Antifungal Stewardship in Invasive Fungal Infections, a Systematic Review.

INTRODUCTION: Invasive fungal infections (IFI) are a group of life-threatening diseases associated with significant morbidity, mortality and high healthcare costs. Some modern management programs known as AFS (antifungal stewardship programs) have now been developed. The purpose of this systematic review is to evaluate the different declinations of antifungal stewardship programs (AFPs). METHODS: Articles were systematically reviewed using the PRISMA checklist 2020. EMBASE and MEDLINE/PubMED were searched using the term "antifungal stewardship" (2012-2022 data) on 2 January 2023. Eligible studies were those that described an AFS and included an intervention, performance evaluation and outcome measures. RESULTS: A total of 22/796 studies were included. Approximately two-thirds (16) were published between 2018 and 2022. 16 (72.7%) stated a minimal complete AFS team. 12 (54.5%) adopted a non-compulsory AFS approach, 6(27.3%) had an Educational AFS and 4(18.2%) a compulsory AFS. Cost analyses of 12 studies showed a decrease for 7 (31.8%) compared to an increase for 5 (22.7%). In terms of outcomes, 18 studies showed a lower (10;45.5%) or the same (8;36.4%) pre-post intervention mortality rate. CONCLUSION: AFS programs seem to be related to lower costs and better outcomes and should thus be implemented in tandem with antimicrobial stewardship programs.

Primary malignant phyllodes tumors of the breast: A retrospective analysis from a referral center.

BACKGROUND: The treatment for primary malignant phyllodes tumors of the breast (B-MPT) consists of wide local excision with negative margins (≥1 cm). However, because of their rarity, prognostic factors, type of surgery and adjuvant treatments are still a matter of debate. METHODS: We conducted a single-center retrospective study to describe outcomes and prognostic factors of patients with primary B-MPT, who underwent breast surgery from January 2000 to December 2021. The primary endpoint was the cumulative incidence of any recurrence. Secondary endpoints were the cumulative incidences of distant and local recurrences. RESULTS: 131 patients were included, of whom all received surgery, 5 adjuvant anthracycline-based chemotherapy and 15 radiation therapy. After a median follow-up of 6.4 years, the cumulative incidences at 5-years of any, local and distant recurrences were of 26% (95% Confidence Interval [CI], 4-34%), 16% (95%CI, 10-24%) and 10% (95%CI, 5.3-16%), respectively. Tumor size ≥ 5 cm was associated with higher distant recurrences (p = 0.05); instead, among small tumors (<5 cm), distant recurrences were higher in those with heterologous differentiation and/or multifocal disease (p = 0.06). Type of breast surgery (mastectomy vs. lumpectomy/excision) was not found to be significantly associated with distant (p = 0.32) or local (p = 0.17) recurrence, even after controlling local recurrence incidence for negative pathologic prognostic factors (p = 0.17). CONCLUSIONS: The natural history of B-MPT is burdened by local and distant recurrences. Pathologic prognostic factors (i.e., tumor size, heterologous differentiation and multifocal disease) more than the type of wide breast surgery (mastectomy vs. lumpectomy) seem to represent the most significant prognostic factor for recurrences.

Immune-Related Adverse Event Likelihood Score Identifies "Pure" IRAEs Strongly Associated With Outcome in a Phase I-II Trial Population.

BACKGROUND: Immune-related adverse events (IRAE) pose a significant diagnostic and therapeutic challenge in patients treated with immune-oncology (IO) drugs. IRAEs have been suggested to correlate with better outcome, but studies are conflicting. Estimating the true incidence of IRAEs is particularly difficult in the early phase I/II trial setting. A key issue is the lack of IRAE diagnostic criteria, necessary to discriminate "pure" IRAEs from other treatment-related adverse events not sustained by an autoimmune process. METHODS: In patients treated with immune-oncology (IO) drugs in phases I-II trials at our institute, we identified high confidence (HC) or low confidence (LC) IRAEs by clinical consensus. We empirically developed an IRAE likelihood score (ILS) based on commonly available clinical data. Correlation with outcome was explored by multivariate Cox analysis. To mitigate immortal time-bias, analyses were conducted (1) at 2-month landmark and (2) modeling IRAEs as time-dependent covariate. RESULTS: Among 202 IO-treated patients, 29.2% developed >1 treatment-related adverse events (TRAE). Based on ILS >5, we classified patients in no IRAE (n = 143), HC IRAE (n = 24), or LC IRAE (n = 35). hazard ratios (HR) for HC were significantly lower than LC patients (HR for PFS ranging 0.24-0.44, for OS 0.18-0.23, all P < .01). CONCLUSION: ILS provides a simple system to identify bona fide IRAEs, pruning for other treatment-related events likely due to different pathophysiology. Applying stringent criteria leads to lower and more reliable estimates of IRAE incidence and identifies events with significant impact on survival.

Evolution of biological features of invasive lobular breast cancer: Comparison between primary tumour and metastases.

