tbuckley/cabot-search huggingface dataset:
Subgroup analysis by prior anti-VEGF or anti-EGFR target therapy in FRESCO, a randomized, double-blind, phase 3 trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (mCRC).
Authors: Ruihua Xu, Jin Li, Yu-Xian Bai, Yanhong Deng, Lei Yang, Haijun Zhong, Zhendong Chen, Hongming Pan, Weijian Guo, Yongqian Shu, Ying Yuan, Jianming Xu, Lin Shen, Ning Wang, Xin Wang, Haidong Chi, Jack Peng, Ye Hua, Weiguo Su, Shukui Qin
Journal: Journal of Clinical Oncology (2018)

3537 Background: Patients with mCRC are typically offered chemotherapy and might also receive target therapy-drugs targeting VEGF or EGFR. In phase 3 FRESCO trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in third-line mCRC patients in China. To explore possible effects of prior target therapy on fruquintinib, we conducted subgroup analysis of patients with prior target therapy (PTT) and those without (non-PTT). Methods: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. P-value was generated from log rank test. Results: Among a total of 278 fruquintinib-treated patients, 111 received prior target therapy (84 with anti-VEGF;40 with anti-EGFR and 13 with both). In PTT subgroup, fruquintinib significantly prolonged OS (Median OS: 7.69 months (m) vs 5.98 m;HR = 0.63;p = 0.023) and PFS (Median PFS:3.65m vs 1.84m;HR = 0.24;p < 0.001) compared to placebo. Patients who received prior anti-VEGF treatment (N = 84) also benefited from fruquintinib in OS (HR = 0.68,95%CI: 0.45-1.03) and PFS (HR = 0.24,95%CI: 0.15-0.38). In non-PTT subgroup, the median OS was 10.35 m for fruquintinib vs 6.93 m for placebo (HR = 0.63,p = 0.01) and the median PFS for fruquintinib was 3.81 m vs 1.84 m for placebo (HR = 0.28,p < 0.001). There were no observed accumulative Grade≥3 treatment-emergent adverse events (TEAEs) in PTT subgroup. Grade≥3 TEAEs rates of fruquintinib were similar in PTT and non-PTT subgroup (61.3% and 61.1%). The most common drug-related Grade ≥3 TEAEs of fruquintinib in PTT and non-PTT subgroup were hypertension (20.7% and 21.6%), hand-foot-skin reaction (7.2% and 13.2%) and proteinuria (5.4% and 1.8%). Conclusions: This subgroup analysis result is consistent with previously reported FRESCO intent-to-treatment population result. Fruquintinib showed clinically meaningful benefits in third-line mCRC patients regardless of prior target therapy without observed accumulative toxicity. Clinical trial information: NCT02314819.
Safety and activity of M7824, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with HPV associated cancers.
Authors: Julius Strauss, Margaret Elena Gatti-Mays, Jason Redman, Ravi Amrit Madan, Elizabeth Lamping, Michell Manu, Andrea Burmeister, Jennifer L. Marte, Lisa M. Cordes, Laureen Ojalvo, Christoph Helwig, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2018)

3007 Background: Therapies targeting PD-1/L1 have produced response rates of 15-20% in patients (pts) with HPV associated cancers (HAC) including cervical (cerv), anal or head and neck squamous cell carcinoma (HNSCC). Another potential target for these diseases is transforming growth factor-β (TGF-β) as genome wide association studies in HPV+ cancers have shown TGF-β to be significantly overexpressed. M7824 is a bifunctional fusion protein targeting PD-L1 and TGF-β comprised of a human IgG1 monoclonal antibody against PD-L1 fused to 2 extracellular domains of TGF-β receptor II, which functions as a TGF-β "trap". We report data from pts with HAC on a fully enrolled dose escalation portion of a phase 1 trial of M7824. Methods: NCT02517398 is a phase 1, 3+3 dose-escalation study. Pts received M7824 at 1, 3, 10, 20, or 30 mg/kg Q2W until PD or unacceptable toxicity. The primary objective was safety and maximum tolerated dose (MTD). A key secondary objective was best overall response per RECIST v1.1. Results: As of Feb 5 2018, 16 pts with HAC (9 cerv, 4 anal and 3 HNSCC) were enrolled. HPV was + in 11 pts and unknown (uk) in 5 pts. Grade 3 treatment related adverse events (TRAEs) occurred in 3/16 (colitis, cystitis, gastroparesis; all cerv). Notably all 3 also had disease reduction. Grade 4 hypokalemia accompanied the gastroparesis. No other grade 4-5 TRAEs were seen. The only DLT was colitis (at 20 mg/kg) and no MTD was reached. 