First-Line Gemcitabine, Nab-Paclitaxel, and Oxaliplatin Chemotherapy With Itraconazole in Patients With Metastatic Pancreatic Cancer: A Single Institution Experience.

BACKGROUND/AIM: Combination chemotherapy with gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) was administered as first-line chemotherapy in patients with metastatic pancreatic cancer (mPC). The efficacy and toxicity of these treatments were retrospectively investigated. PATIENTS AND METHODS: A total of 81 patients (mean age=64 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 were enrolled in the study, and administered nab-paclitaxel (125 mg/m2), gemcitabine (1,000 mg/m2), and oxaliplatin (85 mg/m2) on day 1 and itraconazole (400 mg) on days -2 to +2, repeated every 2 weeks. RESULTS: Metastatic sites observed in patients included the liver (n=55, 68%), peritoneum (n=23, 28%), distant lymph nodes (n=24, 30%), and lungs (n=18, 22%). Within 28 days after initiation of chemotherapy, 15 patients (19%) experienced common ≥3 grade hematological adverse events. The major reason for discontinuation of treatment among the responders was peripheral sensory neuropathy in 36 patients (44%). The overall response rate to treatment was 64% [95% confidence interval (CI)=54-75%]. The median progression-free survival and median overall survival were 8.3 months (95% CI=6.8-9.8 months) and 14.4 months (95% CI=11.4-17.3 months), respectively. Among the 52 responders, 24 (46%) underwent conversion surgery, which did not improve survival (p=0.279). Second-line treatment with irinotecan was required in 71 (88%) patients. Hepatic arterial chemotherapy and radiotherapy were administered to 33 (41%) and 27 (33%) patients, respectively. CONCLUSION: The GnPO-ITC regimen showed promising efficacy with manageable toxicities for controlling disease progression and improving overall survival.

Orbital metastasis of invasive lobular carcinoma of the breast.

We herein report a case of orbital metastasis from the breast cancer in a 58-year-old woman presenting with visual disturbance and bilateral periorbital swelling. She had undergone radical mastectomy for right breast cancer 9 years previously and been receiving hormone therapy for bone metastasis of breast cancer for the past 4 years. Computed tomography and magnetic resonance imaging revealed an ill-defined mass in the bilateral orbits, whereas an excisional biopsy confirmed metastasis of invasive lobular carcinoma (ILC) of the breast. The appearance of eye symptoms in patients who have a history of breast cancer, especially ILC should be investigated, with a consideration of orbital metastasis.

Treatment Options for Leptomeningeal Metastases of Solid Cancers: Literature Review and Personal Experience.

Leptomeningeal metastases (LM) may complicate the clinical course of any solid cancer or hematological malignancy. Diagnosis of such cases requires a multifaceted approach, including careful evaluation of the clinical history, detailed neurological examination, advanced imaging studies, and related laboratory data analysis. Therapeutic options for management of LM have not been standardized yet. Conventional intrathecal chemotherapy with or without involved-field fractionated radiotherapy has only modest efficacy, and the prognosis of most patients remains grim. Therefore, development of new, more aggressive multimodal treatment strategies is definitely needed. Immune checkpoint inhibitors-in particular, molecular targeted therapy-have demonstrated promising results in selected groups of patients. There may be an important role for stereotactic radiosurgery as well. Because organization of prospective randomized multi-institutional trials on treatment of LM of solid cancers may be problematic, practical guidelines for optimal therapeutic strategies in such cases should be established on the basis of integrated results of small-scale prospective and retrospective studies.

Assessment of Intraoperative Microbiological Culture in Patients with Empyema: Comparison with Preoperative Microbiological Culture.

