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Background: Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice. Methods: In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH + or CD24 − /CD44 + CSC by flow cytometry, with consistent reduction by immunohistochemistry. Results: Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH + and CD24 − /CD44 + measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC. Conclusions: Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC. Clinical trial registration: Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.

Objectives: To investigate treatment outcomes of different restorative techniques undertaken by dental therapists for primary molar carious lesions in a sample of children in New Zealand primary care. Methods: This was a randomized controlled trial with children aged 3 to 8 y in New Zealand’s Whanganui region. Children meeting inclusion criteria were randomly allocated to treatment with either the Hall technique (HT), in which a stainless-steel crown (SSC) is placed without any carious tissue removal or tooth preparation, or a non-Hall conventional restorative approach (NHT), including tooth preparation with selective carious tissue removal; this included SSC, amalgam, composite, or glass ionomer cement (GIC) restorations. Restorative outcomes after 12 and 24 mo were categorized as success, minor failure, or major failure. Results: Of the 295 eligible children, 149 and 146 were allocated to the HT and NHT groups, respectively, with a total of 570 carious primary molars treated by 13 dental therapists. The participant follow-up rates at 12 and 24 mo were 95% and 91%. SSCs were the most commonly used restoration in the NHT group (60%), followed by GIC (28%). SSCs were the most successful restorations regardless of whether they were placed with the HT or NHT, with success rates of 89% and 92% at 12 mo and 85% and 86% at 24 mo. In the NHT group, the treatment material was a predictor of minor failure at 12 and 24 mo, with significantly more failures with GICs. Conclusions: SSCs placed by dental therapists are a highly successful restoration for the primary dentition, regardless of whether they are placed with the HT or conventionally. The high failure rate of glass ionomer restorations means that they cannot be recommended for widespread use in New Zealand primary care (Australian New Zealand Clinical Trials Registry, ACTRN12614000844640). Knowledge Transfer Statement: The findings of this study can be used by policy makers and clinicians when deciding on which materials and which approach to use to maximize success and to minimize retreatment rates when providing restorative treatment for carious primary molars in children’s primary oral health care. Results also suggest that undertaking research in the primary care setting may enhance translation of new knowledge and techniques into clinicians’ hands.

Summary The use of oestrogens in the treatment of genuine stress incontinence was assessed by a double‐blind prospective trial in 36 postmenopausal women with genuine stress incontinence who received 3 months of cyclical treatment with either piperazine oestrone sulphate or a matching placebo. Patients were assessed subjectively and objectively before and after treatment by 7‐day bladder charts, urethral pressure profiles (UPP), the Urilos nappy test, vaginal cytology and hormone assays (plasma oestrogens and gonadotrophins). There was no statistical difference in the subjective response to treatment between the two groups. After 6 weeks of treatment there was a greater reduction in the number of pad changes/24 h in the oestrogen‐treated patients that approached statistical significance but, because of a marked response in the placebo group, this difference was not significant after 3 months of treatment. There were also no significant differences between the two groups with respect to the UPP or Urilos measurements but the vaginal cytology and hormone profiles were significantly affected by oestrogens. In view of the possible risks of oestrogen therapy its use in genuine stress incontinence is limited.

Purpose CXCR1, one of the receptors for CXCL8, has been identified as a druggable target on breast cancer cancer stem cells (CSC). Reparixin (R), an investigational oral inhibitor of CXCR1, was safely administered to metastatic breast cancer patients in combination with paclitaxel (P) and appeared to reduce CSC in a window-of-opportunity trial in operable breast cancer. The fRida trial (NCT02370238) evaluated the addition of R to weekly as first-line therapy for metastatic (m) TNBC. Subjects and Methods Subjects with untreated mTNBC were randomized 1:1 to R or placebo days 1–21 in combination with weekly P 80 mg/m2 on days 1, 8, 15 of 28-day cycles. The primary endpoint was PFS by central review. Results 123 subjects were randomized (62 to R + P and 61 to placebo + P). PFS was not different between the 2 groups (median 5.5 and 5.6 months for R + P and placebo + P, respectively; HR 1.13, p = 0.5996). ALDH+ and CD24−/CD44+ CSC centrally evaluated by IHC were found in 16 and 34 of the 54 subjects who provided a metastatic tissue biopsy at study entry. Serious adverse events (21.3 and 20% of subjects) and grade ≥ 3 adverse reactions (ADR) (9.1 and 6.3% of all ADRs) occurred at similar frequency in both groups. Conclusion fRida is the first randomized, double-blind clinical trial of a CSC-targeting agent in combination with chemotherapy in breast cancer. The primary endpoint of prolonged PFS was not met. Clinical Trial Registration/Date of Registration NCT01861054/February 24, 2015.