9/16 (56%) have had disease reduction on treatment including 1 pt (cerv; HPV+) with a durable CR, 4 pts (2 HNSCC, 2 anal; all HPV+) with durable PRs, 1 pt (cerv; HPV uk) with an unconfirmed PR, 2 pts (2 cerv; both HPV uk) with near PRs (-25%, -27%) and 1 pt (anal; HPV uk) with modest reduction (-9%). In all, 6/16 (37.5%) have ongoing responses, 5/6 confirmed. Of pts with known HPV+ disease, 5/11 (45.5%) have ongoing confirmed responses. Conclusions: Data from a phase 1 trial of M7824 suggests a manageable safety profile and an ORR of 37.5% in pts with HAC including a confirmed ORR of 45.5% in pts with known HPV+ disease. M7824 is a promising drug for pts with HAC or HPV+ cancers and continues to be evaluated in phase I and II trials. Clinical trial information: NCT02517398.
A phase II trial of the DNA methyl transferase inhibitor, SGI-110 (guadecitabine), in children and adults with wild type GIST, pheochromocytoma and paraganglioma associated with succinate dehydrogenase deficiency and HLRCC-associated kidney cancer.
Authors: Jaydira Del Rivero, Fernanda Irene Arnaldez, Ramaprasad Srinivasan, Melissa Spencer, Seth M. Steinberg, Karel Pacak, Keith Killian, Lee J. Helman, Paul S. Meltzer, W. Marston Linehan, Brigitte C. Widemann, John Glod
Journal: Journal of Clinical Oncology (2018)

TPS2608 Background: Loss of activity of Krebs cycle components succinate dehydrogenase (SDH) complex or fumarate hydratase (FH) has been identified as a mechanism of tumorigenesis in SDH-deficient gastrointestinal stromal tumor, pheochromocytoma and paraganglioma (PHEO/PGL), and hereditary leiomyomatosis and renal cell cancer (HLRCC). Accumulation of the metabolites succinate or fumarate inhibits α-ketoglutarate-dependent dioxygenases leading to DNA hypermethylation in these tumors. Guadecitabine is a small molecule derivative of decitabine that acts as a DNA methyltransferase inhibitor. We hypothesize that guadecitabine will impact tumor growth by reversing DNA hypermethylation in tumors with Krebs cycle abnormalities (NCT03165721). Methods: This single site, open label, phase II study uses a small optimal two-stage design to evaluate response in three groups of patients: SDH-deficient GIST, SDH-deficient PHEO/PGL and HLRCC-associated renal cell carcinoma. The primary objective is to assess the clinical activity (CR or PR) of guadecitabine in these patients. Adults and children (≥12 years of age) receive guadecitabine subcutaneously at a dose of 45mg/m2/day for 5 consecutive days on a 28-day cycle. Activity is assessed by imaging response of measurable disease using RECISTv1.1 using CT, MRI and/or PET. Toxicity is graded using version 4.0 of the NCI Common Toxicity Criteria. Guadecitabine related toxicities ≥grade 3 will be considered treatment limiting, unless they are reversible within 72 hours with supportive care. Following recovery from toxicity up to 2 dose reductions will be allowed. Initially 7 evaluable patients in each group will be enrolled and if 1 or more (14.3%) have a response, accrual will continue until a total of 21 patients have enrolled. If at least 3 responses (14.3%) are observed among the 21 evaluable patients the agent will be considered worthy of further testing in this disease. Clinical trial information: NCT03165721.
KIFC1 as a novel therapeutic target for p53 mutant colorectal cancer.
