To assess the prevalence of antibiotic-resistant gram-negative bacteria (R-GNB) among patients without recent hospitalization and to examine the influence of outpatient antibiotic exposure on the risk of acquiring R-GNB in this population.2-year retrospective cohort study.Regional Veterans Affairs healthcare system.Outpatients at 13 community-based clinics.We examined the rate of acquisition of R-GNB within 90 days following an outpatient visit from 2018 to 2019. We used clinical and administrative databases to determine and summarize prescriptions for systemic antibiotics, associated infectious diagnoses, and subsequent R-GNB acquisition among patients without recent hospitalizations. We also calculated the odds ratio of R-GNB acquisition following antibiotic exposure.During the 2-year study period, 7,215 patients had outpatient visits with microbiological cultures obtained within 90 days. Of these patients, 206 (2.9%) acquired an R-GNB. Among patients receiving antibiotics at the visit, 4.6% acquired a R-GNB compared to 2.7% among patients who did not receive antibiotics, yielding an unadjusted odds ratio of 1.75  for a R-GNB following an outpatient visit with versus without an antibiotic exposure. Regardless of R-GNB occurrence, >50% of antibiotic prescriptions were issued at visits without an infectious disease diagnosis or issued without documentation of an in-person or telehealth clinical encounter.Although the rate of R-GNBs was low (2.9%), the 1.75-fold increased odds of acquiring a R-GNB following an outpatient antibiotic highlights the importance of antimicrobial stewardship efforts in outpatient settings. Specific opportunities include reducing antibiotics prescribed without an infectious diagnosis or a clinical visit. From 2010 to 2011, ∼13% of outpatient visits resulted in an antibiotic prescription, of which an estimated 30% were likely inappropriate. Injudicious prescriptions of antibiotics in outpatient settings are associated with billion-dollar healthcare expenditures and contribute to the public health threat of antibiotic-resistant bacteria, including an array of gram-negative pathogens. Recent data indicate that an increasing proportion of hospitalizations for infections caused by antibiotic-resistant gram-negative bacteria (R-GNB), particularly extended-spectrum β-lactamase–producing Enterobacterales (ESBLs), are community associated. These reports indicate a pressing need to better understand risk factors associated with acquisition of R-GNB in community settings.Most patients receive their health care in outpatient settings, culminating in nearly 1 billion office visits annually. Whether improved antibiotic stewardship in the outpatient setting can achieve similar effects has not been firmly established, in part because the contribution of outpatient antibiotic exposure to the risk of acquiring R-GNB is not well characterized. Unlike allergic reactions or other adverse effects that come to clinical attention within hours to days of antibiotic administration, events related to acquisition of antibiotic-resistant bacteria can occur weeks after an antibiotic exposure and, in the case of colonization, may never come to clinical attention. Care received across separate healthcare systems, including hospitals and other outpatient settings can further obscure efforts to quantify the relationship between any given antibiotic exposure and the subsequent acquisition of antibiotic-resistant bacteria.Hospital settings have made strides in reducing the risk of acquisition, transmission, and infection due to R-GNB through the advancement of antibiotic stewardship among inpatients as well as other infection control and prevention measures.The Veterans Health Administration (VHA) uses a common electronic medical record to document and support comprehensive care for patients across the continuum of healthcare, which include hospitals, nursing homes, emergency departments, as well as clinics for primary, urgent, and specialty care. Furthermore, pharmacy and laboratory records, including antibiotic prescriptions and results of microbiological cultures, are also fully embedded within the same system. This integrated EMR facilitates assessment of a wide array of factors potentially associated with acquisition of R-GNB. To assess the risk factors related to outpatients acquiring R-GNB, we conducted a retrospective cohort study of veterans who received care at community-based outpatient clinics associated with a large Veterans Affairs medical center (VAMC). The objectives of our study were to assess the incidence of R-GNB among outpatients and to examine risk factors associated with acquisition of R-GNB. The exposure of interest was prescription of antibiotics in the outpatient setting. The Institutional Review Board of the VA Northeast Ohio Healthcare System approved the study protocol.We conducted a retrospective study of patients who received care at any of 13 free-standing community-based outpatient clinics associated with the VA Northeast Ohio Healthcare System (VA NEOHS) between January 1, 2018, and December 31, 2019. We used the VA Informatics and Computing Infrastructure (VINCI) to access the VHA Corporate Data Warehouse (CDW), which contains integrated databases from national clinical and administrative data sets, to identify the study population.In this study, we included patients who had at least 1 outpatient encounter with a community-based primary care provider during the study period with a microbiological culture collected 7–90 days following that encounter. The microbiological cultures were used to assess the outcome of interest, acquisition of R-GNB. The cultures could have been collected in the outpatient setting or within 72 hours of a hospital admission because pathogens identified within this window are considered community acquired. We considered patients who received an antibiotic prescription issued through a primary care provider in the absence of a documented clinical encounter  to have had a “no clinic” outpatient encounter.Pseudomonas aeruginosa, Escherichia coli, Citrobacter koseri, and Klebsiella, Enterobacter, Serratia, Proteus, and Providencia spp. Organisms with antimicrobial susceptibility results other than what is considered the wild type for the species were considered to represent a R-GNB. P. aeruginosa resistance was based on the following agents: fluoroquinolones, cefepime, piperacillin–tazobactam, and imipenem–cilastin. For the remaining GNB, we considered the following 4 phenotypes to indicate resistance: fluoroquinolone resistance; resistance to extended-spectrum cephalosporins ; resistance to β-lactam–β-lactamase inhibitor combinations , and resistance to carbapenems  and Tenth Revision (ICD-10) codes, and common infectious diseases diagnoses and comorbid conditions, from which the Charlson comorbidity index (CCI) was derived. We also assessed encounters in the VA NEOHS in the year prior to the index visit, including antibiotic exposures and the number of primary care visits, outpatient visits with a specialist, emergency room visits, and hospital admissions. Antibiotic prescriptions and infectious disease diagnoses were assessed for each patient’s index visit. Infectious disease diagnoses associated with visits were based on ICD-10 codes and classified into common infectious syndromes, as previously described.The following data were obtained from the CDW and were used to describe the patients at their index visit: age, sex, race, ethnicity and, using t tests or Wilcoxon rank-sum tests to compare continuous variables and χ2 tests to compare categorical variables. We also estimated the odds ratio of R-GNB acquisition for antibiotic exposure relative to no antibiotic exposure at the index visit. To adjust for additional risk factors, we used a multivariable logistic regression including patient characteristics, infectious diseases diagnoses, and recent healthcare utilization. All statistical analyses were performed using R version 4.0.1 software  and implementing functions from the epitab package.The primary outcome was the acquisition of any R-GNB in the 90 days following the index visit. We compared patients with and without acquisition of R-GNB, using independent sample P = .006), more likely to be female , and more likely to be of Black race . We did not detect significant differences in individual chronic conditions or in healthcare exposures prior to the index visit between those with and without R-GNBs detected.During the 2-year study period, 7,215 patients had qualifying visits at 13 outpatient clinic settings. Most patients were older adults (65.5 ± 14.2 years), male (90%), and White (84%). The most common comorbid condition was diabetes mellitus (35%), followed by chronic lung disease (25%). R-GNBs were detected in microbiological cultures of 206 (2.9%) of patients in the 7–90 days following their index visit (Table P = .004). Overall, the most commonly prescribed antibiotics were fluoroquinolones  or a rectal swab (27%) collected prior to a prostate biopsy. Table P = .010) . Even after adjusting for other factors that were significantly associated with R-GNB acquisition , the odds ratio for R-GNB acquisition following a primary care visit with an antibiotic prescription remained statistically significant  was ∼4:1. Third, this retrospective cohort study relied on administrative data, which have inherent limitations, for example, lack of certainty regarding whether or not patients took the antibiotics prescribed. Finally, our approach only accounted for new R-GNB acquisitions among patients via clinical cultures, which may have underestimated the number of individuals colonized with these organisms.Our study has several limitations. First, the work was performed at a single VA healthcare system, which may limit the generalizability of the results. VA healthcare users differ from the general US population in that they are predominantly older, White, non-Latino males with a higher burden of chronic medical conditions.Despite these limitations, the findings presented here shed new light on the risk factors associated with community-acquired R-GNB in the context of a comprehensive healthcare system. Although hospitalizations during the year prior contributed, antibiotics prescribed during the index outpatient visit also contributed. Curtailing unnecessary antibiotic exposure, which includes using narrow-spectrum agents as well as avoiding prescriptions altogether, is the most readily modifiable risk factor that clinicians can use to improve the health and safety of their patients. Our results also suggest 2 specific actions prescribers could take to help improve antibiotic stewardship in the outpatient setting. The first action is to associate diagnostic codes with the clinical encounter that led to an antibiotic prescription. The second action is to avoid prescribing these agents in the absence of a clinical encounter. This recommendation does not preclude the use of telehealth but does call for documentation of the evaluation and clinical decision-making process involved with the antibiotic prescribing event. Given that most healthcare visits take place in outpatient settings, improved efforts to reduce unnecessary antibiotic exposures in that sphere can yield a considerable reduction on the acquisition of R-GNB and potentially enhance the health of a large number of individuals.