BACKGROUND: Invasive lobular carcinoma (ILC) has unique clinical-biological features. Phenotypical differences between primary tumours (PTs) and metastases (M) have been described for invasive ductal carcinoma, but data on ILC are limited. METHODS: We retrospectively analysed patients with recurrent ILC from our institution from 2013 to 2020. We evaluated the discordance of the oestrogen receptor (ER), progesterone receptor (PgR) and HER2 between PT and M, to understand prognostic and therapeutic implications. RESULTS: Thirteen percent (n = 91) of all patients had ILC. We observed 15%, 44% and 5% of ER, PgR and HER2 status discordance between PT and M. ER/PgR discordance was related to receptor loss and HER2 mainly due to gain. PT presented a luminal-like phenotype (93%); 6% and 1% were triple-negative (TNBC) and HER2-positive. In M, there was an increase in TNBC (16%) and HER2-positive (5%). Metastasis-free survival and overall survival (OS) were different according to clinical phenotype, with poorer prognosis for HER2+ and TNBC (p < 0.001); OS after metastatic progression did not differ across phenotypes (p = 0.079). In luminal-like ILC (n = 85) at diagnosis, we found that OS after relapse was poorer in patients experiencing a phenotype switch to TNBC but improved in patients with HER2 gain (p = 0.0028). Poorer survival was reported in patients with a PgR and/or ER expression loss of ≥25%. There was HER2-low enrichment in M1 (from 37% to 58%): this change was not associated with OS (p > 0.05). CONCLUSION: Our results suggest that phenotype switch after metastatic progression may be associated with patients' outcomes. Tumour biopsy in recurrent ILC could drive treatment decision-making, with prognostic implications.

High-dose continuous-infusion ifosfamide in advanced thymic epithelial Tumors: A TYME network study.

BACKGROUND: We reported the efficacy and safety results of high-dose, continuous-infusion Ifosfamide,in patients with advanced thymoma (TM) and thymic carcinoma (TC). METHODS: This was a multicentric, prospective study in patients with advanced TM or TC, who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis or anti-PD(L)1 was allowed. Patients received Ifosfamide (1 g/m2/day) and sodium-2-mercaptoethanesulfonate (1 g/m2/day), as continuous infusion, via a portable pumps for 14 consecutive days. Treatment was administered every 4 weeks until progression or unacceptable toxicity, up to a maximum of 6 cycles. The primary endpoint was the overall response rate (ORR) assessed by RECIST1.1. Secondary endpoints included disease control rate (DCR), Progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Eighteen patients were enrolled from October 2020 to January 2022. Twelve patients had a TC, 5 a TM and 1 a mixed TM/TC. Sixty-one percent of patients (11/18) had stage IVB disease according to Masaoka-Koga, and 39% (7/18) had an ECOG-PS 2. The median number of previous lines of therapy was 2 (range:1-5), and 72% (13/18) and 61% (11/18) of patients were pretreated with an anti-angiogenesis drug and an anti-PD(L)1 drug respectively. The ORR and the disease control rate (DCR) were 28 % (95 %CI: 10 %-53 %) and 67 % (95 %CI: 41 %-86 %), respectively. The median follow-up for PFS was 17.3 months (95 %CI: 4.3-NA), and median PFS was 5.4 months (95 %CI: 2.9-6.4). The median duration of response and SD was respectively 19.6 months (95 %CI: 3.5-NA) and 6.0 months (95 % CI: 3.8-6.4). In patients with TC, the ORR and DCR were 15 % (95 % CI: 2 %-45 %) and 54 % (95 % CI: 25 %-81 %), respectively. In the subgroup of 5 patients with TM, 2 PR and 3 SD were observed. Most patients had only mild (grade 1-2) AEs, the most common being nausea and vomiting (39%; 7/18) and transaminases elevation (33%; 6/18). Twenty-two percent of patients (4/18) experienced an AEs of grade 3 and required ifosfamide dose reduction. No patients had severe AEs. CONCLUSION: High-dose continuous-infusion Ifosfamide can be considered as a valuable treatment option in patients with advanced thymic epithelial tumors.

SARS-CoV-2 vaccine in patients with thymic epithelial tumours with and without active or pre-existing autoimmune disorders: Brief report of a TYME network safety analysis.

