查看“冷缺血时间”的源代码

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        <p style="font-size: 1.1em; margin: 10px 0; color: #334155; text-align: justify;">
            <strong>超进展</strong> (Hyperprogressive Disease, <strong>HPD</strong>) 是一种与<strong>[[免疫检查点抑制剂]]</strong> (ICI) 治疗相关的反常临床现象，表现为治疗后肿瘤生长速率 (TGR) 较治疗前显著增加（通常增加 ≥50% 或 ≥2倍），导致患者生存期急剧缩短。HPD 的发生与特定的基因组改变密切相关。目前临床共识已将 <strong>[[MDM2]]/[[MDM4]]扩增</strong> 确立为 HPD 的<strong>独立预测因子</strong>。对于 <strong>[[EGFR]]突变</strong>，虽然其主要表现为严重的<strong>[[原发性耐药]]</strong>（无效），但约 20% 的患者仍可观察到 HPD 现象，因此二者均被列入免疫单药治疗的<strong>“黑名单”</strong>。在启动免疫治疗前进行 <strong>[[NGS基因检测]]</strong> 是规避这一灾难性事件的关键。
        </p>
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    <div class="medical-infobox mw-collapsible mw-collapsed" style="width: 100%; max-width: 320px; margin: 0 auto 35px auto; border: 1.2px solid #bae6fd; border-radius: 12px; background-color: #ffffff; box-shadow: 0 8px 20px rgba(0,0,0,0.05); overflow: hidden;">
        
        <div style="padding: 15px; color: #1e40af; background: linear-gradient(135deg, #e0f2fe 0%, #bae6fd 100%); text-align: center; cursor: pointer;">
            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">超进展 (HPD)</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Hyperprogressive Disease (点击展开)</div>
        </div>
        
        <div class="mw-collapsible-content">
            <div style="padding: 25px; text-align: center; background-color: #f8fafc;">
                <div style="display: inline-block; background: #ffffff; border: 1px solid #e2e8f0; border-radius: 12px; padding: 20px; box-shadow: 0 4px 10px rgba(0,0,0,0.04);">
                    [[Image:HPD_growth_kinetics_curve.png|100px|肿瘤生长动力学曲线对比]]
                </div>
                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">治疗后斜率陡增</div>
            </div>

            <table style="width: 100%; border-spacing: 0; border-collapse: collapse; font-size: 0.85em;">
                <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">核心定义</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">TGR 增加 ≥ 50%</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">高危基因</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>MDM2扩增</strong>, <strong>EGFR</strong></td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">发生率</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">4% - 29%</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">高发人群</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">高龄 (>65岁)</td>
                </tr>
                <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">处理原则</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>立即停药</strong></td>
                </tr>
                 <tr>
                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">鉴别诊断</th>
                    <td style="padding: 6px 12px; color: #1e40af;">[[假性进展]] (PsPD)</td>
                </tr>
            </table>
        </div>
    </div>

    <h2 style="border-left: 6px solid #1e40af; background: linear-gradient(to right, #eff6ff, #ffffff); color: #1e3a8a; padding: 12px 20px; font-size: 1.25em; margin-top: 40px; font-weight: bold; border-radius: 0 8px 8px 0;">基因警示：免疫治疗“黑名单” (ICI Blacklist)</h2>
    
    <p style="margin: 15px 0 25px 0; text-align: justify; color: #475569;">
        以下基因变异通常提示免疫单药治疗<strong>无效</strong>或<strong>有害</strong>，临床应尽量避免使用或需联合其他疗法。
    </p>