Increasing numbers of women with HIV are experiencing menopause. We use data from a large, representative sample of women with HIV to describe the prevalence and clustering of menopausal symptoms amongst pre-, peri- and post-menopausal women using hierarchical agglomerative cluster analysis. Of the 709 women included, 21.6%, 44.9% and 33.6% were pre-, peri- and post-menopausal, respectively. Joint pain (66.4%) was the most commonly reported symptom, followed by hot flashes (63.0%), exhaustion (61.6%) and sleep problems (61.4%). All symptoms were reported more commonly by peri- and post-menopausal women compared to pre-menopausal women. Psychological symptoms and sleep problems clustered together at all menopausal stages. Somatic and urogenital symptom clusters emerged more distinctly at peri- and post-menopause. We recommend regular and proactive assessment of menopausal symptoms in midlife women with HIV, with an awareness of how particular patterns of symptoms may evolve over the menopausal transition. In 2019, over 30,000 women living with HIV attended for HIV care in the UK, one in three (36.2%) of whom were aged over 50 ); HIV-related  and non-HIV medical history  and menopause-related symptoms. The total number of medical conditions (not including HIV) reported by women (from the list above) was used as a proxy for multimorbidity.Paper questionnaires were completed by all participants and included questions relating to: participant demographic/social factors ; current lifestyle factors  + 10 criteria   to 4 (very severe). A composite score was calculated by summing the scores and categorized as: no/few (0–4), mild –8, moder2 tests or Kruskal-Wallis tests, as appropriate. Thereafter, we described the prevalence of each of the 11 menopausal symptoms by menopausal status.Demographic, lifestyle and clinical characteristics of participants were described and compared by menopausal symptom severity using χClustering was based on responses to the severity of menopausal symptoms and was explored using hierarchical agglomerative cluster analysis of a dissimilarity matrix using wards-linkage  . Using tA total of 868 women living with HIV participated in the PRIME study; of these, 709 (81.7%) completed the MRS questionnaire and therefore provided information on menopausal symptoms and were included in the analysis. Women who were included were more likely to be employed (68.9%) or in a relationship (57.1%) than those who were excluded . In contrast, included women were less likely to report ever being diagnosed with depression than those who were excluded (30.7% vs. 42.9%).≥ 5) and 2.7% reported any recreational drug use in the last six months. In total, 21.6%, 44.9% and 33.6% of women reported being in the pre-, peri- and post-menopausal stages, respectively.The median age of the 709 women included was 49 [interquartile range (IQR): 47–52] years, the majority were of black African ethnicity 71.7%), currently employed (68.9%), had completed at least high school education (88.4%) and in a relationship (57.1%)  was most commonly reported, followed by hot flashes (63.0%), exhaustion 61.6%) and sleep problems (61.4%). Vaginal dryness (34.0%) was the least reported symptom. All symptoms were reported more commonly by peri- and post-menopausal women than those who were pre-menopausal  women reported no/few symptoms, 117 (16.5%) reported mild symptoms, 182 (25.7%) moderate symptoms and the remaining 199 (28.1%) severe symptoms. Peri- and post-menopausal women were more likely to report more severe menopausal symptoms (as measured by the composite score) , the prevalence increased with menopausal stage, with peak prevalence in the post-menopausal group. However, for others  the prevalence increased during peri-menopause but was lower in those who were post-menopausal Fig. .Our cluster analysis Fig.  revealedWomen in the peri-menopausal stage reported a greater variety of symptoms. In this group, although psychological and sleep symptoms remained closely related, joint pain was now part of the second cluster. Within this second cluster, there were two clear subclusters: somatic symptoms  with bladder problems and sexual-related symptoms .Among post-menopausal women, symptoms formed three distinct clusters. Psychological symptoms and sleep problems, urogenital symptoms and heart discomfort ; and finally somatic symptoms (joint pain and hot flashes).severe menopausal symptoms, with severity peaking amongst those who were peri-menopausal. Our study suggests a high burden of potentially menopausal symptoms in women living with HIV aged 45–60 regardless of menopausal status, but with more pronounced symptoms among those who are peri- and post-menopausal. This high prevalence of menopausal symptoms has also been reported previously amongst women with HIV from studies based in the USA, Cambodia, Brazil, Nigeria and Thailand [To the best of our knowledge this is one of the first studies to explore specifically which menopausal symptoms cluster together and change across pre-, peri- and post-menopausal status among women living with HIV. In initial analyses, we found approximately one-in-three women living with HIV aged 45–60 experienced Thailand , 22–29.The MRS has been adapted for use in a range of geographical settings . HoweverIn recent years, there has been greater emphasis on understanding how menopausal symptoms cluster in the general population. Ascertaining different patterns of menopausal symptoms may facilitate understanding of underlying the mechanisms , 37. In These studies focus on grouping women. To our knowledge, ours is the first study to explore the clustering of menopausal symptoms (rather than women) reported by women ageing with HIV using hierarchical agglomerative clustering techniques. Here, we report more distinct symptom clustering in later menopausal stages, particularly of urogenital and somatic symptoms. In contrast, psychological symptoms clustered similarly with sleep problems in all three menopausal stages considered.Women living with HIV experience the additional challenge of distinguishing between symptoms of HIV, comorbidities, side effects of medication, and menopausal symptoms as they approach post-reproductive years. Although previous studies have highlighted how menopausal symptoms are under-recognized by women living with HIV and their healthcare providers , 44, theregardless of menopausal status. The impact of a HIV diagnosis on psychological and/or sleep problems [A notable finding is the persistent clustering of psychological symptoms with sleep problems through all menopausal stages amongst women with HIV. This highlights the enduring presence of mood and sleep-related symptoms in women living with HIV aged 45–60 problems –51, and problems –54 have To date, PRIME is the only study in the United Kingdom providing a large, representative sample of women, and using validated tools, to understand the menopause transition amongst those living with HIV. However, it is important to acknowledge some key limitations of our study: by using hierarchical agglomerative clustering we were able to visualise the correlation between menopausal symptoms that co-occur. There is debate on how to define specific clusters and therefore a restriction of this methodology is the inability to quantify the proportion of women who fall into each of these clusters. Further research to describe the prevalence of these clusters would therefore be valuable. Unfortunately, there were limited or no data available on some factors which are known to be associated with the presence of menopausal symptoms , and therefore could not be considered in this study. The MRS scale, although validated in the general population, has not yet been validated specifically in women living HIV. As previously discussed, the overlap between menopause- and HIV-related symptoms means that we cannot be certain that MRS is capturing menopausal rather than HIV-related symptoms. It is also important to note that we used self-reported menstrual pattern to determine menopausal status. Although this is a method widely used in the general population, there is a risk of misclassifying menopausal status. Additionally, women who reported to have ever been diagnosed with depression were less likely to complete the MRS questionnaire. Therefore, this study may be underestimating issues related to psychological symptoms. Finally, this cross-sectional analysis does not allow us to determine changes in symptoms in individuals over time, highlighting the important need for longitudinal data.In conclusion, drawing upon data from a large, representative sample of women living with HIV aged 45–60 in England, we have identified a high burden of menopausal symptoms across all domains. Although the MRS cannot differentiate between menopause and HIV-related symptoms, the increasing severity of symptoms in peri- and post-menopause as well as the emergence of distinct clusters of urogenital and somatic symptoms, point to the role of reproductive ageing.Of note, psychological and sleep symptoms are prevalent and cluster together throughout all three menopausal stages. We therefore recommend regular and proactive assessment of potentially menopausal symptoms in women living with HIV aged 45–60 , with an


