Deep learning with biopsy whole slide images for pretreatment prediction of pathological complete response to neoadjuvant chemotherapy in breast cancer：A multicenter study

IntroductionPredicting pathological complete response (pCR) for patients receiving neoadjuvant chemotherapy (NAC) is crucial in establishing individualized treatment. Whole-slide images (WSIs) of tumor tissues reflect the histopathologic information of the tumor, which is important for therapeutic response effectiveness. In this study, we aimed to investigate whether predictive information for pCR could be detected from WSIs.Materials and methodsWe retrospectively collected data from four cohorts of 874 patients diagnosed with biopsy-proven breast cancer. A deep learning pathological model (DLPM) was constructed to predict pCR using biopsy WSIs in the primary cohort, and it was then validated in three external cohorts. The DLPM could generate a deep learning pathological score (DLPs) for each patient; stromal tumor-infiltrating lymphocytes (TILs) were selected for comparison with DLPs.ResultsThe WSI feature-based DLPM showed good predictive performance with the highest area under the curve (AUC) of 0.72 among the cohorts. Alternatively, the combination of the DLPM and clinical characteristics offered a better prediction performance (AUC >0.70) in all cohorts. We also evaluated the performance of DLPM in three different breast subtypes with the best prediction for the triple-negative breast cancer (TNBC) subtype (AUC: 0.73). Moreover, DLPM combined with clinical characteristics and stromal TILs achieved the highest AUC in the primary cohort (AUC: 0.82) and validation cohort 1 (AUC: 0.80).ConclusionOur study suggested that WSIs integrated with deep learning could potentially predict pCR to NAC in breast cancer. The predictive performance will be improved by combining clinical characteristics. DLPs from DLPM can provide more information compared to stromal TILs for pCR prediction.     

Chemotherapy and novel therapeutics before radical prostatectomy for high-risk clinically localized prostate cancer

Although both surgery and radiation are potential curative options for men with clinically localized prostate cancer, a significant proportion of men with high-risk and locally advanced disease will demonstrate biochemical and potentially clinical progression of their disease. Neoadjuvant systemic therapy before radical prostatectomy (RP) is a logical strategy to improve treatment outcomes for men with clinically localized high-risk prostate cancer. Furthermore, delivery of chemotherapy and other systemic agents before RP affords an opportunity to explore the efficacy of these agents with pathologic end points.Neoadjuvant chemotherapy, primarily with docetaxel (with or without androgen deprivation therapy), has demonstrated feasibility and safety in men undergoing RP, but no study to date has established the efficacy of neoadjuvant chemotherapy or neoadjuvant chemohormonal therapies. Other novel agents, such as those targeting the vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, clusterin, and immunomodulatory therapeutics, are currently under investigation.     

Response to chemoradiotherapy and lymph node involvement in locally advanced rectal cancer

AIM: To establish the association between lymph node involvement and the response to neoadjuvant therapy in locally advanced rectal cancer.METHODS: Data of 130 patients with mid and low locally advanced rectal adenocarcinoma treated with neoadjuvant chemoradiation followed by radical surgery over a 5-year period were reviewed. Tumor staging was done by endorectal ultrasound and/or magnetic resonance imaging. Tumor response to neoadjuvant therapy was determined by T-downstaging and tumor regression grading (TRG). Pathologic complete response (pCR) is defined as the absence of tumor cells in the surgical specimen (ypT0N0). The varying degrees TRG were classified according to Mandard’s scoring system. The evaluation of the response is based on the comparison between previous clinico-radiological staging and the results of pathological evaluation. χ² and Spearman’s correlation tests were used for the comparison of variables.RESULTS: Pathologic complete response (pCR, ypT0N0, TRG1) was observed in 19 cases (14.6%), and other 18 (13.8%) had only very few residual malignant cells in the rectal wall (TRG2). T-downstaging was found in 63 (48.5%). Mean lymph node retrieval was 9.4 (range 0-38). In 37 cases (28.5%) more than 12 nodes were identified in the surgical specimen. Preoperative lymph node involvement was seen in 77 patients (59.2%), 71 N1 and 6 N2. Postoperative lymph node involvement was observed in 41 patients (31.5%), 29 N1 and 12 N2, while the remaining 89 were N0 (68.5%). In relation to ypT stage, we found nodal involvement of 9.4% in ypT0-1, 22.2% in ypT2 and 43.7% in ypT3-4. Of the 37 patients considered “responders” to neoadjuvant therapy (TRG1 and 2), there were only 4 N+ (10.8%) and the remainder N0 (89.2%). In the “non responders” group (TRG 3, 4 and 5), 37 cases were N+ (39.8%) and 56 (60.2%) were N0 (P < 0.001).CONCLUSION: Response to neoadjuvant chemoradiation in rectal cancer is associated with lymph node involvement.     