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        <table style="width: 100%; border-collapse: collapse; font-size: 0.95em; text-align: left; background-color: #ffffff;">
            <thead>
                <tr style="background-color: #1e3a8a; color: #ffffff;">
                    <th style="padding: 16px 20px; font-weight: 600; width: 22%; border-right: 1px solid #3b82f6;">风险基因</th>
                    <th style="padding: 16px 20px; font-weight: 600; width: 15%; border-right: 1px solid #3b82f6;">风险等级</th>
                    <th style="padding: 16px 20px; font-weight: 600; width: 40%; border-right: 1px solid #3b82f6;">核心机制 (Mechanism)</th>
                    <th style="padding: 16px 20px; font-weight: 600; width: 23%;">临床建议</th>
                </tr>
            </thead>
            <tbody>
                <tr style="border-bottom: 1px solid #e2e8f0;">
                    <td style="padding: 18px 20px; vertical-align: top; background-color: #f8fafc;">
                        <div style="font-size: 1.05em; font-weight: bold; color: #0f172a;">[[MDM2]] / [[MDM4]]</div>
                        <div style="font-size: 0.85em; color: #64748b; margin-top: 4px;">(基因扩增)</div>
                    </td>
                    <td style="padding: 18px 20px; vertical-align: top; border-right: 1px solid #f1f5f9;">
                        <span style="background-color: #fee2e2; color: #991b1b; padding: 2px 8px; border-radius: 4px; font-size: 0.85em; font-weight: bold;">极高 (HPD)</span>
                    </td>
                    <td style="padding: 18px 20px; vertical-align: top; border-right: 1px solid #f1f5f9; color: #334155;">
                        IFN-γ 信号通路反常地促进 MDM2 过表达，导致肿瘤抑制蛋白 p53 被彻底降解，引发肿瘤爆发式生长。
                    </td>
                    <td style="padding: 18px 20px; vertical-align: top;">
                        <span style="color: #b91c1c; font-weight: bold;">绝对禁忌</span>
                        <div style="font-size: 0.9em; color: #64748b; margin-top: 4px;">立即转为化疗或靶向治疗</div>
                    </td>
                </tr>

                <tr style="border-bottom: 1px solid #e2e8f0;">
                    <td style="padding: 18px 20px; vertical-align: top; background-color: #ffffff;">
                        <div style="font-size: 1.05em; font-weight: bold; color: #0f172a;">[[EGFR]]</div>
                        <div style="font-size: 0.85em; color: #64748b; margin-top: 4px;">(驱动突变)</div>
                    </td>
                    <td style="padding: 18px 20px; vertical-align: top; border-right: 1px solid #f1f5f9;">
                        <span style="background-color: #ffedd5; color: #9a3412; padding: 2px 8px; border-radius: 4px; font-size: 0.85em; font-weight: bold;">高 (耐药+HPD)</span>
                    </td>
                    <td style="padding: 18px 20px; vertical-align: top; border-right: 1px solid #f1f5f9; color: #334155;">
                        免疫微环境呈典型的“荒漠型”；Fc 受体介导的信号可能进一步促进癌细胞增殖。
                    </td>
                    <td style="padding: 18px 20px; vertical-align: top;">
                        <span style="color: #c2410c; font-weight: bold;">首选 TKI</span>
                        <div style="font-size: 0.9em; color: #64748b; margin-top: 4px;">耐药后优选化疗+抗血管</div>
                    </td>
                </tr>

                <tr>
                    <td style="padding: 18px 20px; vertical-align: top; background-color: #f8fafc;">
                        <div style="font-size: 1.05em; font-weight: bold; color: #0f172a;">[[STK11]] / [[KEAP1]]</div>
                        <div style="font-size: 0.85em; color: #64748b; margin-top: 4px;">(共突变)</div>
                    </td>
                    <td style="padding: 18px 20px; vertical-align: top; border-right: 1px solid #f1f5f9;">
                        <span style="background-color: #e0f2fe; color: #075985; padding: 2px 8px; border-radius: 4px; font-size: 0.85em; font-weight: bold;">中 (原发耐药)</span>
                    </td>
                    <td style="padding: 18px 20px; vertical-align: top; border-right: 1px solid #f1f5f9; color: #334155;">
                        导致极度缺乏 CD8+ T 细胞浸润的“冷肿瘤”表型，对 ICI 单药反应率极低。
                    </td>
                    <td style="padding: 18px 20px; vertical-align: top;">
                        <span style="color: #0369a1; font-weight: bold;">避免单药</span>
                        <div style="font-size: 0.9em; color: #64748b; margin-top: 4px;">必须考虑联合方案</div>
                    </td>
                </tr>
            </tbody>
        </table>
    </div>