Triple-negative breast cancer is a life-threatening disease, even when identified at early stages. Recent advances have allowed the improvement of life expectancy via a personalized approach with the addition of newer chemotherapies, immunotherapies, and targeted therapies, but at the cost of added side effects. It has become increasingly clear that not all patients need such aggressive treatment. Here, we provide an overview of emerging opportunities to use less toxic therapies in patients at lower risk of recurrence or with mutations that can be effectively targeted using novel approaches. We provide a comprehensive review of completed and ongoing clinical trials with information on how to best stratify these patients for treatments to obtain maximum benefit without unnecessary toxicities.Early-stage triple negative breast cancer (TNBC) has been traditionally treated with surgery, radiation, and chemotherapy. The current standard of care systemic treatment of early-stage II and III TNBC involves the use of anthracycline-cyclophosphamide and carboplatin-paclitaxel with pembrolizumab in the neoadjuvant setting followed by adjuvant pembrolizumab per KEYNOTE-522. It is increasingly clear that not all patients with early-stage TNBC need this intensive treatment, thus paving the way for exploring opportunities for regimen de-escalation in selected subgroups. For T1a tumors (≤5 mm), chemotherapy is not used, and for tumors 6–10 mm (T1b) in size with negative lymph nodes, retrospective studies have failed to show a significant benefit with chemotherapy. In low-risk patients, anthracycline-free chemotherapy may be as effective as conventional therapy, as shown in some studies where replacing anthracyclines with carboplatin has shown non-inferior results for pathological complete response (pCR), which may form the backbone of future combination therapies. Recent advances in our understanding of TNBC heterogeneity, mutations, and surrogate markers of response such as pCR have enabled the development of multiple treatment options in the (neo)adjuvant setting in order to de-escalate treatment. These de-escalation studies based on tumor mutational status, such as using Poly ADP-ribose polymerase inhibitors (PARPi) in patients with BRCA mutations, and new immunotherapies such as PD1 blockade, have shown a promising impact on pCR. In addition, the investigational use of (bio)markers, such as high levels of tumor-infiltrating lymphocytes (TILs), low levels of tumor-associated macrophages (TAMs), and complete remission on imaging, also look promising. In this review, we cover the current standard of care systemic treatment of early TNBC and review the opportunities for treatment de-escalation based on clinical risk factors, biomarkers, mutational status, and molecular subtype. Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Approximately 10–15% of breast cancers are triple-negative. These are typically more aggressive and associated with a higher rate of relapse. In addition, they have a higher predisposition to involve visceral organs like the lungs, liver, and brain, leading to a significantly shorter survival than other subtypes [In the present era of molecular subtyping, great progress has been made in finding effective targeted therapies for most subtypes of breast cancer. As TNBC lacks receptor expression, such as ER/PR, the vast array of endocrine therapy agents, such as selective estrogen receptor modulators (SERMS) and aromatase inhibitors, are out of treatment focus. Therefore, the standard systemic treatment option for early-stage TNBC was, until recently, limited to (neo)adjuvant chemotherapy followed by surgery and radiation . The appDe-escalation has been successfully accomplished in the surgical field for breast cancer. From Halsted’s radical mastectomy described over 100 years ago with axillary lymph node dissection (ALND), which were profoundly morbid procedures, to the current standard-of-care of breast conservation therapy (BCT) with lumpectomy and/or sentinel lymph node biopsy (SLNB) , the fieDe-escalating systemic therapy has been attempted in several ways—to administer less toxic/less aggressive regimens in a (neo)adjuvant setting, to stratify patients by identifying low clinical or molecular risk subgroups in early TNBC to avoid aggressive regimens, or to decrease the duration of therapies . In addiIn this review, we focus on the de-escalation of systemic therapy in early TNBC and review the current literature in this field as well as ongoing and completed trials.The choice of treatment in early TNBC largely depends on the primary tumor size, number of lesions, and lymph node (LN) involvement. Current national and international guidelines recommend neoadjuvant or adjuvant chemotherapy for early TNBC with tumor size ≥ 1 cm and/or with LN involvement, especially with ≥1 ipsilateral LN with metastases > 2 mm. But when it comes to stage 1 TNBC, especially pT1N0M0, there are no clear data since most of these patients were excluded from definitive clinical trials .There is discordance among major guidelines: National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology guidelines (ASCO), European Society for Medical Oncology (ESMO), St. Gallen International Expert Consensus, Dutch guidelines regarding the best clinical practice for early TNBC, which is described in The mainstay for early-stage TNBC with tumor greater than 2 cm in size (T2 or more) (prior to KEYNOTE-522 data) was neoadjuvant chemotherapy (NACT) followed by definitive surgery with or without adjuvant treatment . NACT was also used for T1 tumors if upfront surgery would provide an inferior cosmetic outcome and downstaging was essential. NACT also provides additional benefit in patients with locally advanced breast cancer who are not candidates for breast-conserving surgery (BCS) and wish for breast conservation, or those who are unlikely to have a good cosmetic outcome with upfront BCS .The most common chemotherapy regimen in the United States for use in a (neo) adjuvant setting for cT1N0 is anthracycline and cyclophosphamide (AC) given in dose-dense schedule followed by weekly paclitaxel or dose-dense paclitaxel for a total of 4–5 months . The ratAlthough AC followed by taxane is superior for high-risk patients, alternative therapies are considered for patients with early TNBC who cannot receive anthracyclines, for example, those with a history of cardiac disease or extensive cardiac comorbidities and those who are unwilling to accept the risks of anthracycline-based therapies. For such patients, taxane-based treatment is offered; the common regimen used is docetaxel and cyclophosphamide (TC) . CMF is p = 0.0009) [For patients who cannot complete the full treatment course of NACT, the remainder of the planned course of chemo is usually completed in the adjuvant setting after careful consideration of adjustments for toxicities. For patients who have completed the standard NACT, and if they have attained complete pathologic response (pCR), then further adjuvant chemotherapy is not required. However, if the patients did not achieve complete pCR after NACT, they have a higher risk of disease recurrence. For those patients, adjuvant capecitabine was recommended after the promising results of the CREATE-X trial. It showed that patients with HER2 negative breast cancer with residual disease after NACT who received adjuvant capecitabine had higher rates of five-year disease-free survival (DFS) and overall survival (OS) when compared to those who received no further treatment. Subgroup analysis suggested that the improvement in DFS was mainly due to the improvement in outcomes among patients with early TNBC with 5-year DFS of 69.8% with capecitabine vs. 56.1% in the control group  and 5-year OS of 78.8% vs. 70.3% in the capecitabine vs. the control group  . Recentl 0.0009) . This hiIn July 2021, pembrolizumab was approved by the US Food and Drug Administration (FDA) for combined use with chemotherapy in high-risk TNBC in the neoadjuvant and adjuvant setting based on the KEYNOTE-522 trial. In this phase III trial, patients with previously untreated stage II or III TNBC were randomly assigned to receive NACT with or without pembrolizumab every three weeks during the NACT and continued for another nine cycles after surgery, regardless of the pathologic response to the neoadjuvant treatment. The trial used a regimen of four cycles of paclitaxel and carboplatin plus pembrolizumab followed by AC plus pembrolizumab as neoadjuvant treatment and then adjuvant pembrolizumab for a total of nine cycles. The trial showed that the pCR rates were higher among those who received pembrolizumab plus chemotherapy than chemotherapy alone (64.8% vs.51.2%). This improvement in pCR rates was seen in both programmed cell death (PD-L1) positive and negative stage II or III TNBC. The percentage of patients alive at 18 months without disease progression/local or distant recurrence in the pembrolizumab + chemotherapy group was 91.3% and, in the chemotherapy alone group, was 85.3%  [N = 333). Patients were randomized to receive nab-paclitaxel followed by doxorubicin and cyclophosphamide, with or without atezolizumab, followed by surgery. After surgery, 11 doses of atezolizumab were administered every 3 weeks in the immunotherapy group. pCR was significantly improved in 57.6% of patients in the atezolizumab plus chemotherapy group, and in approximately 41% of the patients in the placebo plus chemotherapy group. In the PD-L1-positive population, pCR was observed in 68.8% of the patients in the atezolizumab group vs. 49.3% in the placebo group [Similar findings were observed in the IMPassion031 clinical trial. IMPassion031 is a phase III randomized clinical trial for patients with TNBC with tumor size > 2 cm  and OS were 91.4% and 95.1% in the durvalumab group, compared to 79.5% and 83.1% in the placebo group, respectively, which was statistically significant . As discussed, with the approval of checkpoint inhibitors along with chemotherapy in the neoadjuvant setting, the treatment for early-stage TNBC has become very aggressive, associated with several irAEs. They key question now is whether all patients need this aggressive treatment, or can the treatment be de-escalated for patients selected based on tissue biomarkers or tumor/genetic mutations.In this section, we discuss the various subtypes of TNBC, which form the basis of current and future efforts of de-escalation. TNBC has immense heterogeneity , which may account for the varied response to systemic therapy. A pivotal study by Lehman et al. analyzed 587 TNBC patients and subdivided TNBCs according to gene expression clustering into six subtypes : basal-lThe evolution of our understanding of this heterogeneity at the molecular level