Operationsrisiko nach neoadjuvanter Therapie gastrointestinaler Karzinome

Zusammenfassung Viele gastrointestinale Tumoren werden im Rahmen multimodaler Therapiekonzepte behandelt. Für den Chirurgen ist die neoadjuvante, präoperative Behandlung von besonderem Interesse, da sie durch therapiebedingte Nebenwirkungen und Komplikationen zu einer Beeinflussung des postoperativen Verlaufs führen kann. Die neoadjuvante Radiochemotherapie ist fester Bestandteil der Therapie beim primären T4-Rektumkarzinom, beim Rektumkarzinomrezidiv und bei tief sitzenden primären Rektumkarzinomen. Durch Erhöhung der R0-Resektionsrate können die lokale Tumorkontrolle verbessert und die Überlebenszeit verlängert werden. Die postoperative Komplikationsrate ist dabei nicht wesentlich erhöht. In der Behandlung des primär resektablen Ösophaguskarzinoms deutet sich ein Vorteil der neoadjuvanten Radiochemotherapie im Vergleich zur alleinigen Chirurgie an. Beim lokal fortgeschrittenen Ösophaguskarzinom bietet die präoperative Radiochemotherapie häufig die einzige Chance zur Resektion, jedoch mit einer deutlich erhöhten postoperativen Morbidität und Mortalität. Die Wirksamkeit und Sicherheit einer neoadjuvanten Chemo- oder kombinierten Radiochemotherapie beim fortgeschrittenen Magenkarzinom wird derzeit im Rahmen von Studienprotokollen untersucht.     

TS、TP及DPD表达与乳腺癌新辅助化疗的关系

目的 检测乳腺癌标本中胸苷酸合成酶（Thymidylate Synthase,TS）、胸腺嘧啶脱氧核苷磷酸化酶（Thymidine Phosphorylase,TP）、二氟嘧啶脱氢酶（Dihydropyrimidine Dehydrogenase,DPD）表达状况,评价TS、TP、DPD的表达与新辅助化疗效果之间的关系.方法 选择81例可手术的乳腺癌患者,手术前均接受CMF方案新辅助化疗,采用免疫组织化学染色的方法对新辅助化疗前麦默通活检系统切取的乳腺癌组织中TS、TP和DPD的表达进行检测.结果 TS、TP阴性患者的部分缓解率要明显高于阳性患者,而DPD阳性患者的部分缓解率明显高于阴性患者,差异具有统计学意义（P＜0.05）;DPD阴性患者Ⅲ～Ⅳ度毒副反应发生率高于阳性患者（P＜0.05）,而TS、TP的表达水平与化疗所产生的毒副反应之间无明显关系（P＞0.05）.结论 TS、TP及DPD的表达与乳腺癌患者接受CMF方案的新辅助化疗的治疗效果相关,而DPD的表达则与含5-FU类化疗药物所产生的毒副反应相关.     

