Prediction of MGMT promotor methylation status in glioblastoma by contrast-enhanced T1-weighted intensity image.

Background: The study aims to explore MRI phenotypes that predict glioblastoma's (GBM) methylation status of the promoter region of MGMT gene (pMGMT) by qualitatively assessing contrast-enhanced T1-weighted intensity images. Methods: A total of 193 histologically and molecularly confirmed GBMs at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KANSAI) were used as an exploratory cohort. From the Cancer Imaging Archive/Cancer Genome Atlas (TCGA) 93 patients were used as validation cohorts. "Thickened structure" was defined as the solid tumor component presenting circumferential extension or occupying >50% of the tumor volume. "Methylated contrast phenotype" was defined as indistinct enhancing circumferential border, heterogenous enhancement, or nodular enhancement. Inter-rater agreement was assessed, followed by an investigation of the relationship between radiological findings and pMGMT methylation status. Results: Fleiss's Kappa coefficient for "Thickened structure" was 0.68 for the exploratory and 0.55 for the validation cohort, and for "Methylated contrast phenotype," 0.30 and 0.39, respectively. The imaging feature, the presence of "Thickened structure" and absence of "Methylated contrast phenotype," was significantly predictive of pMGMT unmethylation both for the exploratory (p = .015, odds ratio = 2.44) and for the validation cohort (p = .006, odds ratio = 7.83). The sensitivities and specificities of the imaging feature, the presence of "Thickened structure," and the absence of "Methylated contrast phenotype" for predicting pMGMT unmethylation were 0.29 and 0.86 for the exploratory and 0.25 and 0.96 for the validation cohort. Conclusions: The present study showed that qualitative assessment of contrast-enhanced T1-weighted intensity images helps predict GBM's pMGMT methylation status.

Concurrent chemoradiotherapy using proton beams can reduce cardiopulmonary morbidity in esophageal cancer patients: a systematic review.

This systematic review was performed to investigate the superiority of proton beam therapy (PBT) to photon-based radiotherapy (RT) in treating esophageal cancer patients, especially those with poor cardiopulmonary function. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 2000 to August 2020 for studies evaluating one end point at least as follows; overall survival, progression-free survival, grade ≥ 3 cardiopulmonary toxicities, dose-volume histograms, or lymphopenia or absolute lymphocyte counts (ALCs) in esophageal cancer patients treated with PBT or photon-based RT. Of 286 selected studies, 23 including 1 randomized control study, 2 propensity matched analyses, and 20 cohort studies were eligible for qualitative review. Overall survival and progression-free survival were better after PBT than after photon-based RT, but the difference was significant in only one of seven studies. The rate of grade 3 cardiopulmonary toxicities was lower after PBT (0-13%) than after photon-based RT (7.1-30.3%). Dose-volume histograms revealed better results for PBT than photon-based RT. Three of four reports evaluating the ALC demonstrated a significantly higher ALC after PBT than after photon-based RT. Our review found that PBT resulted in a favorable trend in the survival rate and had an excellent dose distribution, contributing to reduced cardiopulmonary toxicities and a maintained number of lymphocytes. These results warrant novel prospective trials to validate the clinical evidence.

HDR-brachytherapy for accelerated partial breast irradiation: Long-term experience from a Japanese institution.