along with the development of novel drugs has helped facilitate more personalized anticancer treatment for patients with TNBC, which has led to increased treatment options and a more complicated decision process. The BL1 subtype has abnormal expression of cell-cycle regulating and DNA repair-related genes with sensitivity to PARPi and cisplatin . There iWith earlier diagnosis of breast cancer and technological advancement, we have been able to profoundly de-escalate morbid surgical procedures. In addition to de-escalating surgery, further de-escalation could be attained by de-escalating systemic treatment and/or duration in the neoadjuvant or adjuvant settings or using less toxic treatments, such as targeted therapies.Neoadjuvant or adjuvant chemotherapy decreases the risk of recurrence and improves the overall survival, but the absolute benefit in patients with lower recurrence rates would be small, with a potential for long term side effects. Therefore, often patients end up receiving much more systemic treatment than required with fewer benefits and more toxicities. An approach towards personalized treatment considering age, comorbidities, and clinical and biomarker status is needed for addressing the needs of a specific patient.Neoadjuvant or adjuvant treatment regimens have not shown absolute benefit in low risk TNBC, which includes small node-negative tumors. Even though we have guidelines for the treatment of breast cancer, there are disparities in the systemic therapy recommendations for early TNBC between these guidelines. TNBC with a tumor size less than 1 cm and without lymph node involvement have a good prognosis, and the omission of chemotherapy can be considered in this group. There are no randomized clinical trials that compare adjuvant chemotherapy vs. no adjuvant chemotherapy in TNBC patients with low risk of recurrence, which includes node-negative small tumors . But there were multiple retrospective and observational studies that support these findings. According to a prospective cohort study within the NCCN database, women with pT1a and pT1b TNBC have excellent prognosis without chemotherapy. In pT1aN0 TNBC patients, the 5-year distant relapse-free survival (DRFS) was 93%  in the untreated cohort of 74 patients when compared to 100% DRFS in the adjuvant chemotherapy cohort of 25 patients. In the pT1bN0 TNBC patients, the 5-year DRFS was 90%  in the cohort of 94 untreated patients and 96%  in the cohort of 170 patients who received adjuvant chemotherapy . The 5-yp = 0.014), but not in T1b patients with adjuvant chemotherapy  [p < 0.001). In patients with pT1a TNBC, the 5-year RFS rates with and without chemotherapy were 92.3% vs. 100%  and in pT1b patients, the 5-year RFS with and without chemotherapy were 91.4% vs. 90%  [In a retrospective study of 354 patients with T1N0 TNBC by Ren et al., a significant recurrence-free survival (RFS) benefit was observed in T1c patients  .p value = 0.02. The OS and association between adjuvant chemotherapy was also similar to BCSS . The association between adjuvant chemotherapy and OS was significant (p < 0.001) [Another large retrospective study of 4366 patients with early TNBC by Steenbruggen et al. from the Netherlands Cancer Registry showed that adjuvant chemotherapy is associated with better breast cancer specific survival (BCSS) and overall survival (OS) in pT1c tumors but may not outweigh harms in patients with pT1a and pT1b tumors. In the study, BCSS differed with respect to the pathologic tumor sizes (pT1a adjusted HR (aHR) = 4.28, 95% CI, 1.12–16.44; pT1b aHR = 1.12, 95% CI, 0.51–2.49; pT1c aHR = 0.60, 95% CI, 0.43–0.82). The interaction between tumor size and chemotherapy was statistically significant, with In another study by de Nonneville et al., the subgroup analysis reported that there was no statistically significant better disease-free and metastasis-free survival in patients with T1a and T1bN0 TNBC who received adjuvant chemotherapy . A recenThe anthracycline and taxane-based chemotherapy backbone is the SOC for neoadjuvant chemotherapy along with pembrolizumab in high-risk early TNBC. However, in stage I tumors (tumor size < 2 cm), anthracycline and taxane-based chemotherapy is still considered the standard of care. We tend to use a dose-dense AC-T regimen in most cases, even if the patient has low-risk disease due to the fear of high recurrence rates. Anthracyclines have shown long-term cardiac side effects, including congestive heart failure (CHF) and cardiomyopathy . Prior sN = 400) [The Anthracyclines in Early Breast Cancer (ABC) trial was one among many trials designed to compare AC-T to TC (taxane-cyclophosphamide) chemotherapy in the adjuvant setting in patients with early-stage HER2 negative breast cancer. TC was found to be slightly inferior to the ACT regimen with regards to the overall four-year invasive disease-free survival , but anthracycline-based therapy did not improve outcomes in lower risk groups. In the subset analysis of early TNBC, the absolute benefit was more pronounced in the high-risk group that includes lymph node involvement . AccordiN = 400) . These tPathologic lymph node staging can be used to guide adjuvant treatment in early TNBC. A retrospective study of 381 patients with early TNBC compared the DFS and OS in patients who received adjuvant taxane-based three-drug chemotherapy (AC-T) and two-drug chemotherapy (TC). They reported that taxane-based triplet adjuvant chemotherapy is superior to doublet in patients with one to nine positive LNs but not in patients with node-negative early TNBC . This fuCarboplatin-based regimens are a new focus in the development of de-escalation strategies. Many trials incorporating carboplatin with other chemotherapy including taxane-based regimens, PARPi, and immunotherapy are extensively being studied in the neoadjuvant settings, as discussed below.N = 154), patients with Stage I–III TNBC received carboplatin with nab-paclitaxel for four three-week cycles. Pathologic complete response was noted to be 45.9%, which is comparable to the more toxic anthracycline-containing regimens and may be an early predictor of who could be de-escalated, although longer follow up is required to assess the survival data [Carboplatin-based regimens have been investigated as a de-escalating strategy in neoadjuvant treatment of early TNBC. Trials have demonstrated a promising pCR using an anthracycline-free regimen of carboplatin + taxane. In the WSG-ADAPT-TN trial , EFS, and OS in Stage I–III TNBC patients, with carboplatin + docetaxel (CbD) administered for six three-week cycles compared with carboplatin + standard anthracycline triplet, with overall less toxicity . This pCThe NeoTRIP study (NCT002620280) used a carboplatin-based backbone. This was a phase III randomized controlled trial in which 280 patients with early-stage TNBC were randomized to carboplatin + nab-paclitaxel, with or without immunotherapy, with atezolizumab given every 3 weeks for 8 cycles. Fifty-six percent of patients were PD-L1 positive. The pCR rate was not significantly different between the two study arms (43.5% vs. 40.8%). For patients with PDL1 >5%, pCR was 87.0% vs. 72.0%, PDL1 between 1–5% pCR was 56.2% vs. 44.0%, and PDL1 <1% pCR was 35.1% vs. 41.1% in the treatment arm vs. control arm, respectively. The EFS and OS rates from this study are awaited [These trials indicate that a promising pCR can be achieved using an anthracycline-free regimen with carboplatin and taxanes. Combined with ICIs, we may be able to de-escalate the more toxic chemotherapeutic regimens in the future in a subset of patients. These limited results support further research using anthracycline-free regimens combined with ICIs. The results of the phase II NeoPACT trial, which combines platinum + taxane with pembrolizumab every 3 weeks for 6 cycles, is much awaited (NCT03639948). In the GeparNUEVO trial, durvalumab was given only as neoadjuvant along with the standard anthracycline and taxane based chemotherapy; it was not continued in the adjuvant setting for those who attained pCR, yet the study showed significant improvement in the OS and distant DFS (DDFS) . HoweverWith the fear of the aggressiveness of TNBC, most of the current treatments aim to escalate the available treatment regimens. The above data show that there is a huge potential for de-escalating treatment options in early TNBC, both in the adjuvant and in the neoadjuvant settings without compromising the effectiveness of the treatments. Systemic chemotherapy can be omitted in very low-risk early TNBC patients, and de-escalation can also be executed by carefully selecting patients who need systemic treatment through individual risk assessment. Carboplatin-based treatment regimens can be considered as a new potential anthracycline-sparing de-escalation strategy.We summarize the data regarding recent advances in novel biomarkers, knowledge of mutations for targeted therapies, and the use of early imaging modalities to guide personalized decision making. The use of these strategies may potentially pave the way for de-escalating aggressive regimens.Several studies have shown that stromal tumor infiltrating lymphocytes (sTILs) play an important role in prognosis and response to chemotherapy in patients with TNBC . In 2010p < 0.05). It was also noted that higher expression of two cell phenotypes, PD-L1 positive, IDO-positive antigen presenting cells (APCs) and CD56-positive neuroendocrine (NE) epithelial cell, was associated with a higher pCR when treated with atezolizumab. In patients with PD-L1 positive, IDO-positive APCs who received atezolizumab, pCR was 64.6% vs. 24.6% for those with high and low expression, respectively (p < 0.001) [Similarly, single cell spatial analysis from the NeoTRIPaPDL1 trial (NCT02620280) found that GATA3 and CD20 in the tumor microenvironment, HLA-DR on the epithelial cells, and Ki67 both on the tumor microenvironment and the epithelial cells, were significant for their predictive ability for atezolizumab benefit. Expression of