docs: 任务书 03 医生核对包；TIC 拟合约束文献核查记录

来源：负责人 2026-10-17 要求把 29 例处理结果整理成医生能看的格式并做成长期入口（表格 CSV、文字 PDF、视频不压缩、不向医生提问、问题清单只写现象）；文献核查为负责人要求的质量门依据核对，结论待医生看过后再定。

Co-Authored-By: Claude Opus 5.5 <noreply@anthropic.com>

research-wiki/scratch/2026-10-17-TIC拟合约束文献核查/B-pancreas-solid.md

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+# B. 胰腺实性病变 CEUS / CE-EUS 定量（TIC）文献核查
+
+核查日期 2026-10-17。范围是胰腺实性病变（PDAC、pNEN、肿块型胰腺炎、SPN 等）的经腹 CEUS 和 CE-EUS 定量研究。
+
+**全文来源说明。** 本机访问 PMC、Europe PMC 的 `?pdf=render`、MDPI、Thieme 和 BMC 的 PDF 链接，全部返回 Cloudflare 或机器人验证页（`file` 识别为 HTML），所以**一份 PDF 都没能存进 `reference-pdf/`**。下表的全文都是从 Europe PMC REST 接口取得的出版社 JATS XML（`/europepmc/webservices/rest/<PMCID>/fullTextXML`），转成文本后存在 `/tmp/claude-1000/-home-iomgaa-Projects-CADx-4/d2239309-a620-4197-8b4b-d4e97e3a3537/scratchpad/lit/txt/<PMCID>.txt`。Chen 2021 一篇是从出版社 HTML 转出的，存为 `txt/2021-chen-qims-venous-phase.txt`。XML 和 HTML 都没有页码，所以下文引文一律标**章节名**。
+
+## 1. 文献清单
+
+### 1a. 读过方法部分全文的原始研究（11 篇）
+
+| # | 文本文件（txt/） | 标题 | 年份 / 期刊 | DOI | 人群与例数 | 软件 / 模型 |
+|---|---|---|---|---|---|---|
+| 1 | PMC9689529.txt | Early Assessment of Chemoradiotherapy Response for Locally Advanced PDAC by Dynamic Contrast-Enhanced Ultrasound (Lu et al.) | 2022 Diagnostics | 10.3390/diagnostics12112662 | 局部晚期 PDAC 21 例（入组 23 例），经腹 | VueBox；拟合质量 >75% |
+| 2 | PMC9858178.txt | Prediction of Pathological Grades of pNETs Based on DCE-US Quantitative Analysis (Yang et al.) | 2023 Diagnostics | 10.3390/diagnostics13020238 | pNEN 42 例，经腹 | VueBox；运动补偿；拟合质量 >75% |
+| 3 | PMC12179939.txt | Noninvasive prediction of Ki-67 expression in pancreatic cancer via CEUS quantitative parameters (Yang et al.) | 2025 World J Gastrointest Oncol | 10.4251/wjgo.v17.i6.… | 胰腺癌 54 例，经腹 | SonoLiver（TomTec）；拟合质量 ≥75% |
+| 4 | PMC11580603.txt | Correlation of DCE-US and the Ki-67 labelling index in PDAC (Lin et al.) | 2024 World J Gastroenterol | 10.3748/wjg.v30.i44.4697 | PDAC 30 例，经腹 | GE NovoUltrasound Kit；运动补偿 |
+| 5 | PMC10606620.txt | PDAC: CEUS characteristics correlated with the hypoxic microenvironment (Wang et al.) | 2023 Diagnostics | 10.3390/diagnostics13203270 | PDAC 102 例，其中 72 例拿到了定量参数，经腹 | VueBox 4.3 |
+| 6 | PMC10240015.txt | PDAC with synchronous and metachronous hepatic metastasis predicted by CEUS (Jia et al.) | 2023 Quant Imaging Med Surg | 10.21037/qims-22-1132 | PDAC 133 例，经腹 | QLAB 4.2；人工剔除呼吸造成的错位帧 |
