Multidisciplinary clinical guidelines in proactive monitoring, early diagnosis, and effective management of trastuzumab deruxtecan (T-DXd)-induced interstitial lung disease (ILD) in breast cancer patients.

Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate (ADC), has altered the treatment landscape in breast cancer (BC), irrespective of the HR-receptor status. The use of the agent is increasing, despite the finding that exposure to T-DXd increases the risk of interstitial lung disease (ILD), particularly in BC patients. Although T-DXd-related ILD can be potentially severe and life-threatening, most low-grade cases can be treated safely using a multidisciplinary approach comprising early and accurate diagnosis, effective management, close monitoring, and the prompt administration of steroids. Additionally, increasing patients' education on ILD symptoms ensures close attention and enables prompt reporting, enhancing patient outcomes. It is recommended that predictive biomarkers are assessed in patients with risk factors for developing ILD. Currently, diagnostic criteria comprise newly identified pulmonary opacities, the relation of symptom onset to medication initiation, and the exclusion of other causes of ILD. The general condition of patients is weakened during the management of ILD (BC progression and corticosteroid treatment). Consequently, BC chemotherapy might be attenuated. This highlights the importance of preventing (high-grade) ILD, especially since its use is expanded. Identifying high-risk patients, diagnosing, and customizing treatment is, however, challenging and additional information on patient selection is often not fully clarified. In this paper, we provide updated multidisciplinary clinical guidance for patient selection, proactive monitoring, early diagnosis, and effectively management of T-DXd-induced ILD in HER2-positive BC patients. We describe the risk factors for developing ILD, patients' characteristics of ILD, and the histopathological and radiographic characteristics of ILD, including real-world clinical practice reports. These recommendations provide a structured step-by-step approach for managing each suspected BC-related ILD grade.

Twelve ESMO Congress 2022 breakthroughs: practicing oncologists' perceptions and potential application on presented data.

BACKGROUND: During the European Society for Medical Oncology (ESMO) Congress 2022, outcome data of a great number of clinical trials were presented. For the attending medical oncologist, it is important to structure these data in a way that facilitates a trade-off between treatment burden and benefit. MATERIALS AND METHODS: To illustrate this, we carried out a narrative non-systematic review of 12 selected oral presentations with potential impact on future daily practice, focusing on trial methodology, possible study flaws, reported clinical benefit and implementability. RESULTS: The selected presentations encompassed 10 phase III trials, 1 randomized phase II trial and 1 phase II trial. In 7 out of 12 trials, quality of life and/or patient-reported outcomes had been evaluated. None of the trials, which reported progression-free survival (PFS) data, provided information, which could exclude informative censoring bias. In none of the trials reporting overall survival (OS) data, potential flaws due to undesirable crossover and imbalance between study groups regarding post-progression treatments were addressed. For the 11 reviewed randomized trials, the ESMO-Magnitude of Clinical Benefit Scale (MCBS) grade achieved with the new intervention was calculated based on the presented data. The MCBS grade varied from 1 to 5. CONCLUSIONS: Our review confirms the high-quality standard of current cancer research and the clinical relevance of the research questions answered. However, during presentation of PFS and/or OS data, factors known to affect PFS and OS analysis should be structurally addressed. In order to keep cancer care affordable and sustainable, it could be considered to include an ESMO-MCBS threshold in the drug appraisal process of regulatory authorities.

Alternative academic approaches for testing homologous recombination deficiency in ovarian cancer in the MITO16A/MaNGO-OV2 trial.

BACKGROUND: The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. PATIENTS AND METHODS: Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. RESULTS: The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. CONCLUSIONS: Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.

Prognostic significance of germline BRCA mutations in patients with HER2-POSITIVE breast cancer.

BACKGROUND: HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. MATERIALS AND METHODS: Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. RESULTS: One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). CONCLUSIONS: Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic.

11 ESMO 2021 breakthroughs: practicing oncologist's perceptions on data presentation.

BACKGROUND: The European Society for Medical Oncology (ESMO) 2021 conference provided a high number of randomized phase III trial reports, many of which were claimed to be practice changing. Given the short time available for conference presentations, results and conclusions tend to have greatest priority with less time remaining for study background and study methodology. PURPOSE: On behalf of the ESMO Practicing Oncologists Working Group, 11 potentially practice-changing reports were selected and screened for three main questions: (i) Did the investigators provide sufficient details with regard to Patients and Methods to make the results comprehensible? (ii) Were there any reasons to consider bias? (iii) To which extent did the results presented translate to clinical benefit? RESULTS: In 2 out of 11 trials, the study design presented differed considerably from the study design described at ClinicalTrials.gov. Allocation concealment was not carried out in 6 out of 11 trials. In none of the trials reporting progression-free survival was informative censoring considered an issue. In none of the trials reporting overall survival was desirable crossover considered an issue. Defined trial outcome measures depicted at ClinicalTrials.gov, which could boost or weaken the ESMO-Magnitude of Clinical Benefit Scale score, were often lacking in the presentation. Study success was claimed in a heterogeneous manner, which was often not clearly linked to overall clinical benefit. CONCLUSION: ESMO conference presentations can inform the scientific community and catalyze further research but cannot replace the full papers in peer-reviewed journals, which are needed to estimate the thoroughness of the results, the overall impact on clinical benefit and the consequences for future treatment guidelines.

Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).

BACKGROUND: The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) characterized by high cell proliferation, aggressive behavior, and chemo-resistance. PATIENTS AND METHODS: This is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. RESULTS: From July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS. CONCLUSIONS: The combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity. EUDRACT NUMBER: 2012-003505-10.

Homologous Recombination Repair Deficiency and the Immune Response in Breast Cancer: A Literature Review.

The success of cancer immunotherapy with immune checkpoint blockade (ICB) has demonstrated the importance of targeting a preexisting immune response in a broad spectrum of tumors. This is particularly novel and relevant for less immunogenic tumors, such as breast cancer (BC), where the efficacy of ICB was more evident in the triple-negative (TNBC) subtype, in earlier stages, and in association with chemotherapy. Tumors harboring homologous recombination DNA repair (HRR) deficiency (HRD) are supposed to have a higher number of mutations, hence a higher tumor mutational burden, which could potentially make them more sensitive to immunotherapy. However, the mechanisms involved in ICB sensitivity and patient selection are still yet to be defined in BC: whether the innate system could play a role and how the adaptive immunity could be linked with HRR pathways are the two key points of debate that we will discuss in this article. The aim of this review was to close the loop between what was found in clinical trial results so far, go back to laboratory theory and preclinical results and point out what needs to be clarified from now on.

Prognostic impact of interval breast cancer detection in women with pT1a N0M0 breast cancer with HER2-positive status: Results from a multicentre population-based cancer registry study.

BACKGROUND: Although human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis, patients (pts) with pT1a N0M0 breast cancers (BCs) have an excellent outcome across all subtypes. Interval cancers (ICs) have poorer survival than screen-detected (SD) tumours, and an association has been reported between ICs and HER2 overexpression. We aimed to determine, in a general population of pT1a N0M0 BCs with known screening status, whether HER2-positive ICs have a poorer outcome than HER2-positive SD cancers. METHODS: We evaluated all incident pT1a N0M0 BCs (n = 874) collected in the Emilia-Romagna region (Italy) from 2003 to 2009 and diagnosed in women aged 50-69. Pts unexposed to screening, with unknown HER2 status and/or treated with adjuvant trastuzumab were excluded from analysis. RESULTS: Sixty-one percent of the BCs were SD, whereas 19% were ICs. BCs with high histologic grade, hormone receptor-negative or HER2-positive status (odds ratio=1.7; 95% confidence interval [CI]: 1.1-2.7) were more likely ICs. Median follow-up was 115 months. The 10-year invasive disease-free survival (iDFS) for HER2-positive ICs was lower than that for HER2-positive SD cancers: 75.0% (95% CI: 55.5%-94.5%) versus 93.8% (95% CI: 86.5%-100%). An interaction between ICs and HER2-positive status was found for poorer iDFS after adjusting for prognostic variables (HR = 5.3; 95% CI: 1.6-16.7). CONCLUSIONS: IC detection may identify pts with HER2-positive pT1a N0M0 tumours in whom the rate of recurrence justifies consideration for conventional, anti-HER2, adjuvant treatment.

Methodologies for anti-HLA antibody screening in patients awaiting kidney transplant: a comparative study.

OBJECTIVES: The relevance of anti-HLA antibodies in patients awaiting kidney transplants is well recognized. During the past 40 years, kidney transplant candidates have been tested for these antibodies, and the choice of the detection assay has become essential. Recently, the pioneer method, the complement-dependent cytotoxicity, has been integrated but has not been replaced by more-sensitive solid-phase assays, such as the enzyme-linked immunosorbent assay and the bead-based technology (ie, flow cytometry: FlowPRA, and FlowAnalyzer: Luminex). MATERIALS AND METHODS: We compared the sensitivity and antibody specificity of these 4 techniques for detecting panel-reactive antibodies in a population of 101 consecutive patients awaiting a renal transplant (which had already resulted positive in a prescreening analysis). RESULTS: Sera positive for class I and class II antibodies were 62 and 90 as assessed by the complement-dependent cytotoxicity method, 76 and 58 by using enzyme-linked immunosorbent assay, 83 and 65 with Flow-panel-reactive antibodies, and 90 and 79 by Luminex. Luminex gave more positive scores than the others for class I HLA antibodies, whereas complement-dependent cytotoxicity revealed more positives for those of class II. CONCLUSIONS: Although Luminex appears more efficient among these assays, our results indicate that use of multiple methods is still the best approach for characterizing the immunologic status of these patients.