these biomarkers above the median was linked to a pCR rate increase of 10% or more (< 0.001) .Immune checkpoint inhibitors targeting PD-1 or PD-L1 have become the standard of care in many solid tumor types. In TNBC, PD-L1 expression has been estimated to be 40–65% on the immune cells . NineteeMulti-gene signature has been studied as a comprehensive tool that can capture the immunogenicity of TNBC. The GeparSixto trial was analyzed for mRNA markers and showed that an immune signature composed of seven immune-activating genes  and five immunosuppressive genes  was validated as a marker for immune reaction. The increased mRNA expression level of these genes, including immunosuppressive genes, was associated with pCR .p < 0.0001). However, the sensitivity of detection of ctDNA was low in the study as they could identify the ctDNA in the plasma sample of only 4 out of 33 patients who had somatic mutations [N = 5) of patients remained ctDNA positive after completion of the NACT. In this study, all patients who attained pCR were ctDNA negative. An important finding was that patients who did not achieve pCR but were ctDNA negative had improved survival, comparable to those who attained pCR  [Circulating tumor DNA (ctDNA) is the fragmented DNA released into the bloodstream from the necrosis of the tumor tissue. The detection of ctDNA has been progressively used in studies to demonstrate its predictive role in identifying minimal residual disease after neoadjuvant chemotherapy in early TNBC and thereby identifying the high-risk patients for recurrence. Riva et al., in a prospective study, demonstrated that ctDNA levels are associated with tumor proliferation rate and can be used to monitor tumor progression during NACT. They also found that those who had a slow decrease of ctDNA level during NACT had shorter survival . In the utations . In a st15–13.5) . With moTherapies targeting the tumor microenvironment (TME) are also currently under investigation. Tumor-associated macrophages (TAMs) are known to promote the progression and metastasis of TNBC by releasing inhibitory cytokines, reducing the functions of TILs, promoting regulatory T-cells (Tregs), and modulating the expression of PD-1/PD-L1 on the TME . CabiralAmong the patients with TNBC, approximately 10–30% have germline BRCA (gBRCA) mutations. Approximately 80% of breast cancers that occur in patients with gBRCA1 mutations are triple-negative with a basal-like profile. BRCA 1 and BRCA 2 are tumor suppressor genes that belong to the homologous recombination (HR) repair pathway that repairs double-strand DNA breaks. Platinum-based regimens are a focus of interest in several trials in patients with BRCA mutations. Cisplatin every three weeks for 4 cycles was evaluated in a randomized phase II INFORM clinical trial of neoadjuvant cisplatin vs. AC in gBRCA carriers (70% TNBC patients). The pCR rate was 18% with cisplatin and 26% with AC . Poly ADThere are several ongoing studies to evaluate the role of PARPi as a neoadjuvant treatment in early-stage BRCA mutated breast cancer. MD Anderson reported a study of neoadjuvant talazoparib in patients with gBRCA mutations (NCT02282345). TNBC patients consisted of 15 out of the 20 patients enrolled, and 53% achieved pCR after six months of single agent talazoparib. In this trial, patients subsequently received adjuvant standard chemotherapy based on physician’s discretion . These rN = 151, 95% CI −9.0 to 16.5), which was not statistically significant. In patients with low PTEN, pCR was 16% vs. 13% in placebo, and in patients with altered PTEN, pCR was 18% vs. 12% in placebo, which was not statistically significant. The addition of ipatasertib did not significantly increase pCR rates. The overall pCR rates in this study are much less than typically expected in early TNBC, likely due to the short duration of treatment of 12 weeks and utilization of only paclitaxel as chemotherapy. In addition, there was no significant difference in pCR in PTEN mutated patients who received ipatasertib compared with those who did not have the mutation. This is likely due to the significant heterogeneity among TNBC. Though this was a negative trial, these results support further evaluation of this pathway in combination with chemotherapy [Mutations in PIK3CA, AKT, PTEN, or mTOR can activate the Phosphatidylinositol-3-kinase (PI3K) pathway, leading to cell growth. Deregulation of any PI3K pathway component has been seen in up to 50% of patients and are seen amongst all molecular subtypes. Ipatasertib, a highly selective pan-AKT small molecule inhibitor, was studied initially in the phase II LOTUS trial in the metastatic setting and showed a significant PFS improvement in patients with alteration in the PIK3CA/AKT/PTEN pathway . Subsequotherapy .EGFR overexpression can be used as a target in TNBC as 60% of triple negative tumors have EGFR expression. EGFR expression has been recognized as a poor prognostic factor in TNBC . EGFR inVascular Endothelial Growth Factor (VEGF) inhibitors impair the neovasculature of the tumor, thus impairing tumor growth. Bevacizumab, an anti-angiogenic monoclonal antibody against VEGFR, has been evaluated in multiple studies in TNBC, especially in the metastatic setting. Most of the studies tend to escalate the treatment by the addition of bevacizumab to standard NACT regimens . The addAlmost 10–40% of TNBC expresses androgen receptors (AR); this makes AR a potential target for treatment. Androgen Receptor inhibitors abiraterone and enzalutamide have shown clinical benefit in AR positive (>/=10% by Immunohistochemistry) metastatic TNBC ,74. ThisTrials have attempted to tailor therapy by identifying subsets of chemo-sensitive and chemo-resistant breast cancer. In the ARTEMIS trial, response was assessed in patients with early TNBC after four cycles of NACT with doxorubicin + cyclophosphamide (AC). Those who had more than 70% volumetric reduction, i.e., chemo-sensitive disease, continued with standard of care taxane-based therapy with or without platinum. Patients who had chemo-insensitive disease were given the option to be randomized to either of four Phase II clinical trials based on transcriptomic and genomic profiling results (NCT02276443). These different groups consist of a combination of targeted agents such as androgen-receptor blocker, PDL1-inhibitor, EGFR monoclonal antibody, or VEGF inhibitor with chemotherapy . Results from this trial and other similar studies may help identify agents that might be effective in TNBC, especially in those with chemo-resistant disease. Thereby, this sets up a foundation to enable us to de-escalate management in selected subgroups of patients with early TNBC and possibly even replace traditional chemotherapy with targeted agents. Knowledge from this trial, guided by imaging response along with the other completed trials exploring checkpoint inhibitors and targeted agents, should be used to design novel clinical trials for treatment de-escalation.Many biomarkers are currently being studied to help guide decision making regarding systemic therapy in early TNBC by their predictive and/or prognostic value. The presence of sTILs and the absence of ctDNA after NACT is associated with better outcomes and may help identify cohorts of patients who may be spared adjuvant treatment. PD-L1 is another biomarker but is not very sensitive and/or specific and thus we continue to use PD-1/PD-L1 therapies in both those who are positive and negative. Targeted treatments such as single agent PARPi in BRCA mutated patients in the neoadjuvant setting have shown results comparable to conventional chemotherapy and may be a chemotherapy-sparing option in suitable patients. Other biomarkers, such as immune gene signatures and other targeted treatments, including inhibitors of TAMs, PI3K/AKT/mTOR, EGFR, VEGF, and AR, are currently being studied in this patient population, and we await results that may further enable us to offer personalized options, resulting in de-escalation of treatment.Triple-negative breast cancer is a heterogenous, aggressive breast cancer that has high recurrence rates. Anthracycline and taxane-based chemotherapy with neoadjuvant pembrolizumab has become the standard of care for patients with TNBC with T1c, nodal stage N1-2, or tumor stage T2-4, nodal stage N0-2. The literature shows that pT1b tumors could potentially be spared chemotherapy, and pT1c tumors could derive significant benefit from taxane-based chemotherapy, thus sparing the use of anthracyclines. Treatments targeting mutations and making use of tissue biomarkers or early response on imaging in TNBC are appealing strategies to tailor treatment to a particular tumor, and hence, de-escalate treatment. Better risk stratifications based on molecular profiling of the tumor and the use of predictive biomarkers may minimize the need for systemic therapies. Current trials ongoing in the field of targeted therapies in TNBC include the use of PI3K/AKT/mTOR inhibitors, EGFR targeted agents, androgen receptor inhibitors, and antiangiogenic agents that may lead to the discovery of novel avenues to de-escalate treatment. Future prospective trials should also evaluate incorporating ctDNA after NACT into decision making for adjuvant therapy. As we understand more of the biology and heterogeneity of TNBC, we also expect further targets to be elucidated and therapies to be tested, which will further enable de-escalation. We are currently investigating the impact of short duration immunomodulating therapies to improve the tumor microenvironment , given along with standard chemotherapy in the neoadjuvant setting in early TNBC in a phase 1 clinical trial (NCT04081389), which may help us avoid giving immune therapies for an extended duration, especially after surgery in the adjuvant setting ,76,77. IThere is an urgent need to develop personalized treatments tailored to patients based on their clinical characteristics, comorbidities, and biomarker status, which would provide maximum benefit while curtailing side effects.