Authors: Karuna Mittal, Guanhao Wei, Jaspreet Kaur, Da Hoon Choi, Michelle D. Reid, Padmashree C.G. Rida, Ritu Aneja
Journal: Journal of Clinical Oncology (2018)

e15585 Background: Loss or mutation of p53 gene is the most frequent genetic lesion in late-stage colon cancers. The optimal management of p53 mutant (p53M) colorectal cancer (CRC) remains a therapeutic challenge owing to its resistance to 5-fluorouracil, the first-choice chemotherapy drug for CRC. Thus, the search for novel therapeutic targets for the treatment of p53M CRC is highly warranted. We report that p53 negatively regulates expression of KIFC1 (a centrosome clustering protein), can serve as a potential therapeutic target for p53M CRCs. Methods: We first immunohistochemically stained 203 CRC tissue samples for p53, KIFC1, and FOXM1 and calculated their weighted indices (WIs) for nuclear staining. To validate the clinical findings in silico analysis was performed on the publically available dataset (GSE41258). For determining the mechanistic relationship of KIFC1 and p53, overexpression (OE) of p53 and immunoblotting and ChiP assays were performed. Finally, inhibited KIFC1 by pharmacological and genetic methods to elucidate the role of the KIFC1 inhibition on the vitality of p53-/- CRC cells. Results: p53-/- and p53M CRC [p53-/- n = 82, p53M n = 40 and WT n = 81] exhibited significantly (p < 0.001) higher expression of KIFC1 and FOXM1 when compared with the p53 WT CRC tissue samples and was associated with worse overall survival (HR = 4.249, p = < 0.001)). Similarly, our in silico analysis indicated significantly higher KIFC1 and FOXM1 mRNA expression in p53M (n = 93) CRC and was associated with poor overall survival (HR = 1.46, P = < 0.05). OE of p53 in p53-/- cells decreased the expression of FOXM1 and KIFC1 indicating the negative regulation of KIFC1 via FOXM1 which was further strengthened by ChiP assay (FOXM1 interaction with KIFC1 promoter was significantly higher p = 0.037 in p53-/- cells when compared with p53 WT cells). Inhibition of KIFC1 using shRNA, CW069 (a known KIFC1 inhibitor) and griseofulvin (a known centrosome declustering drug), led to increased multipolarity followed by cell death only in p53-/- CRC cells. Conclusions: Collectively our results indicate that p53 negatively regulates expression of KIFC1 via FOXM1 and contributes to poor outcomes in p53M CRCs. Thus, KIFC1 may serve as a potential therapeutic target for p53M CRCs.
The status of PD-L1 expression and TILs among ESCC patients in China and changes after radiation and chemotherapy.
Authors: Song Wen, Dingzhi Huang, Yi Ba, Hongli Li, Rui Liu
Journal: Journal of Clinical Oncology (2017)

e14567 Background: The status of PD-L1 expression and TILs (tumor infiltrating lymphocytes) is suggested as a predictive biomarker for the clinical effect of PD-1/PD-L1 inhibitors. In our study, weevaluate the status of PD-L1 expression and TILs in ESCC (esophageal squamous cell carcinoma), especially in CD8+ T cells. We also evaluate the changes in PD-L1 expression after chemotherapy or radiation. Then, we analyze the significance of these profiles. Methods: We retrospectively collected a total of 240 patients with histologically confirmed ESCC who underwent a radical operation between May 2009 and January 2015 at TianJin Medical University Cancer Institute &amp; Hospital. Of these 240 patients, 104 patients received neoadjuvant therapy, including chemotherapy, radiotherapy or CCRT. We then examined the expression of PD-L1, CD8 and PD-1 in every patient. Results: We find a significant association between the PD-L1 expression and CD8+ T cell status (P = 0.044), while there is a negative relationship between the PD-L1 expression and PD-1+ T cell status (P = 0.048). Compared with the surgery-only group, there is an increase in the PD-L1 expression in NACRT and NCT (≥3 cycles) groups (P = 0.001 and 0.025). The PD-L1 expression non-significantly decreases in the NCT ( &lt; 3 cycles) group (P = 0.197). We also observe an increase in CD8+ T lymphocytes in the NACRT and NCT ( &lt; 3 cycles) groups (P = 0.116 and 0.036). Conclusions: We find a relatively high expression of PD-L1 and TILs in Chinese ESCC, indicating that PD-1/PD-L1 inhibitors may have a role in treatment. Additionally, there is an increase in PD-L1 and TILs after radiation or chemotherapy. As a result, combining PD-1/PD-L1 inhibitors with traditional cytotoxic therapy is a promising direction.