Purpose: We investigated the long-term oncological outcome of high-dose-rate (HDR) multicatheter interstitial brachytherapy (MIB) for adjuvant accelerated partial breast irradiation (APBI) after breast conserving surgery in Japanese patients. Material and methods: Between June 2002 and October 2011, 86 breast cancer patients were treated at National Hospital Organization Osaka National Hospital (trial number of the local institutional review board, 0329). Median age was 48 years (range, 26-73 years). Eighty patients had invasive and 6 patients non-invasive ductal carcinoma. Tumor stage distribution was pT0 in 2, pTis in 6, pT1 in 55, pT2 in 22, and pT3 in one patient, respectively. Twenty-seven patients had close/positive resection margins. Total physical HDR dose was 36-42 Gy in 6-7 fractions. Results: At a median follow-up of 119 months (range, 13-189 months), the 10-year local control (LC) and overall survival rate was 93% and 88%, respectively. Concerning the 2009 Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology risk stratification scheme, the 10-year LC rate was 100%, 100%, and 91% for patients considered as low-risk, intermediate-risk, and high-risk, respectively. According to the 2018 American Brachytherapy Society risk stratification scheme, the 10-year LC rate was 100% and 90% for patients 'acceptable' and 'unacceptable' for APBI, respectively. Wound complications were observed in 7 patients (8%). Risk factors for wound complications were the omission of prophylactic antibiotics during MIB, open cavity implantation, and V100 ≥ 190 cc. No grade ≥ 3 late complications (CTCVE version 4.0) were observed. Conclusions: Adjuvant APBI using MIB is associated with favorable long-term oncological outcomes in Japanese patients for low-risk, intermediate-risk, and acceptable groups of patients.

Evaluating Neoadjuvant Chemotherapy for Lower Esophageal Squamous Cell Carcinoma by Measuring Esophageal Wall Thickness.

BACKGROUND/AIM: The aim of this study was to evaluate the efficacy of preoperative chemotherapy for stage II-III esophageal squamous cell carcinoma based on an objective computed tomography method. PATIENTS AND METHODS: A total of 82 patients who underwent preoperative chemotherapy followed by surgery for advanced esophageal squamous cell carcinoma from January 2006 to June 2019 were included. Treatment effect was evaluated by measuring the esophageal wall thickness before and after neoadjuvant chemotherapy using contrast-enhanced thoracoabdominal computed tomography. The percentage decrease in esophageal wall thickness was calculated using the following formula: reduction (%)=(wall thickness before preoperative chemotherapy - wall thickness after preoperative chemotherapy)/(wall thickness before preoperative chemotherapy)×100. We demonstrated the efficacy of this measurement method and then analyzed which patient factors might affect the treatment effect. RESULTS: Receiver operating characteristic analysis showed the percentage tumor reduction to be a good predictor of histological therapeutic effect (grade ≥2) (area under the curve=0.727). In the multivariate analysis, tumor location (lower versus upper esophagus) was identified as an independent factor associated with tumor reduction (odds ratio=0.15; 95% confidence interval=0.03-0.79; p=0.025). CONCLUSION: We demonstrated an association between the reduction of esophageal wall thickness in the tumoral area and the histological therapeutic effect of chemotherapy. Secondary analysis showed poorer tumor reduction in patients with lower esophageal cancer than in those with upper esophageal cancer.

Endoscopic imaging modalities for diagnosing the invasion depth of superficial esophageal squamous cell carcinoma: a systematic review.

Endoscopic diagnosis of the invasion depth of superficial esophageal squamous cell carcinoma (ESCC) is an important determinant of the treatment strategy. The three endoscopic imaging modalities commonly used to predict the invasion depth of superficial ESCC in Japan are non-magnifying endoscopy (non-ME), magnifying endoscopy (ME), and endoscopic ultrasonography (EUS). However, which of these three modalities is most effective remains unclear. We performed a systematic review of the literature to compare the diagnostic accuracy of the three modalities for prediction of the invasion depth of superficial ESCC. We used Medical Subject Heading terms and free keywords to search the PubMed, Cochrane Central, and Ichushi databases to identify direct comparison studies published from January 2000 to August 2020. The results of direct comparison studies were used to compare the diagnostic accuracy of each modality. The primary outcome was defined as the proportion of overdiagnosis of pT1b-SM2/3 cancers, and the main secondary outcome was the proportion of underdiagnosis of pT1b-SM2/3 cancers. Other secondary outcomes were the sensitivity and specificity values of the modalities. Four articles were finally selected for qualitative evaluation. Although ME showed no significant advantages over non-ME in terms of sensitivity and specificity, it had a slightly lower proportion of overdiagnosis. EUS had sensitivity and specificity similar to those of non-ME and ME, but EUS had a higher proportion of overdiagnosis. Non-ME and ME are useful for the diagnosis of cancer invasion depth. EUS may increase overdiagnosis, and caution is required in determining its indications.