BACKGROUND: International guidelines recommend severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine for patients with cancer. A substantial risk of developing vaccine-related autoimmune toxicities could be hypothesised for patients with thymic epithelial tumours (TETs) due to their high risk of autoimmune disorders (ADs). Moreover, a cross-reaction between SARS-CoV-2 spike protein antibodies and various tissue proteins has been shown, and antibodies against nucleoproteins showed overlaps in the autoimmune cross-reaction with antibodies to spike protein. Due to the rarity of TETs, no data addressing this hypothesis are available. METHODS: Patients with TETs who received SARS-CoV-2 vaccine, treated in 4 referral centres of the Italian Collaborative Group for ThYmic MalignanciEs (TYME) network between February 2021 and September 2021, were interviewed through a standardised 15-items questionnaire in order to describe the safety of SARS-CoV-2 vaccine in patients affected by TETs. RESULTS: Data from 245 doses of vaccine administered to 126 patients (41 = thymic carcinoma, 85 = thymoma; 38 with AD, of which 26 with active AD) were collected. Nine patients had a previous COVID-19-positive swab. No cases of AD reactivation or worsening of a pre-existing AD were seen in the study population. A new diagnosis of myasthenia gravis likely unrelated to the vaccine was made in two patients after the vaccination. Sixty-four patients (51%) experienced a total of 103 adverse events, all G1/G2, most commonly fatigue, new or worsening muscle pain and chills. None AE required patients' hospitalisation. CONCLUSIONS: SARS-CoV-2 mRNA vaccines appear to be safe in patients with TET, even in case of active or pre-existing AD.

Evolution of low HER2 expression between early and advanced-stage breast cancer.

BACKGROUND: Low human epidermal growth factor receptor 2 (HER2) expression is emerging as an actionable biomarker for the treatment of breast cancer (BC) with novel anti-HER2 drugs. However, the evolution of this biomarker during the course of disease is still poorly characterised, and controversial data exist on its prognostic implications. METHODS: We reviewed data of patients with HER2-negative BC according to the latest ASCO/CAP guidelines referred between January 2014 and December 2020. We grouped patients based on the immunohistochemistry (IHC) expression of HER2, HER2-zero (IHC 0) and HER2-low subgroup (IHC 1+ or 2+/ISH-negative) and evaluated the evolution of HER2 expression between the primary tumour and the first biopsy collected in the advanced setting. Disease-free survival, overall survival and progression-free survival were compared between patients with HER2-zero and HER2-low expression on the primary tumour. RESULTS: 232 patients were included in the analysis. Among the overall population, there was a relevant discordance in HER2 expression between the primary tumour and the matched biopsy (K = 0.33, 95%CI 0.21-0.44): 44% of the HER2-zero primary tumour showed an increased HER2 score on biopsy, and 22% of the HER2-low primary tumours turned into HER2-IHC 0. The findings in the sub-populations of hormone-receptors positive (K = 0.32, 95%CI 0.19-0.45) and triple-negative tumours (K = 0.18, 95%CI -0.09-0.46) were consistent with the primary analysis. No difference in survival outcomes was observed between HER2-low and HER2-zero primary tumours. CONCLUSIONS: HER2-low expression is dynamic in BC and may be enriched in the advanced-stage setting. No prognostic significance was demonstrated for HER2-low expression.

Loss of HER2 in breast cancer: biological mechanisms and technical pitfalls.

Loss of HER2 in previously HER2-positive breast tumors is not rare, occurring in up to 50% of breast cancers; however, clinical research and practice underestimate this issue. Many studies have reported the loss of HER2 after neoadjuvant therapy and at metastatic relapse and identified clinicopathological variables more frequently associated with this event. Nevertheless, the biological mechanisms underlying HER2 loss are still poorly understood. HER2 downregulation, intratumoral heterogeneity, clonal selection, and true subtype switch have been suggested as potential causes of HER2 loss, but translational studies specifically investigating the biology behind HER2 loss are virtually absent. On the other side, technical pitfalls may justify HER2 loss in some of these samples. The best treatment strategy for patients with HER2 loss is currently unknown. Considering the prevalence of this phenomenon and its apparent correlation with worse outcomes, we believe that correlative studies specifically addressing HER2 loss are warranted.

Safety of COVID-19 mRNA Vaccines in Patients with Cancer Enrolled in Early-Phase Clinical Trials.

Pivotal trials of COVID-19 vaccines did not include cancer patients, with questions remaining about their safety and efficacy in this population. Patients enrolled in early-phase clinical trials receive novel treatments with unknown efficacy and safety profiles. Studies on the safety of COVID-19 vaccines in these patients are urgently required. This is a retrospective, real-world, cohort study of patients receiving anticancer treatments and COVID-19 vaccines between 1 February and 25 June 2021 at the Division of New Drugs Development for Innovative Therapies of the European Institute of Oncology. One hundred thirteen patients were enrolled, 40 in early-phase clinical trials, and 20 under novel immunotherapy agents. Nearly three-quarters of the patients experienced at least one adverse event (AE) after the first dose (1D) (74.3%) and second dose (2D) (72.6%). Most of the AEs were local (67.3% 1D and 61.9% after 2D), while 31.8% (1D) and 38.1% (2D) of the patients had systemic AEs. No AEs above grade 2 were observed. Therefore, COVID-19 vaccines appear to be safe in patients enrolled in early-phase clinical trials, including patients receiving novel immunotherapy compounds. All cancer patients should be prioritized for COVID-19 vaccination, regardless of ongoing treatments or enrollment in early-phase trials.