Comparison of plasma cell infiltration in random samples of the bone marrow and osteolyses acquired by CT-guided biopsy in patients with symptomatic multiple myeloma.
Authors: Jens Hillengass, Elena Ellert, Daniel Spira, Stefan Hemmer, Berbara Wagner, Mindaugas Andrulis, Sandra Sauer
Journal: Journal of Clinical Oncology (2016)

8040 Background: The degree of plasma cell infiltration in bone marrow is an important diagnostic and prognostic marker in multiple myeloma. An infiltration of 60% or more has been included into the new criteria of the International Myeloma Working Group defining myeloma necessitating systemic treatment. However, malignant plasma cells infiltrate the bone marrow in different patterns. While some patients show focal accumulations others present with a diffuse or a mixed pattern. Usually bone marrow examination is performed on a random sample from the pelvis or sternum as regions where bone marrow can be reached most easily. It is unclear if the plasma cell percentage of this particular location is really representative for the whole bone marrow compartment. Methods: To investigate the differences between plasma cell infiltration of the bone marrow in random samples compared to that in focal lesions, we performed immunohistochemistry on conventional bone marrow trephines of the iliac crest and on samples from CT-guided or open biopsies of osteolyses in 31 patients with symptomatic multiple myeloma at first diagnosis, respectively. Results: Location of guided biopsy was outside the pelvis in 4 and from an osteolysis in the pelvis in 26 patients. A median plasma cell infiltration of 30% (0 - 90%) was found in the random sample. In the osteolyses median infiltration was 60% (0 - 100%). From 21 patients with a plasma cell percentage of less than 60% in the random sample 10 (48%) showed 60% or more plasma cells in the osteolysis. Conclusions: Routinely performed random sample of the iliac crest might underestimate the degree of plasma cell infiltration in the whole skeleton. This ongoing study will also address the question if malignant plasma cells in osteolyses are genetically different from those from the random sample.
Phase I results of mitoxantrone in combination with clofarabine in children, adolescents and young adults with refractory/relapsed acute leukemia.
Authors: Jessica Hochberg, Javier E. Oesterheld, Olga Militano, Liana Klejmont, Lauren Harrison, Berkley Nickerson, Mitchell S. Cairo
Journal: Journal of Clinical Oncology (2016)

10533 Background: Despite excellent outcomes in pediatric ALL, multiply relapsed patients have low response rates and low OS. The prognosis for relapsed/refractory AML is also poor. Clofarabine and Mitoxantrone have proven efficacy in children with leukemia and offer possible synergistic activity. Objective: To determine the maximal tolerated dose and overall response rate of clofarabine in combination with mitoxantrone as reinduction therapy for refractory/relapsed acute leukemia. Methods: Patients 0-30.99yr old with ALL, AML or NHL in relapse OR induction failure were given clofarabine (escalating doses 20, 30, 35 and 40mg/m2/day) Day 1-5, in combination with mitoxantrone 12mg/m2/day on Day 3-6. Dose escalation 3+3 design. CNS prophylaxis with intrathecal liposomal AraC. Patients allowed up to 3 cycles pending response and anthracycline exposure. Results: A total of 18 patients. Median Age is 13yrs (8months-23yrs); 11 ALL (3 = IF, 6 = Relapse 1, 2 = Relapse 2), 6 AML (4 = IF, 1 = Relapse 1, 1 = Relapse 2), 1 NHL (PD). There were 2 Grade III/IV toxicities at Dose Level 4 (Clofarabine 40mg/m2) (1 hepatic toxicity, 1 prolonged myelosuppression) hence 3 additional patients were enrolled at Dose Level 3 (Clofarabine 35mg/m2). Median time to neutrophil recovery was 24 days. Fourteen of 17 (82%) leukemia patients achieved a CR after 1 cycle of therapy. Of these, 93% achieved MRD negativity ( < 0.1%). Thirteen of 14 patients achieving CR went on to receive alloHSCT with continued remission at a median follow up time of 444 days (range 73-761) with a 1 year OS 64.2% (CI95: 36.8-82.2). Conclusions: The combination of clofarabine and mitoxantrone reinduction therapy is safe and well tolerated in children, adolescents and young adults with poor risk hematologic malignancies. The Phase I MTD of this combination has been established at 35mg/m2/dose Clofarabine. Efficacy data from the Phase I portion is encouraging with an 82% CR rate, 93% negative MRD and 64% 1 year OS in these high risk acute leukemia patients. An extended multicenter Phase II Study is ongoing. Clinical trial information: NCT01843672.