PURPOSE: Assessing microbiological culture results is essential in the diagnosis of empyema and appropriate antibiotic selection; however, the guidelines for the management of empyema do not mention assessing microbiological culture intraoperatively. Therefore, we tested the hypothesis that intraoperative microbiological culture may improve the management of empyema. METHODS: We performed a retrospective analysis of 47 patients who underwent surgery for stage II/III empyema from January 2011 to May 2019. We compared the positivity of microbiological culture assessed preoperatively at empyema diagnosis versus intraoperatively. We further investigated the clinical characteristics and postoperative outcomes of patients whose intraoperative microbiological culture results were positive. RESULTS: The positive rates of preoperative and intraoperative microbiological cultures were 27.7% (13/47) and 36.2% (17/47), respectively. Among 34 patients who were culture-negative preoperatively, eight patients (23.5%) were culture-positive intraoperatively. Intraoperative positive culture was significantly associated with a shorter duration of preoperative antibiotic treatment (p = 0.002). There was no significant difference between intraoperative culture-positive and -negative results regarding postoperative complications. CONCLUSIONS: Intraoperative microbiological culture may help detect bacteria in patients whose microbiological culture results were negative at empyema diagnosis. Assessing microbiological culture should be recommended intraoperatively as well as preoperatively, for the appropriate management of empyema.

Preoperative prognostic nutritional index level is associated with tumour-infiltrating lymphocyte status in patients with surgically resected lung squamous cell carcinoma.

OBJECTIVES: The prognostic nutritional index (PNI) is an indicator of systemic immune-nutritional condition and is a well-known prognostic biomarker in lung cancer patients. Tumour-infiltrating lymphocytes (TILs) is a specific histological feature of cancers, influencing an individual's immunological tumour responses. However, whether PNI can reflect lung cancer patients' prognosis through local immunity such as TIL is unclear. METHODS: We selected 64 lung squamous cell carcinoma patients who underwent curative operations. We investigated the significance of preoperative PNI level and evaluated the relationship between PNI and immune cells surrounding the lung cancer tissue using immunohistochemical analysis of a cluster of differentiation (CD)3, CD4, CD8 and CD68. RESULTS: A low-PNI level was significantly associated with a worse postoperative prognosis (P = 0.042). The PNI (hazard ratio 2.768, 95% confidence interval 1.320-5.957; P = 0.007) was an independent prognostic factor. The low-PNI group had a significantly shorter recurrence-free survival and overall survival (P = 0.013 and P = 0.002, log-rank test) compared with the high-PNI group. A significant positive correlation between PNI components including preoperative peripheral blood lymphocyte count and serum albumin concentration, and TILs, was observed. Absolute numbers of TILs in the preoperative high-PNI group were significantly increased compared with those in the preoperative low-PNI group (CD3+ cells; P = 0.002, CD4+ cells; P = 0.049 and CD8+ cells; P = 0.024). CONCLUSIONS: The preoperative PNI level was strongly associated with the postoperative outcome in lung cancer patients. Considering the positive relationship between preoperative PNI level and TIL status, preoperative immune-nutritional condition may influence lung cancer patients' postoperative prognosis through local immunity as well as systemic immune response.

S-1, Oxaliplatin, Nab-paclitaxel and Itraconazole for Conversion Surgery for Advanced or Recurrent Gastric Cancer.

AIM: To evaluate the efficacy of chemotherapy with itraconazole for advanced or recurrent gastric cancer. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2 (HER2) negative unresectable gastric cancer referred to our hospital were included. The regimen comprised 160 mg/m2 nab-paclitaxel i.v. and 100 mg/m2 oxaliplatin i.v. on day 1, 60 mg/m2 S-1 orally on days 1-3, and 400 mg itraconazole orally on days -2 to 2, repeated every 2 weeks for 6-8 cycles. RESULTS: Twenty-three patients aged 40-80 years (median age=68 years) were enrolled, of whom 21 had stomach cancer and two gastroesophageal junction cancer. Regarding stage, two, one, and 20 patients had stage IIIA, IIIB, and IV, respectively. Among patients with liver metastases, 2/10 had simultaneous lung metastases. Nine patients had peritoneal dissemination, and five patients with stage IV disease developed recurrence after primary surgery followed by adjuvant S-1. The other 18 patients had no history of surgery or chemotherapy. The response rate was 70% (complete response in two; partial response in 14). Among 12 patients (67%) who underwent conversion surgery, R0 resection was conducted in eight, and no residual tumour was observed in two. For the population overall, the median overall survival was 24 months (95% confidence intervaI=21 months-not reached) and the 1-year overall survival rate was 95% (95% confidence intervaI=67-98%). Grade 3/4 neutropenia and grade 2 peripheral sensory neuropathy occurred in five (22%) and six (26%) patients, respectively, while no patient developed grade 3/4 thrombocytopenia. CONCLUSION: Chemotherapy with itraconazole is promising for patients with unresectable gastric cancer.