+| 7 | 2021-chen-qims-venous-phase.txt | Enhancement patterns in the venous phase of CEUS: solid pancreatic lesions (Chen et al.) | 2021 Quant Imaging Med Surg | 10.21037/qims-20-1248 | 胰腺实性病变 57 例，经腹 | QLAB 10.8 曲线拟合；ROI 是 5 mm 方框 |
+| 8 | PMC12896552.txt | CEUS of SPN and pancreatoblastoma in children (Tang et al.) | 2026 Diagnostics | 10.3390/diagnostics16030474 | 22 例（SPN 为主，胰母细胞瘤 3 例），经腹 | SonoLiver；呼吸补偿 |
+| 9 | PMC13323896.txt | Quantitative CE-EUS in differential diagnosis of pancreatic solid neoplasms (Tacelli et al.) | 2026 iGIE | 见 PMC | 73 例（PDAC 51、pNEN 22），EUS | VueBox；ROI 包住整个病灶；运动校正 |
+| 10 | PMC3548695.txt | Quantitative low MI CE-EUS for chronic pseudotumoral pancreatitis vs pancreatic cancer (Gheonea et al.) | 2013 BMC Gastroenterol | 10.1186/1471-230X-13-2 | 51 例（PDAC 32、假瘤性胰腺炎 19），EUS | Image Pro Plus 逐帧强度；**没有模型拟合** |
+| 11 | PMC12618712.txt | Perfusion Assessment in CEUS Imaging for Estimating Pancreatic Cancer Response to Sonoporation-Enhanced Chemotherapy (Adler et al.) | 2025 Ultrasonic Imaging | 10.1177/01617346251367758 | 不可切除 PDAC 13 例，经腹，Sonazoid 输注 | 自写 MATLAB；按 NCC 选帧并配准；**没有 TIC 模型拟合** |
+
+另有一篇范围外但相关、也读了全文：PMC5952595.txt，Engjom et al. 2018 BMC Med Imaging（10.1186/s12880-018-0259-3）。研究对象是囊性纤维化患者的胰腺**实质**灌注，不是肿瘤，共 45 例。用的是 bolus-and-burst 药代模型（MATLAB DCE-US 软件），处理方式是人工运动校正加剔除帧。
+
+### 1b. 读过全文但属于综述或病例报告，只作旁证
+
+- PMC5331837.txt：Dietrich et al. 2017, Endosc Ultrasound, "Dynamic contrast-enhanced endoscopic ultrasound: A quantification method"，综述，10.4103/2303-9027.193595。
+- PMC12346609.txt：Spadaccini et al. 2025, Cancers，综述。
+- PMC11419544.txt：Saima et al. 2024, Endosc Ultrasound，单例病例报告。
+
+### 1c. 只有摘要
+
+- Kersting et al. 2009, Gastroenterology, 10.1053/j.gastro.2009.08.049：PDAC 45 例、炎性肿块 15 例，用 Axius ACQ。
+- Săftoiu et al. 2015, Gastrointest Endosc, 10.1016/j.gie.2014.11.040：多中心研究，PC 112 例、CP 55 例，CEH-EUS 的 TIC 加人工神经网络。
+- Wang L et al. 2023, Eur Radiol, 10.1007/s00330-023-09393-7：89 例乏血供实性病变，含 SPN。
+- Stangeland et al. 2017, Ultrasound Int Open, 10.1055/s-0043-110475（PMC5605004）：胰腺 bolus-and-burst 的观察者间一致性，10 例。这篇在 PMC 有全文，但 PMC 页面和 Thieme PDF 都抓不下来。
+
+## 2. 逐条约束核查
+
+### 约束 1：用 Lognormal 模型拟合胰腺病灶的 TIC 有没有先例；拟合用的是显示域灰度还是线性化数据
+
+**Lognormal：在胰腺实性病变文献里未找到依据。** 读过的 11 篇全文中，没有一篇在方法里写出 "lognormal" 或 "log-normal"（对全部文本做过关键词检索）。用 VueBox 的几篇只写 "curve fitting"，没写用的是哪个模型：
+
+- Lu 2022（PMC9689529.txt，§2.5 Quantitative Perfusion Analysis）："All CEUS images were analyzed with VueBox@ software (Bracco, Italy) … After curve fittings, results were considered credible when the quality of fit >75%."