Sleep-disordered breathing in a sample of 495 children in Southern Italy.

AIM: Our objective was to investigate the occurrence of sleep-related breathing disturbances in a large cohort of school-aged children in Southern Italy, and to evaluate the association with anthropometric data and clinical findings of oropharynx and nasal airways. STUDY DESIGN: A two-phase cross-sectional study was conducted with children from schools in Turi, Italy. MATERIALS AND METHODS: A screening phase aimed to identify symptomatic children and clinical data from a cohort of 495 children by a self-administered questionnaire, and an instrumental phase for the definition of sleep-related disorders and clinical analysis of oral status were performed. According to the answers, children were classified into 3 groups: habitual snorers, occasional snorers, and non-snorers. All habitual snoring children underwent a polysomnographic home evaluation, and those with oxygen desaturation index (ODI) > 2 were considered for nocturnal polygraphic monitoring (NPM). Children with apnoea/ hypopnea index (AHI) > 3 received a diagnosis of obstructive sleep apnoea syndrome (OSAS). Moreover, a complete oral examination was performed. RESULTS: A total of 436 questionnaires (response rate: 88.08%) were returned and scored (202 M, 234 F; Mean age ± Standard deviation: 6.2 ± 1.8); 18 children (4%) were identified as habitual snorers, 140 children (32%) were identified as occasional snorers, and 278 children (64%) were identified as non-snorers. The percentage of female children who were habitual snorers was higher than the percentage of male children (4.7% vs 3.6%). Habitual snorers had significantly more nighttime symptoms. OSAS was diagnosed in 2 children by NPM. A statistically significant association between snoring, cross-bite, open-bite and increased over-jet was found. CONCLUSION: Habitual snoring and OSAS are significant problems for children and may be associated with diurnal symptoms. The presence of malocclusion increases the likelihood of sleep-related breathing disturbances.

Inter-observer agreement between physicians, nurses, and respiratory therapists for respiratory clinical evaluation in bronchiolitis.

Care providers for children with bronchiolitis use various tools to evaluate respiratory status. The use of a single tool by different types of care provider requires a high level of inter-observer agreement, an aspect rarely studied. This study, involving 82 physicians, nurses, and respiratory therapists aimed to evaluate inter-observer agreement for clinical evaluations in children hospitalized for a first episode of bronchiolitis. Respiratory evaluation included three frequently reported parameters of respiratory status: respiratory rate, retraction signs, and wheezing. The frequency of concordance for observers from the same and from different care provider groups was assessed using a weighted kappa statistic and considering all possible combinations of care providers. We also calculated inter-provider agreement as a function of patient age, regardless of care provider type. Overall inter-observer agreement for all provider pairs was 93.1%, with a weighted kappa statistic of 0.72 (95% CI, 0.66-0.78), indicating substantial agreement, with no difference as a function of pair composition. Inter-observer agreements for the various age groups ranged from 87% to 93%, with kappa scores ranging from 0.62 to 0.78. We conclude that a simple clinical evaluation for respiratory status assessment has a high level of inter-observer agreement within and between physicians, nurses and respiratory therapists. Thus, once the validity of this test has been confirmed in a large population sample, it should be possible to use this test to monitor children hospitalized with bronchiolitis and as an endpoint in clinical trials.

[Role of Abelcet in children with febrile neutropenia]. / Intérêt d'Abelcet dans la prise en charge des enfants neutropéniques fébriles.

AIM OF STUDY: In order to optimise the use of new forms of Amphotericine B (Ampho B), a decisional tree was created at the end of 2001 in the paediatric hemato-oncology unit for the empirical antifungal treatment in febrile neutropenic children: the standard remained conventional Ampho B and Abelcet was proposed in case of antecedent or occurrence of a deterioration of the renal function (DRF). In order to validate the place of Abelcet we initiated a retrospective study over year 2002. RESULTS: 21 treatments were begun in 14 children for a median duration of 8 days (1-48 days). Three kind of indications were found: DRF antecedent (10 episodes: A group), DRF occurrence during a treatment with conventional Ampho B (7 episodes: B group), age lower than 1 year (3 episodes). 81% of the children were thus treated according to the decisional tree. The clinical tolerance was good in 90% of the cases, with a premedication in half of the cases. The study of the renal function showed a good renal tolerance for 6 episodes out of 9 evaluable in A group, 3 resolutions and 2 stabilisation of the renal failure for the 5 evaluable episodes of the B group. Seven to ten days of treatment by Abelcet were necessary to obtain the renal failure resolved. CONCLUSION: This study confirms the interest of Abelcet in the empirical antifungal treatment in febrile neutropenic children and specially in children having antecedents of DRF related or not to a treatment with conventional Ampho B.