Complications arising from transfemoral, percutaneous implantation of an indwelling port-catheter system for hepatic infusion chemotherapy: Case series of the management and salvage of the system.

INTRODUCTION: Regional hepatic arterial infusion of chemotherapy is performed for unresectable liver tumors via percutaneously implanted port-catheter systems; while these port-catheter systems are effective administration routes, they are associated with various complications. Withdrawal of the system is considered if the complications occur, but repeated hepatic arterial infusion of chemotherapy (HAIC) via an implanted port-catheter system is a last-resort treatment for unresectable advanced liver cancer, and the treatment must be continued. We discuss various cases with complications arising in the indwelling port area in hepatic arterial infusion of chemotherapy and report whether the system was salvaged. METHODS: Between August 2013 and October 2017, eight patients (six males and two females) aged 61-80 years (mean age 76.6 years) with complications arising in a transfemoral indwelling port site for HAIC were referred to our department. All patients requested preservation of the system, especially the catheter. Each patient was assessed for the presence of "gross infection" based on a comprehensive evaluation of clinical findings and blood test results. In cases of "no gross infection," we performed catheter salvage procedures. If there was no clinical improvement following the catheter salvage procedure, the port-catheter system was withdrawn. This research work has been reported in line with the PROCESS criteria. RESULTS: The port-catheter systems were withdrawn in two patients: one due to lasting infection and the other due to ulcer recurrence. Three cases were treated by removal of hematoma through an incision and ointment. The system was withdrawn in one of these cases due to exacerbation of ulcer; thus, the catheters were salvaged in five patients. None of these five patients experienced a relapse from 3 months to over 1 year after the procedure. CONCLUSION: The success of subcutaneous HAIC significantly impacts a patient's prognosis, especially for unresectable tumors and residual tumor recurrences. Initially, we chose to preserve the devices without removal, particularly if there was no infection. However, this approach led to a delay in chemotherapy, prolongation of healing time, and additional complications. These cases demonstrate the importance of a thorough consultation with the patient's oncologist to discuss whether or not the device should be conserved.

A combination of platelet-to-lymphocyte ratio and carbohydrate antigen 19-9 predict early recurrence after resection of pancreatic ductal adenocarcinoma.

BACKGROUND: Early recurrence (ER) after surgical resection is an important factor that impacts the survival of patients with pancreatic ductal adenocarcinoma (PDA). We examined risk factors for ER after PDA resection. METHODS: One hundred and thirteen PDA patients who underwent R0 or R1 resection were retrospectively analyzed. Thirty-four patients (30.1%) received neoadjuvant chemotherapy (NAC) for borderline resectable (BR) (n=13) or initially unresectable (n=21) disease. ER was defined as that diagnosed within 6 months after surgery. Receiver operating characteristic analysis was performed for each variable to determine the optimal cutoff value. RESULTS: ER occurred in 21 patients (18.6%). In univariate analysis, preoperative platelet-to-lymphocyte ratio (PLR) ≥144, carbohydrate antigen (CA) 19-9 ≥162 U/mL, and pathological tumor size ≥3 cm were significantly associated with ER. High PLR and CA19-9 were independent risk factors for ER by multivariate analysis. Area under the curve (AUC) for predicting ER from a combination of PLR and CA19-9 was 0.765 (95% confidence interval: 0.664-0.866), which increased the AUC compared to that for each risk factor alone. Patients with both risk factors had a significantly worse overall survival than those with one or no risk factors. When 24 patients with BR-PDA were considered, NAC was associated with a reduced likelihood of having risk factors and with a low ER rate. CONCLUSIONS: A combination of PLR and CA19-9 is a useful predictor of ER after macroscopic curative resection for PDA. NAC may reduce the risk of ER in selected patients.

[Two Cases of Bilateral Orbital Metastases of Breast Cancer].