+- Yang 2023（PMC9858178.txt，§2.5 Quantitative Analysis）："After curve fitting, various CEUS quantitative parameters were obtained, including the rise time (RT), peak intensity (PE), time to peak (TP), mean transit time (mTT) and area under the curve (AUC)"
+- Chen 2021（2021-chen-qims-venous-phase.txt，Methods / US and CEUS）："Curve fitting was performed, and the time-to-peak, peak intensity, and half-life time were estimated using the QLAB software." 文中没有写拟合函数。
+- 推断（不是原文）：VueBox 的团注模型通常就是 lognormal，但这些胰腺论文里都没有这样写，不能把它当成「胰腺 lognormal 先例」引用。
+
+**线性化还是显示域：**
+
+- 支持用线性化数据（来自综述，不是胰腺原始研究）：Dietrich 2017（PMC5331837.txt，§Functional assessment of tumor response）："'Linear data' are uncompressed US data that are used to produce TICs, which are then analyzed for amplitude and temporal components. Linear data processing seems to be the only mathematically valid method for determining tumor response to antivascular drugs analyzing TIC." 同一节又写："Despite studies published in the literature up to now, there is no consensus concerning the following. … The different principles transforming the raw US signals into the resulting curve to be analyzed (raw data – smoothing)"
+- 支持用线性化数据（综述）：Spadaccini 2025（PMC12346609.txt，§2 EUS and CH-EUS）："DCE-US is a functional imaging technique that allows quantitative estimation of the perfusion of a mass using raw linear data and calculation of objective parameters describing its vasculature"
+- 在视频上近似线性化（原始研究）：Gheonea 2013（PMC3548695.txt，Methods）："We manually exported recordings … in uncompressed audio-video interleaved (AVI) format at six frames per seconds … The software used for post-processing equalized the brightness, contrast and gamma levels on a frame-by-frame basis, thus linearizing the recording."
+- 直接用显示域 8 位灰度（原始研究，没有拟合模型）：Adler 2025（PMC12618712.txt，§Technical Details）："Images were captured … in a 4-D (Y, X, RGB, Time) uint8 … data format. For analysis, the three RGB color channels were converted into a single grayscale channel using the following formula: Gray=0.299*Red+0.587*Green+0.114*Blue"
+- 显示域 dB 刻度：Chen 2021 图 2 图注："peak intensity estimated to be 19.2 to 13.1 dB"（QLAB 输出，以 dB 为单位）。
+
+### 约束 2：拟合参数的取值范围（峰高、峰时刻 ±5 s、σ 在 0.08–2.5、t0、基线），以及参数贴边界就判失败
+
+**未找到依据。** 11 篇全文里都没有报告拟合参数的上下界、初值，也没有「参数贴边界即判失败」这类规则。检索过 constrain、bound、initial value、starting value、truncat 等词，命中的都与拟合无关。唯一和「参数取值不合理就剔除」沾边的是 Engjom 2018，对象是胰腺实质，模型是 bolus-and-burst，剔除的是**输出参数**，不是拟合参数贴边界：
+
+- Engjom 2018（PMC5952595.txt，§Exclusion of datasets）："Post analysis exclusions of outliers represented by MTT > 15sek were performed to exclude non-physiological values from the analysis."
+- 同文 §Inclusion："Further three analyses were excluded from the analysis performed by observer 2 due to non-physiological values (MTT > 15 s)"
+
+### 约束 3：模型的峰不能落在拟合区间的头尾
+
+**未找到依据。** 所有文献都没有讨论模型峰的位置相对于拟合窗的约束。相关的只有分析窗起点由人工设定：
+
+- Tacelli 2026（PMC13323896.txt，图 1 图注）："The vertical red cursor indicates the user-selected contrast-arrival time, which is used to define the analysis windows."
+
+### 约束 4：拟合优度门槛，以及不合格怎么处理
+
+**我们用的 R² ≥ 0.35 或「残差与噪声同量级」、NRMSE ≤ 0.45：未找到依据。** 胰腺文献里实际用的是 VueBox 或 SonoLiver 输出的「quality of fit」，门槛都是 75%：
+
+- Lu 2022（PMC9689529.txt，§2.5）："After curve fittings, results were considered credible when the quality of fit >75%."
+- Yang 2023（PMC9858178.txt，§2.5）："The results were considered reliable when the quality of fitting exceeded 75%."
+- Yang 2025（PMC12179939.txt，§Quantitative analysis of CEUS and related parameters）："To maintain study quality, we established a quality of fit threshold of ≥ 75% for the TIC."