Coexistence of multiple liver metastases from sigmoid colon cancer and a gastrointestinal stromal tumor in the small intestine.

A 60-year-old man was referred to our hospital for the evaluation and treatment of general malaise. Contrast-enhanced computed tomography detected sigmoid colon cancer that had invaded the bladder, multiple liver metastases, and a small intestinal tumor. Hartmann's procedure was performed, with partial bladder and small bowel resection. A pathological examination revealed that the patient had sigmoid colon cancer and a gastrointestinal stromal tumor. The biopsy findings of a tumor in segment 8 of the liver indicated the presence of adenocarcinoma, thereby indicating the origin of multiple liver metastases from sigmoid colon cancer. On chemotherapy, the tumors in liver segments 2/3 and 8 shrank. However, the tumor in segment 6 enlarged. Since radical resection of all metastatic liver tumors was possible, hepatectomy was performed 10 months after the initial surgery. A pathological examination revealed that the tumors in segments 2/3, 4, and 8 were adenocarcinomas and the tumors in segments 4, 6, and 7 had originated from the gastrointestinal stromal tumor. This suggested the coexistence of liver metastases from sigmoid colon cancer and the gastrointestinal stromal tumor. In cases involving multiple primary tumors, it is necessary to consider the possible coexistence of multiple metastases from different primary tumors.

Cytology Reporting System for Lung Cancer from the Japan Lung Cancer Society and the Japanese Society of Clinical Cytology: An Extensive Study Containing More Benign Lesions.

INTRODUCTION: The Japan Lung Cancer Society (JLCS) and the Japanese Society of Clinical Cytology (JSCC) have proposed a new four-tiered cytology reporting system for lung carcinoma (JLCS-JSCC system). Prior to the proposal, the Papanicolaou Society of Cytopathology (PSC) had proposed a revised reporting system (PSC system), which comprises the "neoplastic, benign neoplasm, and low-grade carcinoma" category (N-B-LG category), in addition to the 4 categories of the JLCS-JSCC system. This study aimed to evaluate the interobserver agreement of the JLCS-JSCC system with an additional dataset with more benign lesions in comparison with the PSC system. METHODS: We analyzed 167 cytological samples, which included 17 benign lesions, obtained from the respiratory system. Seven observers classified these cases into each category by reviewing one Papanicolaou-stained slide per case according to the JLCS-JSCC system and PSC system. RESULTS: The interobserver agreement was moderate in the JLCS-JSCC (k = 0.499) and PSC (k = 0.485) systems. Of the 167 samples, 17 samples were benign lesions: 7 pulmonary hamartomas, 5 sclerosing pneumocytomas, 2 squamous papillomas, one solitary fibrous tumor, one meningioma, and one lymphocytic proliferation. There were diverse sample types as follows: 11 touch smears, 3 brushing smears, 2 aspirations, and one sputum sample. Fourteen samples (82.3%) were categorized into "negative" or "atypical" by more than half of the observers in the JLCS-JSCC system. Conversely, 3 samples were categorized as "suspicious" or "malignant" by more than half of the observers in the JLCS-JSCC system. On the other hand, 11 samples (64.7%) were categorized into the N-B-LG category by more than half of the observers in the PSC system. CONCLUSIONS: The concordance rate in the JLCS-JSCC system was slightly higher than that in the PSC system; however, the interobserver agreement was moderate in both the JLCS-JSCC and PSC systems. These results indicate that both the JLCS-JSCC and PSC systems are clinically useful. Therefore, both systems are expected to have clinical applications. It may be important to integrate the 2 systems and construct a universal system that can be used more widely in clinical practice.

The potential for reducing alcohol consumption to prevent esophageal cancer morbidity in Asian heavy drinkers: a systematic review and meta-analysis.