Glioblastoma (GBM) remains the most frequent and lethal primary brain tumor in adults, despite advancements in surgical resection techniques and adjuvant chemo- and radiotherapy. The most frequent recurrence pattern (75-90%) occurs in the form of continuous growth from the border of the surgical cavity, thus emphasizing the need for locoregional tumor control. Fluorescence-guided surgical resection using 5-ALA has been widely implemented in surgical protocols for such tumors. Recent literature also highlights the applicability of 5-ALA-mediated photodynamic therapy to obtain locoregional tumor control further. This study aims to identify if 5-ALA mediated photodynamic therapeutic effect after gross total glioblastoma resection has inadvertently occurred due to the exposition of protoporphyrin IX charged peripheral tumoral cells to operative room light sources.Of 146 patients who were intervened from glioblastoma between 2015 and 2020, 33 were included in the present study. Strict gross total resection  had been accomplished, and adjuvant chemoradiotherapy protocol was administered. Two comparison groups were created regarding the location of the recurrence . The cutoff point was determined to be 1 centimeter because of the visible light penetrance to the normal brain tissue., p-value=0,046). Results obtained in univariate analysis were corroborated posteriorly in multivariate analysis , p=0,017).In univariate analysis, both groups only differed regarding 5-ALA administration, which was significantly related to a minor relative risk of presenting the recurrence within the first centimeter from the surgical cavity In the present study, a probable inadvertent 5-ALA photodynamic therapeutical effect has been detected in vivo. This finding widely opens the door for further research on this promising theragnostic tool. Glioblastoma (GBM)  remains in vitro. It has shown promising results in selective tumoral cell death, thus sparing normal brain parenchyma  when 5-ALA has been administrated in conjunction with visible light exposure to the surgical field during the surgery.in vivo, thus encouraging further investigation in humans.The present study aims to determine if locoregional photodynamic therapy has been inadvertently produced The central nervous system (CNS) tumor database of the Hospital Clínic de Barcelona, Spain, was queried to identify all patients treated for glioblastoma between 2015 and 2020. A total of 146 patients were initially identified. Patients finally included in the present study were those whose gross total resection of the contrast-enhancing lesion was achieved, resulting in 33 individuals. Supratotal resection (contrast-enhancing lesion plus 100% of hyperintense area in T2-weighted FLAIR) was not obtained. Variables included in the study were demographic characteristics, initial symptoms, initial functional status, tumor location, preoperative tumor volumetry, tumor superficiality classification , leptomeThe study’s principal objective was to evaluate if there are differences regarding the location of the recurrence concerning the surgical field in patients whose 5-ALA was administrated versus patients whose 5-ALA was not administrated and if an unnoticed photodynamic therapeutical effect could explain these differences after controlling for possible confounding variables.®, Feldkirchen, Germany). T1-weighted gadolinium-enhanced and T2-weighted FLAIR sequences were used to define preoperative enhancing tumor volume and infiltrative volume outside the enhanced areas, respectively. Residual tumor volume was measured in postoperative MRI performed up to 48 hours from the surgery and co-registered with the preoperative dataset. Only patients presenting gross total resection of the contrast-enhancing lesion were included. A variable amount of infiltrating non-contrast enhancing tumor (hyperintense in T2-weighted FLAIR sequence) may have been resected. Still, in any of the included participants, FLAIR area resection reached 100%, thus not considered supratotal resection. For these patients, the follow-up MRI when recurrence after first-line treatment was detected was posteriorly evaluated. Radiologic tumor recurrence was defined according to the response assessment in neuro-oncology (RANO-HGG) 2010 criteria . Patients were then categorized into the two groups previously described in the study population. An example is provided in The initial and residual tumors were measured onto volumetric MRI acquired through a 1,5 T scanner (Siemens) within the first 48 hours from the surgery, through a semiautomatic region of interest (ROI) analysis with Iplan cranial v.3.0 software  and p-value. Multivariate analysis was calculated using logistic regression, and differences were presented with the p-value and RR.Descriptive analysis was realized for both comparison groups. Continuous variables were described using median and range, and categoric variables were defined using absolute and relative frequencies. Comparative analysis was realized after that. For univariate analysis, differences between groups for continuous variables were evaluated using the Mann-Whitney U test and presented with the p-value. Differences between groups for categoric variables were assessed using the Chi-square test and given Thirty-three patients from 146 initially identified to be treated for glioblastoma were finally included in the statistical analysis. Gross total resection  was achieved, and complete adjuvant therapy (chemo- and radiotherapy) was administered, thus homogenizing the sample.The median age was 63,5 and 63 years for groups A and B, respectively, with male predominance in group A  and slight female predominance in group B . Initial symptoms were more frequent behavioral changes in group A and seizures in group B, without significant differences in initial functional status  of 95 and 90 for each group, respectively). Tumors were more frequently located in the temporal lobe  in group A and frontal  and parietal  lobes in group B, principally cortical positioned in both groups, without significant differences. Median preoperative volumetry was slightly different between groups: 25,43cc for group A and 30,64cc for group B, without reaching statistical significance. In most cases, neither leptomeningeal dissemination nor ependymal disease was detected. For group B, intraoperative MRI and neuromonitoring were more frequently needed as intraoperative adjuvants without reaching statistical significance. No significant differences were related to the tumor’s molecular characteristics . All patients received adjuvant chemo- and radiotherapy without significant differences in the treatment protocol. Regarding chemotherapy, temozolomide was the first choice in both groups . Regarding radiotherapy, hyperfractioned protocol was also the first option in both groups . After treatment of the tumor, no significant differences were found between groups regarding hospital length of stay, complications, and functional status. Group’s characteristics are summarized in When evaluating the relation between 5-ALA administration and the location of the recurrence, significant differences were found in the univariate analysis. 5-ALA administration was significantly related to a minor relative risk of presenting the recurrence within the first centimeter from the surgical cavity  Table 2.The relation initially found between 5-ALA administration and minor relative risk to present the recurrence within the first centimeter from the surgical field was posteriorly evaluated in conjunction with other possible confounding variables in the multivariate analysis. Items included in the statistical analysis, different from 5-ALA administration, were superficiality classification, radiotherapy protocol administered, chemotherapy protocol administered, ependymal disease, leptomeningeal dissemination, and light exposure time. Again, only the relation between 5-ALA administration and negligible risk for the location of the recurrence up to the first centimeter from the surgical cavity reached statistical significance ; p=0,017) Table 4.Because the most frequent recurrence pattern in patients affected by HGG occurs in the form of continuous growth from the border of the surgical cavity, 5-ALA metabolites (protoporphyrin IX) can be activated at the visible light wavelength (380-700 nm), and its penetrance in cerebral tissue may reach up to 1 cm depth, the apparent 5-ALA photodynamic therapeutical effect may have been inadvertently produced on operated patients affected from glioblastoma when 5-ALA has been administered preoperatively, and tumoral intracellular protoporphyrin IX intraoperatively activated through operative room light sources. The present study aimed to analyze if this hypothesized 5-ALA photodynamic effect has been inadvertently produced in a cohort of patients affected by glioblastoma.in vivo 5-ALA photodynamic therapeutical effect in patients affected by GBM IDH wild-type. The presented results may have been facilitated, at least partially, due to the superficial location  of the tumors in most of the individuals included in the study. This location eases light exposure in the hole surgical cavity and promotes photodynamic reactions in patients in the 5-ALA group.Considering the previously exposed statements, the authors hypothesized that the recurrence of patients with 5-ALA that was administrated preoperatively would be less probable located within the first centimeter from the surgical cavity. To accurately evaluate this hypothesis, confusion control is of utmost importance. Restrictive inclusion criteria, group comparativeness evaluation, and multivariate analysis were used. Our results have shown that recurrences were significantly less frequent within the first centimeter from the surgical cavity in the 5-ALA group, thus increasing the possibility of having detected an inadvertent In addition to the principal analysis, differences regarding the location of the recurrence were evaluated concerning light exposure times only for the subgroup of patients whose 5-ALA was administered preoperatively. Paradoxically to what we would expect, the median light exposure time was minor in patients whose 5-ALA was administered and recurrence located beyond 1 cm from the surgical field, without reaching statistical significance. It is described in the literature that the dose of light delivered is essential to obtain maximum photobleaching of photosensitizer, thus resulting in optimal effectivity of the therapy. Advanced photobleaching is the fluence rate that causes more than 95% photobleaching of photosensitizer and is related to better results. For 5-ALA photodynamic therapy, advanced photobleaching is achieved at 4 mm from the surface of a light diffuser emitting power of 200 mW/cm for 1 hour –34. In tIn the literature, few studies have reported their preliminary experience with 5-ALA photodynamic therapy in patients affected by high-grade gliomas. Regarding its efficacy as a surgical adjuvant, one group combined fluorescence-guided surgery (FGS) and postoperative photodynamic therapy; 5-ALA photodynamic therapy was performed with an implanted catheter in patients with primary GBM on the day of FGS. Photodynamic therapy was then realized at 24-hour intervals for five sessions, and the results were compared with the control group . Delayed mean tumor progression (8.6 vs. 4.8 months) and increased mean survival (52.8 vs. 24.6 weeks) were observed in the group that received both FGS and photodynamic therapy when compared with the control group . Anotherde novo lesions and 14 months for recurrent ones, respectively, and overall survival was 19 months and eight months for the same groups, respectively  surrounding the surgical cavity.A possible inadvertent 5-ALA photodynamic therapeutical effect may have been detected in patients affected by GBM after gross total resection. These results, in conjunction with favorable data published in the literature and previously presented in the present study, encourage further investigation of this promising therapy as a surgical add-on after primary GBM resection or recurrence or as a sole rescue treatment in non-resectable or recurrent cases of this primary brain cancer.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study involving human participants was reviewed and Photodynamic therapy in glioblastoma approved by Barcelona’s Clínic hospital ethical board. According to legislation, participant informed consent was not necessary to be obtained because of the study’s retrospective nature, anonymized recorded clinical data, and the impossibility of identifying participants directly or through identifiers in study results.AF and JG-S designed and led the present study. AF and AM developed the theory and performed the computations. AF and AM collected the clinical and economic data. AF, AM, AD, TT, PR, LP, DD, AS, and JG-S performed the analytical methods and interpreted them. AF drafted the manuscript. JG-S, AD, PR, AS, and JE critically revised the manuscript. JE gave institutional, material, and logistic support. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