+- 胰腺文献里**没有找到 80% 的门槛**。
+
+**不合格怎么处理。** 上面三篇都没写低于 75% 的曲线怎么办，是剔除、重画 ROI 还是别的做法。只有间接证据：
+
+- Wang 2023（PMC10606620.txt，§3.6）："A total of 72 of 102 lesions obtained the ROIs parameters." 同文局限性一段："quantitative analysis parameters were not obtained for all lesions." 文中没写这 30 例为什么没拿到参数。
+- Lu 2022（§3.1）："Among these, two cases were excluded for lack of 2 min DICOM clips."
+
+### 约束 5：ROI 怎么画（整个病灶还是增强部分），两种 ROI 是否并用
+
+**包住整个病灶：**
+- Tacelli 2026（PMC13323896.txt，§CE-EUS postprocedural analysis）："manually selected a region of interest (ROI) in the healthy pancreatic parenchyma and an ROI encompassing the largest assessable surface area of the targeted focal lesion"；图 1 图注："the tumor ROI (yellow) completely encompasses the pNEN … ROIs are size-matched and positioned to avoid vessels and ducts."
+- Gheonea 2013（PMC3548695.txt，Methods）："The whole lesion was taking into account when selecting the corresponding ROI. We used an irregular shape to trace the contour of the lesion whenever possible. Otherwise, we chose a significant portion of the lesion (in several chronic pancreatitis cases)."
+- Adler 2025（PMC12618712.txt，§Polygon / §Ellipse）：用多边形勾出整个病灶，外加一个 0.5 cm 宽的瘤周环。原文："Lesion analysis employed a concentric ring system derived from an inscribed ellipse. … rings with a constant radial distance of 0.5 cm"
+
+**只取实性或增强最强的部分，避开坏死和囊变：**
+- Yang 2023（PMC9858178.txt，§2.5）："A region of interest (ROI) was placed manually in a solid part of the pancreatic lesion and another ROI was placed in the surrounding pancreatic parenchyma."
+- Lin 2024（PMC11580603.txt，§Quantitative analysis）："The regions of interest (ROI) were manually placed in the solid component of lesions and surrounding parenchyma. The ROIs for the lesion and parenchyma were selected at the same depth, as much as possible."
+- Wang 2023（PMC10606620.txt，§2.3.2）："Regions of interest (ROI) were placed manually in the strongest enhancement of the suspected tumor."
+- Tang 2026（PMC12896552.txt，§2.5）："Place the ROI within the most intensely enhanced solid region of the lesion, avoiding areas with grossly visible cystic changes, necrosis, and calcifications. Place an ROI of identical size within normal tissue at the same depth to minimize variability."
+- Chen 2021（Methods）："The ROI was square shaped with a side length of 5 mm. The two ROIs for each case were located at a similar depth where possible. Representative areas were selected, avoiding blood vessels and interfaces."
+
+**用增强范围来定病灶边界，再在中心和周边各放一个 ROI：**
+- Jia 2023（PMC10240015.txt，§Time-intensity curve analysis）："The first step was to delineate the actual size of the lesion, as the size of the lesion shown in the grayscale images may contain areas of necrosis, inflammation, and so on. We defined the area of fast wash-out in the venous phase of CEUS as the actual size of the pancreatic lesion. In the second step, regions of interest (ROIs) were placed in the center and around the lesion"
+
+**整个病灶和去掉暗区后的增强部分并用（对应我们的 roi_all 加 roi_perf）：未找到依据。** 胰腺文献普遍并用的是「病灶 ROI 加同深度的胰腺实质参照 ROI」，再算比值。例如 Lin 2024 原文："To minimize the influence of different ROI lesion depths on the results in different patients, the ratios of the quantitative parameters of a solid pancreatic lesion to those of surrounding normal pancreatic parenchyma were calculated." Yang 2023、Tang 2026、Jia 2023 也是同样做法。
+
+### 约束 6：洗入期截断、呼吸运动造成曲线震荡，论文怎么处理
+
+**洗入期截断：未找到处理方法。** 文献的做法是在采集时从注射开始录，并要求录满 2 分钟，不满足的病例剔除：
+- Yang 2025（PMC12179939.txt，§CEUS instrument and method）："Timing began at the moment of injection. … Observation lasted over 2 minutes, and images were saved."