Alcohol consumption is a major risk factor for esophageal cancer. In Asia, heavy drinkers are considered to have a higher risk of esophageal cancer than nondrinkers and light drinkers. However, no study has shown an association between alcohol reduction and the morbidity of esophageal cancer in Asian heavy drinkers. Therefore, this study investigated the significance of reducing alcohol consumption to prevent esophageal cancer in Asian heavy drinkers by conducting a systematic review and meta-analysis. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 1995 to December 2020. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using a random-effects model. I2 statistics were used to detect heterogeneity. This study included 21 articles in the qualitative synthesis. Light drinkers and heavy drinkers were categorized based on alcohol consumption amount as ≤ 25 ethanol g/day and ≥ 66 ethanol g/day, respectively, as described in many previous studies, and five cohort studies were eligible for this meta-analysis. The HR of esophageal cancer among heavy drinkers versus nondrinkers was 4.18 (95% CI 2.34-7.47, I2 = 74%). On the other hand, the HR of esophageal cancer among light drinkers was 1.82 compared with nondrinkers (95% CI 1.57-2.10, I2 = 0%). Heavy drinkers have a higher esophageal cancer incidence than light drinkers and nondrinker. It is possible that alcohol reduction may decrease the risk of esophageal cancer in Asian heavy drinkers.

Fruit and vegetable consumption and risk of esophageal cancer in the Asian region: a systematic review and meta-analysis.

The consumption of fruit and vegetables was reported to be associated with a reduced risk of esophageal cancer (EC) in many studies of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) from different regions worldwide. Therefore, to provide precise information to reduce the risk of EC in Asia, we performed a systematic review and meta-analysis of studies conducted in the Asian region about fruit and vegetable consumption and the risk of EC. We searched the MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases from January 2010 to December 2020. The summary relative risk (SRR) and 95% CI were calculated using a random-effects model. In addition, I2 statistics were used to detect heterogeneity. Twenty-two studies were eligible for meta-analysis (16 case-control studies and 6 cohort studies). The SRR for the lowest versus highest fruit consumption was 0.64 (95% CI 0.53-0.77, I2 = 82%). That for the lowest versus highest vegetable consumption was 0.61 (95% CI 0.50-0.74, I2 = 81%). Based on subgroup analysis, a validated Food Frequency Questionnaire (FFQ) was significantly associated (SRR for fruit: 0.54; 95% CI 0.40-0.74, SRR for vegetable: 0.60; 95% CI 0.48-0.76) with low heterogeneity (I2 = 48% for fruit, I2 = 0% for vegetables). Egger's funnel plot asymmetry test demonstrated publication bias (P < 0.001 for fruit, P = 0.009 for vegetables). Fruit and vegetable consumption might be associated with a lower risk of EC in the Asian region. However, further substantial prospective studies with a validated FFQ and well-controlled important confounding factors are required to confirm the association.

Infrequent RAS mutation is not associated with specific histological phenotype in gliomas.

BACKGROUND: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. METHODS: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. RESULTS: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. CONCLUSION: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.

A Rare BRAF Fusion in Advanced Rectal Cancer Treated with Anti-Epidermal Growth Factor Receptor Therapy.

Recently, v-raf murine sarcoma viral oncogene homologue B (BRAF) fusions have been identified in multiple cancer types using comprehensive genomic profiling (CGP) assays. BRAF fusions are extremely rare, occurring in <0.5% of patients with metastatic colorectal cancer (mCRC). Until now, there is no standard treatment for mCRC with BRAF fusions. Here, we report a recurrent colorectal cancer case that harbored an EXOC4-BRAF fusion. A 40-year-old female patient with a 2-year history of type 2 diabetes was diagnosed with pathologically confirmed stage IV rectal adenocarcinoma with liver metastasis. She underwent R0 resection after neoadjuvant therapy; however, her disease recurred at multiple metastatic sites (lymph nodes, ovary, and peritoneal gland). A rectal cancer surgical specimen was submitted for CGP (Foundation One) to identify potential targets to develop treatment strategies. An EXOC4-BRAF fusion was identified, and she achieved partial response to FOLFOX + panitumumab which is a fully human antibody directed against epidermal growth factor receptor. No EXOC4-BRAF fusions in colorectal cancer cases have been reported to date. Further studies investigating molecular mechanisms and novel targeted therapy approaches are required.