    <div style="background-color: #fff7ed; border: 1px solid #fdba74; border-radius: 8px; padding: 20px 25px; margin: 30px 0;">
        <h3 style="margin-top: 0; color: #c2410c; font-size: 1.15em; display: flex; align-items: center; font-weight: bold;">
            <span style="font-size: 1.2em; margin-right: 10px;">⚖️</span> 专家辨析：EGFR 突变属于哪一级风险？
        </h3>
        <p style="margin-bottom: 15px; text-align: justify; font-size: 1em; color: #334155; line-height: 1.6;">
            <strong>结论：属于“高危规避”范畴，但机制与 MDM2 不同。</strong>
        </p>
        <ul style="padding-left: 20px; color: #475569; font-size: 0.95em; margin: 0; line-height: 1.7;">
            <li style="margin-bottom: 8px;"><strong>耐药是主旋律：</strong> 大多数 EGFR 突变患者对 PD-1/PD-L1 单药表现为<strong>[[原发性耐药]]</strong>（有效率 < 5%）。这是因为 EGFR 通路激活会导致 PD-L1 表达上调（虽然高表达，但是是假象），同时抑制 T 细胞募集，形成“免疫荒漠”。</li>
            <li style="margin-bottom: 8px;"><strong>HPD 是潜在风险：</strong> Kato 等人的研究指出，约 <strong>20%</strong> 的 EGFR 突变患者在免疫治疗后出现 HPD。虽然比例低于 MDM2 扩增（>50%），但考虑到 EGFR 患者本身可选的有效靶向药物众多，<strong>冒险使用免疫单药的获益-风险比极低</strong>。</li>
            <li style="margin-bottom: 0;"><strong>临床决策：</strong> 无论是否发生 HPD，EGFR 突变患者在一线、二线治疗中均应优先使用 <strong>[[EGFR-TKI]]</strong>。TKI 耐药后，标准推荐是含铂双药化疗+抗血管生成，而非免疫单药。</li>
        </ul>
    </div>

    <h2 style="border-left: 6px solid #1e40af; background: linear-gradient(to right, #eff6ff, #ffffff); color: #1e3a8a; padding: 12px 20px; font-size: 1.25em; margin-top: 40px; font-weight: bold; border-radius: 0 8px 8px 0;">HPD vs PsPD：生死鉴别</h2>
    
    <div style="overflow-x: auto; margin-bottom: 30px; border-radius: 8px; box-shadow: 0 10px 15px -3px rgba(0, 0, 0, 0.1); border: 1px solid #e2e8f0;">
        <table style="width: 100%; border-collapse: collapse; font-size: 0.95em; text-align: left; background-color: #ffffff;">
            <thead>
                <tr style="background-color: #1e3a8a; color: #ffffff;">
                    <th style="padding: 16px 20px; font-weight: 600; width: 20%; border-right: 1px solid #3b82f6;">特征维度</th>
                    <th style="padding: 16px 20px; font-weight: 600; width: 40%; border-right: 1px solid #3b82f6;">超进展 (HPD)</th>
                    <th style="padding: 16px 20px; font-weight: 600; width: 40%;">假性进展 (PsPD)</th>
                </tr>
            </thead>
            <tbody>
                <tr style="border-bottom: 1px solid #e2e8f0;">
                    <td style="padding: 18px 20px; font-weight: bold; color: #0f172a; background-color: #f8fafc;">临床状态</td>
                    <td style="padding: 18px 20px; background-color: #fff1f2; border-right: 1px solid #f1f5f9;">
                        <span style="color: #991b1b; font-weight: bold;">迅速恶化</span>
                        <div style="font-size: 0.9em; color: #7f1d1d; margin-top: 4px;">疼痛加剧，PS 评分下降</div>
                    </td>
                    <td style="padding: 18px 20px; background-color: #f0fdf4;">
                        <span style="color: #166534; font-weight: bold;">良好/稳定</span>
                        <div style="font-size: 0.9em; color: #14532d; margin-top: 4px;">无明显痛苦，感觉良好</div>
                    </td>
                </tr>
                <tr style="border-bottom: 1px solid #e2e8f0;">
                    <td style="padding: 18px 20px; font-weight: bold; color: #0f172a; background-color: #ffffff;">发生时间</td>
                    <td style="padding: 18px 20px; border-right: 1px solid #f1f5f9;">极早 (< 8周)</td>
                    <td style="padding: 18px 20px;">任意时间 (常见 12周内)</td>
                </tr>
                <tr style="border-bottom: 1px solid #e2e8f0;">
                    <td style="padding: 18px 20px; font-weight: bold; color: #0f172a; background-color: #f8fafc;">液体活检 (ctDNA)</td>
                    <td style="padding: 18px 20px; border-right: 1px solid #f1f5f9; color: #b91c1c; font-weight: bold;">显著飙升 ↗</td>
                    <td style="padding: 18px 20px; color: #15803d; font-weight: bold;">显著下降 ↘ 或转阴</td>
                </tr>
                <tr>
                    <td style="padding: 18px 20px; font-weight: bold; color: #0f172a; background-color: #ffffff;">临床决策</td>
                    <td style="padding: 18px 20px; border-right: 1px solid #f1f5f9;">
                        <span style="background-color: #fee2e2; color: #991b1b; padding: 2px 8px; border-radius: 4px; font-size: 0.85em; font-weight: bold;">立即停药</span>
                    </td>
                    <td style="padding: 18px 20px;">
                        <span style="background-color: #dcfce7; color: #166534; padding: 2px 8px; border-radius: 4px; font-size: 0.85em; font-weight: bold;">继续用药</span>
                    </td>
                </tr>
            </tbody>
        </table>
    </div>