+- Lu 2022（§2.2 排除标准）："(3) patients without complete 2 min DICOM clips for analysis."；§3.1："two cases were excluded for lack of 2 min DICOM clips."
+- Lin 2024（§The CEUS inspection process）："Timing was initiated immediately after contrast injection, and the digital imaging and communications in medicine images of CEUS were stored continuously for 150 seconds"
+
+**呼吸运动，做法一：用软件自带的运动补偿。**
+- Yang 2023（§2.5）："The motion compensation function was applied to reduce the breath motion artifact."
+- Lin 2024（§Quantitative analysis）："Motion compensation was used to minimize the effects of respiratory artefacts."
+- Tang 2026（§2.5）："Respiratory artifact effects were minimized using compensation techniques."
+- Tacelli 2026（图 1 图注）："Final VueBox output with motion-corrected and normalized TICs"
+
+**呼吸运动，做法二：剔除帧。**
+- Jia 2023（§Time-intensity curve analysis）："each frame was examined using the QLAB software; frames where the lesion was out of the ROI due to the patient's respiratory movements were removed"
+- Adler 2025（§Frames selection）："Frame selection was based on cross-correlation with the reference frame. … The top 10% of frames exhibiting the highest correlation values are retained. Subsequently, this subset of frames is further filtered to include only those with NCC values exceeding 0.66"；作者自己承认："these thresholds were not subjected to formal optimization through training due to the limited dataset."；§Registration："Deformation fields are calculated based on the B-mode video (assumed less noisy) and then applied to the corresponding CEUS frames"
+- Engjom 2018（胰腺实质，§Manual motion correction）："a manual single frame exclusion procedure and movement correction was performed"
+
+**呼吸运动，做法三：剔除病例。**
+- Engjom 2018（§Subjects）："Subjects with insufficient sonographic visualisation of the pancreas, extensive respiratory movements or technical flaws in the recorded perfusion/reperfusion phases were excluded retrospectively."；§Inclusion："We excluded 8 CF patients and 5 controls due to poor pancreatic ultrasound visualisation, or failure to track the same region of interest throughout the examination."
+- Tacelli 2026（§Methods）："Patients who did not consent or had poor-quality or unstable videos were excluded."
+- Gheonea 2013（Methods）："We excluded all patients with low quality examinations (n = 3)"
+
+**采集时的要求：**
+- Lu 2022（§2.4）："Patients were required to breathe steadily during CEUS examinations."
+- Chen 2021（Methods）："The patients were instructed to maintain smooth and regular breathing patterns during the observation time"
+
+## 3. 我没把握的地方
+
+- PDF 一份都没下下来，原因见开头。引文核对的是 Europe PMC 提供的出版社 XML 全文，内容应当和 PDF 一致，但没有页码。如果需要页码，要人工在浏览器里下载 PDF。
+- VueBox 的拟合模型、「quality of fit」的定义，以及它是否在内部把视频线性化，在这几篇胰腺论文里都没有写。这些要查 Bracco 的技术文档或 VueBox 的验证论文（多为肝脏和体模研究），不在我负责的范围内。因此「胰腺 VueBox 研究等于 lognormal 先例」**不能**从这些论文推出。
+- Chen 2021 写了 QLAB 的「Curve fitting」，但没给函数形式。QLAB 默认是不是 gamma-variate 或其他函数，我没有核实。
+- Wang 2023 有 30/102 例没拿到定量参数，原文没写原因，不能把它当成「拟合质量不合格就剔除」的证据。
+- 只有摘要的几篇（Kersting 2009、Săftoiu 2015、Wang L 2023 Eur Radiol、Stangeland 2017）的方法细节没读到。其中 Săftoiu 2015 摘要写 "After excluding all of the recordings that did not meet the technical and procedural criteria"，正文可能写了剔除标准或拟合门槛，值得设法取得全文。Wang L 2023 Eur Radiol 含 SPN，和我们的 SPN 类最相关。
+- 胰腺 CEUS 里明确写 lognormal 的研究，在我的检索范围内没找到（Europe PMC 关键词检索加两轮网页检索）。但检索不到不等于不存在，尤其是中文期刊和会议摘要我没有检索。