Two cases of breast cancer with bilateral orbital metastases associated with intracranial metastases are presented. Case 1:A 61-year-old woman who was diagnosed with breast cancer 14 years earlier presented with rapid deterioration of visual acuity, eye pain, and limitation of left-sided extraocular motility. Magnetic resonance(MR)images showed an enhanced lesion in the left orbital apex, ethmoid sinus, and right middle fossa. The first gamma knife radiotherapy(35 Gy, 5 Fr)was performed successfully, but was followed by recurrence 18 months later in the right intraorbital, where newly formed iso-intensity masses in the extraconal compartment were found. The second gamma knife radiosurgery was performed for three masses(20 Gy). Case 2:A 35-year-old woman with breast cancer who was diagnosed 22 months earlier was treated for meningeal carcinomatosis by whole-brain radiation(30 Gy, 10 Fr)and intrathecal chemotherapy. Eight months later, swelling in both eyelids and limitation of extraocular motility developed rapidly. MR imaging revealed an infiltrating lesion in the cone with heterogenous signal that was encasing, but not infiltrating the optic nerves. The extraconal lesion extended into the soft tissue of the lower eye lid. She expired one week after diagnosis. With the increasing number of long-term survivors with breast cancer, intraorbital metastases may be found during the course of treatment for intracranial lesions. Understanding the unique clinical presentation and characteristic MR findings of this rare entity are emphasized.

The preoperative modified Glasgow prognostic score for the prediction of survival after pancreatic cancer resection following non-surgical treatment of an initially unresectable disease.

AIM OF THE STUDY: Recent advances in chemotherapy have increasingly enabled conversion surgery (CS) in patients with initially unresectable pancreatic cancer (PC), but patient selection remains controversial. We examined the characteristics of patients who would benefit from this procedure. MATERIAL AND METHODS: The clinical and pathological data of 38 patients with unresectable PC, who underwent CS after a favourable response to chemo(radio)therapy at our institute, were investigated. Univariate and multivariate analyses were performed to identify predictors for overall survival (OS). Several inflammation-based scores, such as the modified Glasgow prognostic score (mGPS), were also evaluated. RESULTS: The patients included 13 with locally advanced disease and 25 with metastatic disease. After non-surgical treatment with a median duration of six months, 27 patients (71%) underwent R0/1 resection, and the remainder underwent R2 resection. The two-year and five-year OS from the initial treatment for all patients were 64% and 29%, respectively, and the median survival was 29.1 months. Univariate analysis showed that age < 62 years, preoperative CA19-9 decrease rate ≥ 89%, preoperative mGPS-0, and R0/1 resection were related to a favourable OS. R0/1 resection and mGPS-0 were independent prognostic factors according to multivariate analysis. CONCLUSIONS: Preoperative mGPS is a potential predictor of survival and can aid selection of patients for whom CS could yield promising prognosis for initially unresectable PC.

Repurposing itraconazole as an anticancer agent.

Itraconazole, a common anti-fungal agent, has demonstrated potential anticancer activity, including reversing chemoresistance mediated by P-glycoprotein, modulating the signal transduction pathways of Hedgehog, mechanistic target of rapamycin and Wnt/ß-catenin in cancer cells, inhibiting angiogenesis and lymphangiogenesis, and possibly interfering with cancer-stromal cell interactions. Clinical trials have suggested the clinical benefits of itraconazole monotherapy for prostate cancer and basal cell carcinoma, as well as the survival advantage of combination chemotherapy for relapsed non-small cell lung, ovarian, triple negative breast, pancreatic and biliary tract cancer. As drug repurposing is cost-effective and timesaving, a review was conducted of preclinical and clinical data focusing on the anticancer activity of itraconazole, and discusses the future directions for repurposing itraconazole as an anticancer agent.

Itraconazole Modulates Hedgehog, WNT/ß-catenin, as well as Akt Signalling, and Inhibits Proliferation of Cervical Cancer Cells.

BACKGROUND/AIM: Repurposing itraconazole as an anticancer agent has been evaluated in several studies. The present study investigated whether itraconazole exerts an anticancer effect on cervical cancer cells. MATERIALS AND METHODS: CaSki and HeLa cells were cultured in itraconazole and vehicle after which colony-forming and cell viability assays were performed. Transcription and protein expression were assessed by cDNA microarray analysis and immunoblotting, respectively. RESULTS: Itraconazole suppressed proliferation of CaSki and HeLa cells in a dose- and time-dependent manner. Furthermore, CaSki cells were more significantly affected by itraconazole than HeLa cells. The microarray analysis showed an 8-fold down-regulation in the expression of GLI1, WNT4 and WNT10A among itraconazole-treated CaSki cells. Moreover, the transcription of sterol carrier protein-2 and ATP-binding cassette transporter-1 was unaffected by itraconazole. Immunoblots showed suppression in ß-catenin expression and Akt phosphorylation. CONCLUSION: Itraconazole is a multi-targeting anticancer agent and a promising therapeutic agent for cervical cancer.