Giant cell tumor of bone - Analysis of 213 cases involving extra-craniofacial bones.

We elucidated clinicopathological characteristics of giant cell tumor of bone (GCTB) in Japan, and significant clinicopathological factors for predicting local recurrence. Clinicopathological profiles of 213 patients with GCTB (100 male, 113 female) involving extra-craniofacial bones were retrieved. Pathological slides obtained at the initial surgery were reviewed. Fourteen pathological and five clinical features were statistically analyzed to disclose prognostic significance. Patient age ranged from 12-80 years (Average 38.7). Long bones were most frequently affected (86.4%), especially around the knee (62.9%). Histological features are basically similar to those previously reported. Within a follow-up period (24-316 months, average 106.1 months), the local recurrence rate is 29.1%. Metastasis has occurred in 9 patients. Cox regression analysis of representative clinicopathological features shows that younger age, higher mitotic count, smaller zones of stromal hemorrhage, considerable vascular invasion and absence of ischemic necrosis are significant predictors for local recurrence. Initial operative method (curettage) is a significant risk factor in univariate analysis but not by multivariate analysis (P = 0.053). Denosumab administration increases risk but not significantly (P = 0.053). Histone 3.3 G34W immunopositivity is not significant for predicting local recurrence.

Retrograde endoscopic submucosal dissection for early thoracic esophageal carcinoma.

Although the standard treatment for intramucosal esophageal cancer without lymph node metastasis is endoscopic submucosal dissection (ESD), we sometimes encounter patients who are not able to undergo a transoral endoscopic examination. Here, we report a surgical procedure consisting of transgastric retrograde ESD to treat early esophageal cancer (T1a-EP, N0, M0) because of a stricture after hypopharyngeal cancer surgery. This retrograde ESD procedure can be a safe and effective treatment option for early esophageal cancer. This is the first report of a surgical retrograde ESD method for esophageal cancer.

A case of medulloblastoma in a patient with fetal ventricular enlargement.

Medulloblastoma is the second-most common malignant tumor in children. Medulloblastoma has been categorized into four distinct molecular subgroups: WNT, sonic hedgehog (SHH), group 3, and group 4. We report on a male child with medulloblastoma, in whom an enlarged ventricle was diagnosed in utero. Magnetic resonance imaging showed cyst formation in the cerebellar hemisphere initially, with tumor growth being indicated later. Tumor resection was performed when the boy was 12 months old. The histological findings showed extensive nodularity. Further genetic analysis revealed the tumor to be SHH type. This is the first description of a medulloblastoma observed from the fetal stage. Our findings in this case indicate that cyst formation may be the pre-neoplastic lesion of SHH-subtype medulloblastomas.

Distal gastrectomy for early gastric conduit carcinoma after Ivor-Lewis esophagectomy.

A metachronous neoplasm can develop in a gastric conduit used for reconstruction after esophagectomy for thoracic esophageal cancer. Surgical resection is sometimes necessary to treat this neoplasm. We report a method for performing minimally invasive gastrectomy with preservation of the proximal residual stomach through laparotomy for cancer in the distal side of gastric conduit after Ivor-Lewis esophagectomy. Furthermore, Roux-en-Y reconstruction was performed after gastrectomy. This minimally invasive partial gastrectomy for early gastric conduit cancer and followed Roux-en-Y reconstruction may lead to a favorable clinical outcome.

Analysis of prognostic factors in patients with lymph node recurrence after radical esophagectomy: importance of locoregional therapy.