More than 2 years into the COVID-19 pandemic, SARS-CoV-2 still impacts children’s health and the management of pediatric hospitals. However, it is unclear which hygiene and infection control measures are effective and useful for pediatric hospitals. Here, we report infection control measures implemented at a tertiary care children’s hospital. We evaluated frequency of SARS-CoV-2 detection in admitted patients, in-hospital transmission and infection related findings. Furthermore, we aimed to capture perspectives of health-care workers and caregivers on effectiveness and burden of infection control measures. Knowledge gained can inform management of the ongoing and future pandemics.We designed a retrospective observational study and survey at a pediatric tertiary care referral center. Local infection control measures and respective guidelines regarding COVID-19 were reviewed. Three thousand seven hundred sixteen children under 18 years were tested for SARS-CoV-2 at the University Children’s Hospital Tuebingen and data on SARS-CoV-2 transmission were retrieved from internal records. Two surveys were conducted among 219 staff members and 229 caregivers.Local infection control measures comprised the formation of a task force, triage, protective hygiene measures and an adaptable SARS-CoV-2 test strategy. Between January 2020 and March 2021, SARS-CoV-2 infection was detected in 37 children presenting to our hospital, 21 of these were admitted. One hospital-acquired infection occurred. About 90% of health-care staff perceived the majority of measures as effective and appropriate. However, visitor restrictions and cancellation of scheduled treatments were perceived least effective by hospital staff and as a particular burden for patients and their caregivers. Visits at the pediatric emergency department significantly decreased during the pandemic. We drafted a pandemic action plan by ranking infection control measures according to local transmission stages.SARS-CoV-2 infection control measures implemented in our tertiary care children’s hospital were evaluated by health-care workers as mostly effective and appropriate. In particular, good communication, transparency of decision-making as well as universal masking and infection screening were assessed as successful measures of infection control management. Visitor restrictions and cancellation of routine appointments, in contrast, were perceived as a particular burden on patient care and should be avoided. An established pandemic action plan may guide children’s hospitals in the future.The online version contains supplementary material available at 10.1186/s12887-022-03299-x. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of coronavirus disease 2019 (COVID-19), challenging health-care systems worldwide. Children in general develop milder disease in comparison to adults . This poThis report will summarize infection control measures undertaken in a tertiary care children’s hospital during the first year of the pandemic, when a vaccine against SARS-CoV-2 was not yet widely available. The aim is to evaluate frequency of SARS-CoV-2 detection in admitted patients, in-hospital transmission and infection related findings with local infection control measures in place. Additionally, perspectives of health-care workers and caregivers on effectiveness and burden of infection control measures will be captured. Knowledge gained will result in the development of a pandemic action plan that may guide children’s hospitals in managing the ongoing SARS-CoV-2 and future pandemics.The University Children’s Hospital Tuebingen is a large tertiary care facility in southern Germany with a total of 170 beds. Risk groups treated at our hospital include those receiving hematopoietic stem cell transplantation, solid organ transplant, cardiac surgery, as well as children with rheumatologic diseases, cystic fibrosis and those requiring home ventilatory support. The hospital comprises a pediatric intensive care unit (PICU) and a neonatal intensive care unit (NICU). It has an emergency department (ED) as well as several outpatient clinics for high-risk patients and serves as regional primary and secondary care referral center.http://www.limesurvey.org, Additional file Data were collected from January 2020 until March 2021. Local guidelines developed during the course of the pandemic were obtained from the documentation of the local Corona task force, chronologically ordered by their release date and systematically reviewed. Data on SARS-CoV-2 tests conducted for pediatric patients during that time were provided by the local virology department  and SPSS  were used for data collection and analysis.p > 0.05)  and a visual inspection of their histograms, normal Q-Q plots and box plots showed that the number of ED visits was not normally distributed for both periods, with a skewness of 0.71  and a kurtosis of 0.51 (SE 0.66) for the period before and a skewness of 1.53 (SE 0.33) and a kurtosis of 1.3 (SE 0.66) for the period after [p-value < 0.05 was considered statistically significant.The weekly number of unscheduled ED visits in children under 18 years in the year 2020 were compared with the number of visits during the corresponding weeks in the 5-year period from 2015 to 2019. A Shapiro-Wilk’s test  and hospital management. The task force created the first local guidelines by the end of January 2020. During the following months a range of local infection control measures were implemented. A subordinate pediatric task force team adapted the respective measures to the needs of the pediatric setting. Infection control measures are described in Table From February 2020, capacities for local tests on SARS-CoV-2 were built up by our virology department ; 37  had a positive result. Twenty one children were admitted to the hospital with a positive SARS-CoV-2 PCR test. Seventeen were diagnosed on admission and two prior to admission, all of these were immediately isolated. Details about demography, clinical course, treatment and outcome of the admitted patients have been published elsewhere [The online survey was completed by 219 staff members, including 112 (51%) nurses, 39 (18%) physicians and 61 (28%) participants of other professions . At that time point, vaccination against SARS-CoV-2 had yet been received by 89 (41%) of the participants, 99 (45%) were willing to get themselves vaccinated, 21 (10%) were unwilling to get vaccinated. 179 (82%) felt well or rather well informed about the current status of the pandemic and infection control measures at the children’s hospital, 33 (15%) felt partly informed, and 6 (3%) rather badly informed; 163 (74%) felt well or rather well protected from COVID-19 by the infection control measures at the children’s hospital, 51 (23%) felt partly protected and 5 (2%) rather not protected. The perception of the effectiveness and burden of different infection control measures at the children’s hospital are presented in Fig. Sixty-four (29%) participants estimated that the maintenance of care for chronically ill children had highly or rather suffered during the pandemic, 55 (25%) found it had partly suffered and 57 (26%) found it had not or rather not suffered. Complications caused by the infection control measures (e.g. delay of an urgently needed treatment) had been experienced frequently by 6 (3%) and sporadically by 69 (32%) participants, while 110 (50%) had not experienced any complications.Two hundred twenty-nine caregivers of patients who visited the emergency department or the outpatient clinic were offered participation in the additional questionnaire. Five persons refused to participate and 19 questionnaires were completed incorrectly. Two hundred five questionnaires were eligible for evaluation. 17.2% of all participants indicated that they considered the risk of SARS-CoV-2 infection during their visit at the children’s hospital to be very high or high, whereas 21.5 and 26.8% reported the risk as very high or high at their local pediatrician and in everyday life situations, respectively. 29.7 and 13.4% of the caregivers, respectively, stated that already arranged outpatient or inpatient appointments had to be cancelled or postponed.During the local spread of the pandemic, the number of ED visits and hospital admissions at our children’s hospital markedly decreased compared to previous years. While the number of ED visits remained low during the course of 2020 admission numbers rose again to the level of previous years by June 2020 , cohorting patients, limiting exposure through visitor restrictions and cancellation of non-urgent appointments, use of telemedicine options, home-office options for non-clinical work, and timely and accurate information sharing and communication , 12. HowSuccessful pandemic management in pediatric hospitals means acceptance of infection prevention and control measures by frontline workers. Acceptance has been attributed to the formation of dynamic incident management teams and timely and accurate communication , 14. We Although not perfectly reliable, rapid antigen-tests have been recommended as a useful screening instrument for SARS-CoV-2 due to the rapid turnaround time, the simplicity and the relatively low costs . The broDuring the study period, a single case of in-hospital SARS-CoV-2 transmission was detected in our children’s hospital. It is impossible to compare the effectiveness of single infection control measures on nosocomial transmission. However, the introduction of a strict hygiene bundle in a similar setting as ours was associated with a significant reduction of nosocomial SARS-CoV-2 transmission . MoreoveFrontline health-care workers are at increased risk of contracting SARS-CoV-2 while assessing and managing patients not only on COVID-19 wards, but also in routine care or from infected colleagues . Clear iScreening of patients, caregivers and staff was considered an effective infection control measure by the vast majority of our survey participants. Of note, health-care workers experienced their own tests - if at all - less burdening compared to screening tests in caregivers or patients. Possibly, this result reflects the caring nature of health-care personnel in the pediatric setting. Despite the perceived burden, especially for pediatric patients, universal and repeated screening strategies seem to be an accepted infection control measure among hospital staff.Strategies to limit exposure to SARS-CoV-2 within children’s hospitals include restriction of visitors and cancelling or postponing non-urgent appointments in order to prevent crowding, re-allocate consultation and ward rooms, and to preserve medical staff for care of potential COVID-19 patients , 27. AlmVisitor restrictions in pediatric health-care should be kept ready as an escalation step for scenarios of high local virus transmission and adapted to the respective risk groups. Obligatory masking combined with rapid antigen tests at hospital entry are probably sufficient to prevent most hospital-acquired infections, maintain quality of routine health care for children at a high level, and allow sick children to receive visitors.Cancellation of routine treatments and operations in pediatrics freed human resources in our hospital, allowed the implementation of a pediatric COVID-19/respiratory infections ward and aimed to have sufficient staff available to care for children with COVID-19. However, instead of the initially expected increase, emergency outpatient visits significantly decreased in our children’s hospital compared to previous years, as already noticed by others . COVID-1In an emerging and dynamically evolving respiratory pandemic, preparedness, decisive containment action, overarching communication structures and the ability to adapt rapidly to changing challenges are critical to the management of tertiary care children’s hospitals. In summary, we show that proactive, transparent decision-making is of particular importance for hospital staff alongside effective SARS-CoV-2 transmission mitigation measures . However, visitor restrictions and cancellation of routine appointments were assessed as a particular burden with negative consequences for patient care and should be avoided.We recommend that children’s hospitals, especially those with a relevant proportion of susceptible high-risk patients, have a pandemic action plan in place to avoid nosocomial transmission while maintaining adequate care for non-pandemic related sick children. We drafted a plan according to our experience and ranked single infection control measures according to the stage of local transmission. This pandemic action plan may guide children’s hospitals in the future.Additional file 1. SARS-CoV-2 diagnostic test procedures.Additional file 2. Questionnaire of the online survey among health-care staff and extract of the questionnaire for caregivers (English translation).Additional file 3. Results of survey on the perception of infection control measures by hospital staff, stratified by profession.