Itraconazole Inhibits AKT/mTOR Signaling and Proliferation in Endometrial Cancer Cells.

BACKGROUND: Itraconazole is a common antifungal agent that has demonstrated anticancer activity in preclinical and clinical studies. This study investigated whether itraconazole exerts this effect in endometrial cancer (EC) cells. MATERIALS AND METHODS: Cell viability was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and gene and protein expression were assessed by microarray analysis and immunoblotting, respectively, in five EC cell lines. RESULTS: Itraconazole-suppressed proliferation of AN3-CA, HEC-1A and Ishikawa cells (p<0.05) but not of HEC-50B or SNG-II cells. Itraconazole did not suppress GLI1 or GLI2 transcription but did inhibit the expression of mammalian target of rapamycin (mTOR) signaling components in AN3-CA and HEC-1A cells, while inducing that of microtubule-associated protein 1A/1B-light chain 3-II, a marker of autophagy. ATP-binding cassette transporter A1 gene was down-regulated in Ishikawa, HEC-50B and SNG-II cells. CONCLUSION: Itraconazole treatment suppresses the growth of EC cells by inhibiting AKT/mTOR signalling.

Malignant transformation of hepatocellular adenoma with bone marrow metaplasia arising in glycogen storage disease type I: A case report.

Malignant transformation of hepatocellular adenoma (HA) is relatively rare and has been reported to be associated with dysregulation of the ß-catenin pathway. The presence of bone marrow metaplasia in HA is an uncommon histological characteristic. The current report presents the case of a 46-year-old woman with glycogen storage disease type I (von Gierke's disease) who underwent resection of hepatocellular carcinoma (HCC) arising in a HA with associated bone marrow metaplasia producing three series of hematopoietic cells. The serum level of proteins induced by des-gamma-carboxy prothrombin (DCP) gradually increased as the tumors grew; following hepatic resection, DCP levels returned to normal. Nuclear accumulation of ß-catenin was shown in HCC by immunohistochemistry; however, no mutation was detected in exon 3 of ß-catenin. To the best of our knowledge, this is the first report of HA with absolute bone marrow metaplasia producing three series of hematopoietic cells. This occurrence suggests that elevated DCP may be an indicator of malignant transformation of HA.

Expression of Hedgehog Signals and Growth Inhibition by Itraconazole in Endometrial Cancer.

BACKGROUND: There exist limited therapeutic opportunities for the treatment of endometrial cancer (EC). Itraconazole, a common anti-fungal agent and a potent inhibitor of the Hedgehog pathway, has been shown to be clinically effective for various types of cancers, but its clinical efficacy for EC is unknown. Herein, we evaluated the efficacy of itraconazole in treating EC. MATERIALS AND METHODS: We performed immunohistochemistry on EC tumour samples including serous endometrial intraepithelial carcinoma (SEIC). We further evaluated the in vitro efficacy of itraconazole for inhibiting proliferation and migration of EC cell lines. RESULTS: Sonic Hedgehog and glioma-associated oncogene homolog 1 (GLI1) were expressed in SEIC and endometrioid adenocarcinoma. We found that itraconazole significantly inhibited tumour cell growth in both dose-dependent and time-dependent manners and inhibited migration of HEC-1A cells. CONCLUSION: Hedgehog signaling plays a role in carcinogenesis and malignant progression in EC. Itraconazole at a physiological dose may suppress progression of EC.

Impact of Itraconazole After First-line Chemotherapy on Survival of Patients with Metastatic Biliary Tract Cancer.