新辅助化疗对结直肠癌的作用

目的探讨短程5-FU/CF方案新辅助化疗对结直肠癌细胞凋亡、增殖和p53表达以及术后并发症和预后的影响。方法分别采用脱氧核糖核苷酸末端转移酶介导的缺口末端标记法（TUNEL）和免疫组化SP法检测68例患者结直肠癌组织的细胞凋亡指数（AI）和ki-67增殖指数（PI）及凋亡相关基因p53的表达,并比较新辅助化疗组和对照组患者术后并发症的发生情况和预后情况。结果新辅助化疗组肿瘤细胞的AI均数为3.56%,明高于对照组的2.29%（P〈0.01）,PI均数为22.60%明显低于对照组的33.60%（P〈0.01）,p53阳性表达率为28.9%（11/38）明显低于对照组的56.7%（17/30）（P〈0.05）。两组中大肠癌细胞的AI与PI均呈负相关（r=-0.790,r=-0.663）（P〈0.01）。两组术后并发症的发生差异无显著性（P〈0.05）。两组的复发转移率和复发转移平均时间差异有显著性（P〈0.05）。结论短程5-FU/CF方案新辅助化疗可以显著诱导结直肠癌细胞凋亡,并抑制其增殖;降低结直肠癌组织p53的阳性表达率,而不增加术后并发症的发生,能延缓和减少结直肠癌术后的复发转移。     

The Role and Limitations of 18-Fluoro-2-deoxy-<Emphasis Type="SmallCaps">d</Emphasis>-glucose Positron Emission Tomography (FDG-PET) Scan and Computerized Tomography (CT) in Restaging Patients with Hepatic Colorectal Metastases Following Neoadjuvant Chemotherapy: Comparison with Operative and Pathological Findings

Background Recent data confirmed the importance of 18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in the selection of patients with colorectal hepatic metastases for surgery. Neoadjuvant chemotherapy before hepatic resection in selected cases may improve outcome. The influence of chemotherapy on the sensitivity of FDG-PET and CT in detecting liver metastases is not known. Methods Patients were assigned to either neoadjuvant treatment or immediate hepatic resection according to resectability, risk of recurrence, extrahepatic disease, and patient preference. Two-thirds of them underwent FDG-PET/CT before chemotherapy; all underwent preoperative contrast-enhanced CT and FDG-PET/CT. Those without extensive extrahepatic disease underwent open exploration and resection of all the metastases according to original imaging findings. Operative and pathological findings were compared to imaging results. Results Twenty-seven patients (33 lesions) underwent immediate hepatic resection (group 1), and 48 patients (122 lesions) received preoperative neoadjuvant chemotherapy (group 2). Sensitivity of FDG-PET and CT in detecting colorectal (CR) metastases was significantly higher in group 1 than in group 2 (FDG-PET: 93.3 vs 49%, P < 0.0001; CT: 87.5 vs 65.3, P = 0.038). CT had a higher sensitivity than FDG-PET in detecting CR metastases following neoadjuvant therapy (65.3 vs 49%, P < 0.0001). Sensitivity of FDG-PET, but not of CT, was lower in group 2 patients whose chemotherapy included bevacizumab compared to patients who did not receive bevacizumab (39 vs 59%, P = 0.068). Conclusions FDG-PET/CT sensitivity is lowered by neoadjuvant chemotherapy. CT is more sensitive than FDG-PET in detecting CR metastases following neoadjuvant therapy. Surgical decision-making requires information from multiple imaging modalities and pretreatment findings. Baseline FDG-PET and CT before neoadjuvant therapy are mandatory. The abstract was presented before the 58th Cancer Symposium of the Society of Surgical Oncology, Atlanta, GA, USA, 2005, and before the 2005 Congress of the American Hepato-Pancreato-Biliary Association, Fort-Lauderdale, FL, USA.     

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies

BackgroundDuctal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC).ObjectiveTo assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC.Design, setting, and participantsA single-center retrospective review of all patients with cT1–4/N0–1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients.Outcome measurements and statistical analysisMetastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models.Results and limitationsA total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation.ConclusionsMen undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed.Patient summaryThis study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.