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        <span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献与权威点评</span>
        
        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [1] <strong>Champiat S, et al. (2017).</strong> <em>Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated With Anti-PD-1/PD-L1.</em> <strong>[[Clinical Cancer Research]]</strong>. 2017;23(8):1920-1928.<br>
            <span style="color: #475569;">[核心定义]：首次系统性定义了 HPD，提出了基于 TGR (肿瘤生长速率) 的评估标准，并指出高龄是独立风险因素。</span>
        </p>

        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [2] <strong>Kato S, et al. (2017).</strong> <em>Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate.</em> <strong>[[Clinical Cancer Research]]</strong>. 2017;23(15):4242-4250.<br>
            <span style="color: #475569;">[基因发现]：开创性研究，首次揭示 MDM2/4 扩增与 EGFR 突变是 HPD 的特异性基因组驱动因素，HPD发生率在 MDM2 扩增组高达 50% 以上。</span>
        </p>
        
        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [3] <strong>Singavi AK, et al. (2017).</strong> <em>Predictive biomarkers for hyperprogression (HP) in response to immune checkpoint inhibitors (ICI).</em> <strong>[[Annals of Oncology]]</strong>. 2017;28(suppl_5):v403-v427.<br>
            <span style="color: #475569;">[泛癌种验证]：在更大规模的泛癌种队列中验证了 MDM2 扩增与 HPD 的强相关性，进一步巩固了其作为“免疫黑名单”基因的地位。</span>
        </p>

        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [4] <strong>Ferrara R, et al. (2018).</strong> <em>Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy.</em> <strong>[[JAMA Oncology]]</strong>. 2018;4(11):1543-1552.<br>
            <span style="color: #475569;">[肺癌数据]：大型回顾性研究，证实在 NSCLC 中，HPD 仅发生于免疫治疗组（约 13.8%），化疗组无此现象。虽然 EGFR 突变患者预后极差，但其 HPD 发生率在该研究中低于 MDM2 扩增者。</span>
        </p>
    </div>

    <div style="margin: 40px 0; border: 1px solid #e2e8f0; border-radius: 8px; overflow: hidden; font-family: 'Helvetica Neue', Arial, sans-serif; font-size: 0.9em;">
        <div style="background-color: #eff6ff; color: #1e40af; padding: 8px 15px; font-weight: bold; text-align: center; border-bottom: 1px solid #dbeafe;">
            超进展 (HPD) · 知识图谱
        </div>
        <table style="width: 100%; border-collapse: collapse; background-color: #ffffff;">
            <tr style="border-bottom: 1px solid #f1f5f9;">
                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">黑名单基因</td>
                <td style="padding: 10px 15px; color: #334155;">[[MDM2]] (扩增) • [[EGFR]] (突变) • [[MDM4]] • [[STK11]] (原发耐药)</td>
            </tr>
            <tr style="border-bottom: 1px solid #f1f5f9;">
                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">关键机制</td>
                <td style="padding: 10px 15px; color: #334155;">[[IFN-γ悖论]] • [[p53失活]] • [[Fc受体]] • [[肿瘤生长速率]] (TGR)</td>
            </tr>
            <tr style="border-bottom: 1px solid #f1f5f9;">
                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">鉴别诊断</td>
                <td style="padding: 10px 15px; color: #334155;">[[假性进展]] (PsPD) • [[iRECIST]] • [[ctDNA]] (液体活检)</td>
            </tr>
            <tr>
                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">临床管理</td>
                <td style="padding: 10px 15px; color: #334155;">[[NGS筛查]] • [[立即停药]] • [[挽救性化疗]] • [[EGFR-TKI]]</td>
            </tr>
        </table>
    </div>

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