Association of mesenchymal subtype with the presence of immune infiltrates in squamous cancer classifier.
Authors: Rob Seitz, David Richard Hout, Brian Z Ring, Dan B Bailey
Journal: Journal of Clinical Oncology (2017)

e23073 Background: Lehmann and colleagues (Lehmann 2011) devised a classification system for triple negative breast cancer (TNBC) consisting of seven subtypes—IM, BL1, BL2, LAR, M, MSL, and UNS. Recent work has shown the IM group (characterized by the presence of immunomodulatory genes) is due to tumor infiltrating lymphocytes (TILs), and should be measured independently of the other subtypes. Furthermore, the m subtype (characterized by genes associated with epithelial-mesenchymal transition (EMT)) was shown to have a highly inverse relationship with the IM group (Lehmann 2016). We (Ring 2016) modified the original algorithm into a 101-gene algorithm that also confirmed this inverse relationship between IM and m signatures (Grigoriadis SABCS 2016). While this is a novel and interesting finding, we wanted to know whether this inverse relationship applies to other epithelial cell origin cancers such as squamous lung cancer. Methods: We downloaded gene expression data from 548 squamous cell lung cancers from the TCGA database, and applied the 101-gene TNBC algorithm to the lung cohort without optimization or adjustment. Results: Of the 548 samples, 389 (71%) were able to be classified by the 101-gene algorithm. Of these, 82 (21%) had an m phenotype. 128 patients (33%) were positive for the IM signature. The expected overlap of patients positive for both IM and m was 27 patients (7%). The observed overlap was 0 patients (chi-squared = 29; p &lt; 0.001). Conclusions: The unoptimized 101-gene TNBC algorithm validated the observation that gene expression signatures for IM and m are inversely correlated. While any attempt to apply a TNBC algorithm to squamous lung cancer would need careful optimization and validation, these data support that the inverse relationship noted in TNBC may transcend the tissue of origin.
Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC.
Authors: D. Ross Camidge, Solange Peters, Tony Mok, Shirish M. Gadgeel, Parneet K. Cheema, Nick Pavlakis, Filippo De Marinis, Daniil L. Stroyakovskiy, Byoung Chul Cho, Li Zhang, Denis Moro-Sibilot, Ali Hassan Zeaiter, Emmanuel Mitry, Bogdana Balas, Barbara Müller, Alice Shaw
Journal: Journal of Clinical Oncology (2018)

9043 Background: The primary ALEX (NCT02075840) analysis showed superior investigator (INV)-assessed PFS with ALC vs CZ (HR 0.47, 95% CI 0.34–0.65, p<0.001; median 11.1 months [m] CZ, not estimable [NE] ALC) in untreated ALK+ NSCLC. We report updated data (cutoff Dec 1 2017). Methods: ALEX enrolled patients (pts) with stage IIIB/IV ALK+ NSCLC (by central IHC) and no prior systemic therapy for advanced NSCLC; asymptomatic CNS metastases (mets) were allowed. Pts were randomized 1:1 to receive ALC 600mg BID (n = 152) or CZ 250mg BID (n = 151). Primary endpoint: PFS (INV, RECIST v1.1), with q8w CNS imaging in all pts. Secondary endpoints: ORR, time to CNS progression, DOR, OS, and safety. Results: With 10m longer follow-up (median 22.8m CZ vs 27.8m ALC), ALC significantly reduced risk of disease progression/death by 57% vs CZ (ITT; stratified HR 0.43, 95% CI 0.32–0.58): median PFS (INV) was 34.8m ALC vs 10.9m CZ. Median PFS by baseline (BL) CNS mets status was 27.7m ALC vs 7.4m CZ (HR 0.35, 95% CI 0.22–0.56) in pts with, and 34.8m vs 14.7m (HR 0.47, 95% CI 0.32–0.71) in pts w/out BL CNS mets. In the BL CNS mets group, the number of