AIM: We evaluated the efficacy and safety of itraconazole after first-line chemotherapy in patients with metastatic biliary tract cancer (BTC). PATIENTS AND METHODS: We retrospectively reviewed data from patients with histologically-diagnosed BTC with distant metastases who had received one or more lines of chemotherapy and subsequent itraconazole chemotherapy. RESULTS: Among 28 enrolled patients, 26 (93%) received docetaxel (35 mg/m(2)), gemcitabine (1,000 mg/m(2)), and carboplatin (AUC4) on day 1 and oral itraconazole solution (400 mg) on days -2 to 2, repeated every 2 weeks. Two patients received docetaxel plus itraconazole with irinotecan. Two complete responses and 14 partial responses were observed, with a response rate of 57%. The median overall survival was 12.0 months. During 160 cycles, 21 (75%) and 17 (61%) patients had grade 3/4 neutropenia and thrombocytopenia, respectively. Two patients (7%) experienced febrile neutropenia. CONCLUSION: Combination chemotherapy with itraconazole after first-line chemotherapy is promising for patients with metastatic BTC.

Combination Chemotherapy with Itraconazole for Treating Metastatic Pancreatic Cancer in the Second-line or Additional Setting.

BACKGROUND: We evaluated chemotherapy with itraconazole (a common anti-fungal agent that is a potent inhibitor of the Hedgehog pathway, P-glycoprotein, and angiogenesis) for treating progressive pancreatic cancer. PATIENTS AND METHODS: We retrospectively reviewed the medical charts of patients with histologically-diagnosed pancreatic cancer who had received first- or second-line chemotherapy and subsequent chemotherapy with itraconazole. RESULTS: A total of 38 patients received docetaxel (35 mg/m(2)), gemcitabine (1,000 mg/m(2)), and carboplatin (area under the curve, 4 mg/min/ml) on day 1 and oral itraconazole solution (400 mg) on days -2 to 2, repeated every 2 weeks. One complete response and 13 partial responses were observed, for a response rate of 37%. Eight (21%) patients experienced febrile neutropenia. The median overall survival was 11.4 months (95% confidence interval=8.5-21.2 months). CONCLUSION: Combination chemotherapy with itraconazole is promising for prolonging overall survival, with acceptable toxicities in the second-line setting of pancreatic cancer.

[A case of disease-free, long survival in a patient with mixed adenoneuroendocrine carcinoma of the gallbladder treated with induction CDDP/CPT-11 chemotherapy and resection].

A 57-year-old woman with a complaint of a right upper quadrant mass was referred to our hospital. Multimodal studies such as PET-CT revealed large hepatic tumors and swollen para-aortic lymph nodes, the origin of which was unclear. Pathological analysis of a biopsy specimen obtained from the liver tumor led to a diagnosis of neuroendocrine carcinoma. After 4 CDDP/CPT-11 chemotherapy treatment courses, remarkable shrinkage of liver tumors and disappearance of the swollen lymph nodes were achieved. Subsequently, liver tumor and extrahepatic bile duct resection and lymphatic dissection were performed. Pathological analysis of the resected specimens revealed that the liver tumors and metastatic lymph nodes originated from the gallbladder, leading to a diagnosis of mixed adenoneuroendocrine carcinoma. After 5 courses of adjuvant chemotherapy using the same regimen, the patient has remained disease free for 24 months since the initialdiagnosis.

Impact of itraconazole on the survival of heavily pre-treated patients with triple-negative breast cancer.

BACKGROUND/AIM: Recurrent triple-negative breast cancer (TNBC) patients have poor prognoses and limited treatment options, especially after progression during prior chemotherapy. The present study aimed to determine the impact of itraconazole with chemotherapy in these patients. PATIENTS AND METHODS: Medical records of recurrent TNBC patients receiving itraconazole with chemotherapy between 2008 and 2012 were retrospectively reviewed. RESULTS: Thirteen patients who progressed during prior chemotherapy (12 with visceral organ metastases) were enrolled. All patients had received docetaxel, carboplatin, and gemcitabine with itraconazole. Additionally, 3 patients with pleural effusion and 2 with inflammatory breast cancer received bevacizumab. No febrile neutropenia, platelet transfusion, or chemotherapy-related death was observed during treatment with itraconazole. The response rate, median progression-free survival, and median overall survival were 62% (95% confidence interval (CI): 35-88%), 10.8 months (95%CI: 7.6-15.3 months), and 20.4 months (95%CI: 13.1-41.4 months), respectively. CONCLUSION: Chemotherapy with itraconazole is promising for heavily pre-treated TNBC patients.