More than half of patients with colorectal cancer (CRC) present with metastatic disease or develop recurrent disease on first-line and second-line options. Treatment beyond the second line remains an area of unmet need for patients with progressive or recurrent disease.We retrospectively reviewed data of adult (>18 years old) patients with mCRC who received regorafenib + 5FU combination therapy at Houston Methodist Hospital with outcomes of interest including response rate, discontinuation due to side effects, and overall survival.Seven patients received regorafenib + 5FU combination therapy for mCRC after receiving at least two other lines of therapy (including at least one fluorouracil-based therapy). Four patients (57%) achieved disease control in 7-12 weeks after therapy initiation while three patients developed recurrent disease. In patients who achieved disease control, no new adverse events were reported among patients with this combination.Regorafenib and Fluorouracil combination could be considered an option beyond the second line for patients with treatment-refractory metastatic colorectal cancer. Further studies, including a prospective trial, are needed to investigate the efficacy and safety of regorafenib plus 5FU therapy compared to other limited available therapies. In the United States, about 20-40% of patients diagnosed with colorectal cancer go on to eventually develop metastasis , and aboRegorafenib  is a tyrosine kinase inhibitor that can inhibit multiple kinases essential for neoplasm growth , 12. ThiIn this study, we report our center’s experience with using a combination therapy of regorafenib and intravenous 5-FU (in addition to leucovorin) for the treatment of patients with refractory mCRC.This is a case series of mCRC patients  who were treated with off–label regorafenib in combination with 5-FU in the third-line setting and beyond. We included adult patients (age > 18 years old) who were treated at Houston Methodist Cancer Center between November 2017 and July 2021.The medical records of all eligible patients were reviewed and evaluated retrospectively for various disease-specific and treatment-specific variables, including demographic information , performance status, diagnosis , metastatic sites, mutational data , and prior therapies . This study was approved by the institutional review board of the Houston Methodist Research Institute (IRB ID: PRO00031738).Clinical outcomes of interest included the best response to combination therapy of 5-FU and regorafenib, progression-free survival (PFS), overall survival (OS), and adverse effects. PFS was defined as the time from combination therapy initiation to clinically proven disease progression whereas OS was defined as the time from treatment initiation to death from any cause. We also captured doses of 5-FU and regorafenib at the time of therapy initiation and time of last follow-up or discontinuation. Additionally, notes were reviewed for any documented adverse events, and they were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.Seven patients received regorafenib + 5-FU combination therapy for metastatic CRC. Five patients were males and two were females. Ethnically, five of the patients were of Caucasian descent and two were of Asian descent. Patient age ranged from 33-59 years old on diagnosis and from 45-65 years old on therapy initiation. Five patients had left-sided colon cancer, one had right-sided colon cancer and one had rectal cancer. The majority  were stage IV on diagnosis and all had a history of resection and were treated with at least three prior lines of therapy. All patients had a mutated KRAS or NRAS except patient # 7 and none had microsatellite instability.The most common metastasis site was the liver  followed by the lung (in 5 patients). Metastasis was confirmed by imaging with CT/PET scans. All patients received fluorouracil, oxaliplatin, and irinotecan-based chemotherapy and an anti-VEGF therapy prior to combination therapy. Additionally, two patients received regorafenib as a monotherapy prior to the use of combination therapy. Other commonly used therapies such as monotherapy or combination therapy included trifluridine/tipiracil, ramucirumab, and capecitabine. Details of therapies used prior to regorafenib + 5-FU combination therapy are listed in Disease status was assessed by imaging with CT/PET scans at the start of treatment and routinely during follow-up appointments. Disease control was achieved in four (57.1%) patients. One patient had a partial response (patient # 2) and the other three patients had stable disease on therapy afterward. The best response was achieved 7-12 weeks after the initiation of therapy and two patients (# 1 and # 2) continued to experience disease control for more than 8 months after therapy initiation. Conversely, three patients progressed on therapy 6-8 weeks after initiation and were transitioned to a different therapy. At the time of the last follow-up, which ranged from 2 to 20 months, five out of the seven patients were alive. From a safety perspective, only two out of seven patients (patients # 5 & 7) were transitioned to a different therapy due to reported tolerance. Clinical outcomes of all seven patients are summarized in 2 bolus and 5-FU continuous infusion of 2400 mg/m2 over 46 hours starting on day 1 of therapy; however, three patients required a 20% dose reduction in 5-FU for tolerability.All patients were started on a regorafenib dose of 40-80 mg which was escalated in one to two weeks to a goal dose of 120 mg and up to 160 mg as tolerated see Table 1.Patient # 5 was initially started on 80 mg of regorafenib which was subsequently increased to 120 mg, however, the patient developed grade 3 hand-foot syndrome (HFS) which was switched to another treatment plan. Patient # 7 was started on regorafenib initially as monotherapy before the addition of 5-FU. This patient developed regorafenib-related pneumonitis necessitating home oxygen and discontinuation of combination therapy. The patient improved on a steroid course with taper.Other patients reported mild adverse effects that led to dose adjustments. For instance, patient #1 developed grade 2 HFS which necessitated regorafenib dose adjustments from the goal dose of 120 mg to 80 mg daily. Further adjustments included holding regorafenib on the days of 5-FU infusion and a 20% dose reduction in 5-FU dosage. Patient #3 had a history of hypertension and had recorded hypertensive urgency with a systolic blood pressure >180 mmHg. The patient’s blood pressure medications were adjusted, and he had no recurrence of hypertensive urgency. The other patient tolerated the medication at the goal dose of 120 mg. Treatment dose and adverse effects for all seven patients are summarized in The metastatic spread of colorectal cancer is generally associated with a poor prognosis, and chemotherapy is currently the mainstay of management for this disease , 4. At tNevertheless, although this personalized approach to treat refractory mCRC can be used in a certain subset of patients, currently the only FDA-approved standardized treatment strategy for mCRC beyond the second line is the use of regorafenib or the combined agent trifluridine/tipiracil . RegorafRegorafenib is a multi-kinase inhibitor that targets tumor angiogenesis, oncogenesis, and factors that lead to maintenance of the tumor microenvironment , 15. FDAIn this brief case series, we present seven clinical cases of heavily pre-treated patients with treatment-refractory mCRC who received combination therapy of regorafenib and 5-FU, including one patient who was maintained on therapy for 10 months. Four patients responded to the combination treatment: three patients achieved stable disease, one had a partial response, and one had a mixed response.in vitro studies with multiple human colorectal cancer cell lines and determined that there were synergistic effects seen when Regorafenib was combined with 5-FU. Lin et al.  as a result of regorafenib-related adverse events; most commonly diarrhea and hand-foot skin reactions, with four patients dropping out due to treatment-related adverse effects . It shouOur data illustrate the potential clinical benefits of regorafenib plus 5-FU combination beyond the second or third lines of treatment for mCRC patients. Consequently, the efficacy and safety of regorafenib combination therapy with 5-FU as a potential option beyond the second line should be prospectively evaluated and compared to other salvage therapies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institutional review board statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Houston Methodist Hospital. The patients/participants provided their written informed consent to participate in this study.EH: writing , visualization, IM: conceptualization, writing , writing (review & editing), data curation, visualization, AE: writing (review & editing), final draft (review & editing), data curation, visualization, and critical review, CM: writing (review & editing), data curation, VA: writing (review & editing), data curation, GU: writing (review & editing), data curation, MA: conceptualization, project administration, supervision, validation, visualization. All authors contributed to the article and approved the submitted version.