pts who received WBRT (n = 16 ALC, n = 17 CZ) or SRS (n = 4 ALC, n = 6 CZ) was balanced, as was the number of BL lesions (median 2 per arm). Updated secondary endpoint data (INV): ORR 82.9% ALC (95% CI 75.95–88.51; n = 152) vs 75.5% CZ (95% CI 67.84–82.12; n = 151); median DOR 33.3m ALC (95% CI 31.1–NE; n = 126) vs 11.1m CZ (95% CI 7.5–13.0; n = 114), stratified HR 0.33, 95% CI 0.23–0.48. OS data are still immature (events ALC 28.3%, CZ 31.8%; stratified HR 0.76, 95% CI 0.50–1.15). Despite significantly longer treatment (Tx) duration with ALC (27.0m vs 10.8m), proportion of pts with grade 3–5 AEs (44.7% vs 51.0%), AEs leading to dose reduction (16.4% vs 20.5%) or interruption (22.4% vs 25.2%) were lower with ALC vs CZ. Proportion of pts with AEs leading to discontinuation: 13.2% each arm. Fatal AEs: 5% CZ (2 Tx-related AEs) and 4% ALC pts (0 Tx related). Conclusions: ALC 600mg BID showed superior efficacy vs CZ (PFS HR 0.43, median 34.8m ALC vs 10.9m CZ) in untreated ALK+ NSCLC, regardless of BL CNS mets, and favorable and durable tolerability despite longer Tx duration, consolidating ALC as the new standard of care. Clinical trial information: NCT02075840.
Patient self-initiated antibiotic therapy for fever during neoadjuvant and adjuvant breast cancer chemotherapy.
Authors: Shin Ogita
Journal: Journal of Clinical Oncology (2016)

e21667 Background: Infection ,specially febrile neutropenia (FN) , is the major cause of morbidity and mortality of neoadjuvant (NEO) and adjuvant (ADJ) chemotherapy for breast cancer. Timely evaluation by health care professionals and antibiotics (ABx) are recommended. However, access to care can be delayed at night and weekend. Most pts receiving NEO and ADJ chemotherapy are low risk for complication of FN and can be safely managed with oral ABx at home. Our hospital began patient self-initiated approach for fever and this study analyzed the strategy outcome. Methods: Retrospective review of electronic medical records of pts who underwent anthracycline and taxane based NEO or ADJ chemotherapy for breast cancer at a hospital was performed. Pts were prescribed with 7 days of ciprofloxacin+ amoxicillin/ clavulanate on the 1st day of chemotherapy unless contraindicated and instructed to start immediate ABx for axillary temperature ≥ 38 °C. G-CSF was not routinely given. Chemotherapy induced infection was defined as any infection occurring from the 1stchemotherapy day to 3 weeks after the last chemotherapy. Results: From February 2011 to December 2014, 855 pts received NEO or ADJ chemotherapy. 362 pts received triweekly doxorubicin+ cyclophosphamide (AC) or fluorouracil+ epirubicin+ cyclophosphamide (FEC) and triweekly docetaxel, 357 pts received triweekly AC / FEC and weekly paclitaxel, 122 pts received triweekly docetaxel+ cyclophosphamide (TC), and 14 pts received docetaxel+ carboplatin + trastuzumab (TCH). Prophylactic ABx was prescribed to 794 pts (93%). 331 pts (39%) used ABx for fever. 15 pts (1.7%) were hospitalized due to infection (5 FN, 4 surgical site infection, 2 pneumonia, 2 zoster, 1 perianal abscess, 1 appendicitis). Three of 61 pts (5%) who did not have prescribed prophylactic ABx were hospitalized due to infection whereas 12 of 794 (1.5%) with prophylactic ABx prescription were hospitalized from infection (p = 0.085). There was no therapy related death. Conclusions: Patient self-initiated ABx therapy for fever during NEO or ADJ breast cancer chemotherapy was safe and may reduce infection related hospital admission. Prospective validation is needed to generalize this strategy.