (250 mg m−2 PO divided over 3 days) given on a weekly basis upon completion of treatment with DOX.


'''救援协议 (Rescue protocols)'''

23 只狗 （36%） 在 DOX 化疗失败后接受了抢救方案治疗。使用的抢救方案包括长春新碱/环磷酰胺 （n=14）、节律化疗 （n=2）、长春碱/环磷酰胺 （n=3）、长春新碱 （n=2） 和卡铂 （n=1）。一只狗接受了另一种剂量的 DOX 治疗，因为在初始 DOX 方案完成 90 天后，狗在接受节拍化疗时发生了复发。

Twenty-three dogs (36%) were treated with a rescue protocol after failing DOX chemotherapy. Rescue protocols used included vincristine/ cyclophosphamide (n=14), metronomic chemotherapy (n=2), vinblastine/cyclophosphamide (n=3), vincristine (n=2) and carboplatin (n=1). One dog was treated with another dose of DOX, as relapse occurred while the dog was being treated with metronomic chemotherapy 90 days after the completion of the initial DOX protocol.


'''其他治疗 (Other treatments)'''

DOX治疗组中的三只狗（5%）接受了其他病变的手术治疗，包括两只接受脾切除术的狗和一只接受肝叶切除术的狗。

Three dogs (5%) in the DOX-treated group underwent surgical treatment for additional lesions, including two dogs that underwent splenectomy and one dog that underwent a liver lobectomy.

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===  '''不良事件 (Adverse events)''' === 

表 3 列出了与 DOX 相关的 AE。报告了 16 例血液学毒性和 56 例胃肠道毒性。报告了 5 例 IV 级中性粒细胞减少症发作，但均在临床上无症状。一只狗发烧，但这与中性粒细胞减少事件无关。胃肠道毒性通常为轻度至中度，仅报告IV级厌食和呕吐各一次。

AEs associated with DOX are listed in Table 3. Sixteen hematologic and fifty-six gastrointestinal toxicities were reported. Five episodes of Grade IV neutropenia were reported, but all were clinically silent. One dog experienced a fever, but this was not associated with a neutropenic event. Gastrointestinal toxicities were generally mild to moderate with only one episode each of Grade IV anorexia and vomiting reported.

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===  '''治疗后的反应和结果 (Response and outcome following therapy)''' === 

接受DOX治疗的64只狗（100%）有可供分析的结果信息，这些数据总结在表4和表5中。一只狗没有接受预定的反应评估超声心动图，因此没有相关的反应信息;但是，提供了这只狗的生存数据。客观缓解率为41%，生物缓解率（CR+PR+SD）或临床获益为68%。20 只狗 （32%） 对 DOX 治疗没有反应。图 2 和 3 分别显示了 DOX 治疗犬的 PFS 和 DOX 和 CTL 组犬的 OS 的 Kaplan-Meier 生存概率曲线。在确定PFS之前，有三只狗失去了随访，因此从该分析中被删失。在确定 OS 之前，有 6 只狗丢失了随访，另外 4 只狗死于与 HSA 无关的原因;这 10 只狗从操作系统分析中被删失。DOX治疗组狗的PFS和MST分别为66天和116天。未经治疗的 CTL 犬的 MST 为 12 天。

Sixty-four dogs (100%) undergoing treatment with DOX had outcome information available for analysis, and these data are summarized in Tables 4 and 5. One dog did not undergo the scheduled response assessment echocardiogram and thus did not have associated response information available; however, survival data are provided for this dog. The objective response rate was 41%, and the biologic response rate (CR+PR+SD), or clinical benefit, was 68%. Twenty dogs (32%) failed to respond to treatment with DOX. Kaplan–Meier survival probability curves illustrating PFS for DOX-treated dogs and OS for dogs in both the DOX and CTL groups are presented in Figs 2 and 3, respectively. Three dogs were lost to follow-up before PFS could be determined and were thus censored from this analysis. Six dogs were lost to follow-up before OS could be determined and an additional four dogs died from causes unrelated to HSA; these 10 dogs were censored from OS analysis. The PFS and MST for dogs in the DOX-treated group were 66 and 116 days, respectively. The MST for untreated CTL dogs was 12 days.


===  '''变量作为预后因素 (Variables as prognostic factors)''' === 

分析的与PFS和OS相关的变量分别列于表6/表S1，支持信息和表7/表S2。通过单因素分析，诊断时存在血小板减少症 （P =0.022） 且肿瘤大小大于中位数 （P =0.013） 或平均 （P =0.001） 最长直径与 PFS 降低显著相关。诊断时存在血小板减少症也与OS降低显著相关（P=0.034）。对于DOX治疗组的狗，诊断时存在转移与PFS（P = 0.591）或OS（P = 0.56）的降低没有显着相关性，尽管没有转移的治疗狗有更长寿的趋势。全分期（MST=114 d）、部分分期（MST=94 d）或无分期（MST=139 d）治疗犬组的OS差异无统计学意义，P=0.10。在接受同步节拍治疗的狗和未同时接受节拍疗法的狗之间没有发现 PFS 或 MST 的统计学差异。DOX剂量（30mg m-2 vs 1 mg kg-1）和给药频率（每2周与每3周一次）与PFS或OS无关。

Variables analysed for association with PFS and OS are presented in Table 6/Table S1, Supporting Information, and Table 7/Table S2, respectively. By univariate analysis, the presence of thrombocytopenia (P =0.022) at diagnosis and tumour size greater than the median (P =0.013) or mean (P =0.001) longest diameter were significantly associated with decreased PFS. The presence of thrombocytopenia at diagnosis was also significantly associated with decreased OS (P =0.034). For dogs in the DOX-treated group, the presence of metastasis at diagnosis was not significantly associated with decreased PFS (P =0.591) or OS (P =0.56), although there was a trend for treated dogs without metastasis to live longer. There was no significant difference in OS between groups of treated dogs that underwent full staging (MST=114 days), partial staging (MST=94 days),or no staging (MST=139 days), P =0.10. No statistical difference in PFS or MST was found between dogs receiving and those not receiving concurrent metronomic therapy. DOX dosage (30 mg m−2 versus 1 mg kg−1) and administration frequency (every 2 weeks versus every 3 weeks) were not associated with PFS or OS.


===  '''尸检 (Necropsy)''' === 

DOX治疗组中的三只狗进行了尸检。组织病理学证实所有三只狗都存在右心房 HSA。脾脏HSA也在一只狗中得到证实。

Three dogs in the DOX-treated group had a necropsy performed. Histopathology confirmed the presence of right atrial HSA in all three dogs. Splenic HSA was also confirmed in one dog.

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