PURPOSE: Lymph node (LN) recurrence is frequently encountered in esophageal cancer. The aim of this study was to determine the effects of various factors, including loco-regional treatment of LN-only recurrence, on the survival rate. METHODS: Among 941 patients who underwent curative resection for esophageal squamous cell carcinoma in 2003-2016, we retrospectively reviewed 117 patients (12.4%) who developed LN-only recurrence. RESULTS: One, 2, 3, and 4 or more metastatic LNs were found in 72, 22, 6, and 17 patients, respectively, after a median disease-free interval of 8.4 months (range 1.1-62.0). Among all cases, recurrence was out of the surgical field in 53 cases (45.3%). Recurrent LNs were controlled by loco-regional treatment in 29 (43.9%) and by chemotherapy alone in 3 patients (7.0%). The 3-year survival rates of patients who did and did not achieve local control were 53.2% and 5.2%, respectively. Univariate analysis showed significant relationships between post-recurrence survival rate and pStage I-II at initial surgery, no history of radiotherapy, recurrence in ≤ 2 LN, and loco-regional treatment of LN recurrence. Multivariate analysis identified recurrence in ≤ 2 LN (HR 0.3169, 95% CI 0.1023-0.5314, p = 0.0038) and loco-regional treatment (HR 0.1973, 95% CI 0.0075-0.3871, p = 0.0416) as the only two significant and independent prognostic factors of survival. CONCLUSIONS: Recurrence limited to ≤ 2 LN and loco-regional treatment (chemoradiotheapy or surgery) for LN recurrence were associated with favorable survival of patients with history of radical esophagectomy followed by LN recurrence. Our results emphasize the importance of local control of LN recurrence regardless of location.

Continuous ghrelin infusion attenuates the postoperative inflammatory response in patients with esophageal cancer.

PURPOSE: The aim of this study was to clarify whether ghrelin infusion is useful for suppressing inflammatory responses after esophagectomy. METHODS: A phase I study of ghrelin administration after esophagectomy was performed in 20 patients with esophageal cancer. The anti-inflammatory effect of ghrelin was compared with 20 consecutive patients who did not receive ghrelin infusion. Additionally, 10 patients with intermittent infusion for 10 days were compared with 10 patients with continuous infusion for 5 days. The primary endpoint was the duration of systemic inflammatory response syndrome (SIRS). Secondary endpoints included postoperative complications, serum C-reactive protein (CRP), interleukin-6 (IL-6), and growth hormone (GH) levels. RESULTS: No adverse events of ghrelin administration occurred. Patients with ghrelin infusion had higher plasma ghrelin levels on postoperative day (POD) 3 (p = 0.003) and shorter SIRS duration (p = 0.007) than patients without ghrelin infusion. Although SIRS duration was similar (p = 0.19), patients with continuous ghrelin infusion had significantly higher plasma ghrelin (p < 0.001) and GH levels (p = 0.002) on POD 3 than patients with intermittent ghrelin infusion. Serum CRP and IL-6 levels on POD 3 tended to be lower in the continuous infusion versus intermittent infusion group. CONCLUSIONS: Ghrelin was safely administered after esophagectomy and may reduce excess postoperative inflammatory responses. Continuous infusion is better for this purpose than intermittent infusion.

Rechallenge of anti-PD-1/PD-L1 antibody showed a good response to metastatic breast cancer: a case report.

Rechallenge of immune checkpoint inhibitors has been reported for neoplasms other than breast cancer. Reported here is a case of a 55-year old woman diagnosed as having triple-negative right breast cancer with multiple metastases including lung. Atezolizumab and nab-paclitaxel were administered followed by epirubicin-cyclophosphamide. With subsequent eribulin, the overall best response was progressive disease, and curative surgical resection was performed. Three months after surgery (1.5 years after initial response of lung metastasis), right lung metastasis emerged at a site different from baseline. Based on the microsatellite instability-high status, pembrolizumab was administered and showed a good response. The patient has been treated with pembrolizumab, maintaining partial response, for over 9 months, which suggests the benefit of immune checkpoint inhibitors rechallenge in breast cancer.