[Vincristine treatment for function- and life-threatening infantile hemangioma]. / Traitement par vincristine des hémangiomes graves du nourrisson.

AIM: To evaluate the efficacy of vincristine treatment for function- and life-threatening hemangiomas. PATIENTS AND METHOD: Nine infants, eight girls and one boy, received vincristine treatment (VCR) for endangering hemangiomas. In six cases, the hemangiomas involved head and neck in a segmental unilateral or bilateral distribution (3/6 also had laryngeal and 2/6 tracheal location causing respiratory distress, 5/6 had eyelid and orbital involvement); one infant had disseminated neonatal hemangiomatosis (skin, liver, kidney); two infants had liver hemangiomas with cardiac failure. VCR was prescribed after failure of high-dosage corticosteroid treatment in six, and of both corticosteroids and interferon alpha 2b (5 months) in one; two infants received VCR as first line treatment. RESULTS: A dosage of 1 mg/m(2) IV injection was delivered, with weekly injections first, and then tapering, increasing the interval between injections, depending on the clinical response. The nine infants received from 5 to 25 injections (average: 16), for a length of treatment of 1.5-8 months (average: 5.5 months). In seven patients a clear clinical response was observed at the end of the first month of treatment, while a slow protracted response was noted in two. Transient mild side effects were present in four patients. DISCUSSION: Corticosteroid treatment, although a worldwide recognized treatment of problematic hemangiomas, cannot always control the growth of alarming hemangiomas. Interferon alpha 2a and 2b have proven a 90% effectiveness: treatment for cortico-resistant, function- and life-threatening, hemangiomas.

Lymphocyte-predominant Hodgkin's lymphoma in children: therapeutic abstention after initial lymph node resection--a Study of the French Society of Pediatric Oncology.

PURPOSE: To clarify treatment strategy for lymphocyte-predominant Hodgkin's lymphoma (LPHL), the French Society of Pediatric Oncology initiated a prospective, nonrandomized study in 1988. Patients received either standard treatment for Hodgkin's lymphoma or were not treated beyond initial adenectomy. PATIENTS AND METHODS: From 1988 to 1998, 27 patients were available for study. Twenty-four patients were male, and median age was 10 years (range, 4 to 16 years). Twenty-two, two, and three patients had stage I, II, and III disease, respectively. Thirteen patients (stage I, n = 11; stage III, n = 2) received no further treatment after initial surgical adenectomy (SA). Fourteen patients received combined treatment (CT; n = 10), involved-field radiotherapy alone (n = 1), or chemotherapy alone (n = 3). The two groups were comparable for clinical status, treatment, and follow-up. RESULTS: Twenty-three of 27 patients achieved complete remission (CR). With a median follow-up time of 70 months (range, 32 to 214 months), overall survival to date is 100%, and overall event-free survival (EFS) is 69% +/- 10% (SA, 42% +/- 16%; CT, 90% +/- 8.6%; P <.04). If we considered only the patients in CR after initial surgery (n = 12), EFS was no longer significantly different between the two groups. Patients with residual mass after initial surgery (n = 15) had worse EFS if they did not receive complementary treatment (P <.05). CONCLUSION: Although based on a small number of patients, our study showed that (1). no further therapy is a valid therapeutic approach in LPHL patient in CR after initial lymph node resection, and (2). complementary treatment diminishes relapse frequency but has no impact on survival.

[Severe candidosis infections in neutropenic patient in onco-hematologic department]. / Infections candidosiques sévères chez le patient neutropénique en onco-hématologie pédiatrique.

Incidence of severe candidal infections is rapidly increasing since 15 years and is becoming a major concern in onco-hematology practice, especially due to its poor prognosis in neutropenic patients. Diagnosis of candidemia is suspected in case of persistent fever resistant to a large antibiotherapy and requires to search for secondary locations as cutaneous and hepatosplenic candidal infection. Improvement of yeasts detection in blood culture bottles with specific medium is now helpful but use of specific immunoserodiagnosis or PCR methods is at this point unuseful. Fluconazole and Amphotericine B remain the recommended treatments for candidemia. Indications for "new antifongal drugs" are still limited regarding their high cost and the limited clinical studies.

[Giorgio Baglivi and Lecce]. / Giorgio Baglivi e la citta di adozione.

The article underlines the influence of the rich and variegated environment of Lecce on the cultural training of the young Giorgio Baglivi, adopted by a clever and humanitarian physician. Analogous importance had the ecclesiastical institutions, offering in an economically stagnating period, a continuous high-level cultural diffusion.