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Abstract Introduction A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. Methods This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15–180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. Results The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). Conclusions xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy.

Ameloblastoma, a benign epithelial odontogenic tumor, has an intriguing feature by virtue of its diverse histopathologic variants. One such variant that is not yet acclimatized in the literature due to the paucity of cases is “hemangiomatous ameloblastoma” (HA). HA exhibits the histology of conventional ameloblastoma with marked vascularity, which resembles the enamel organ and dental sac. Herein, we present the case of a 33-year-old male patient with swelling of the lower left back region of the jaw for 6 months, which on imaging presented multilocular radiolucency. Incisional biopsy was suggestive of ameloblastoma, and an excisional procedure showed odontogenic epithelial islands with marked vascular proliferation, based on which the diagnosis of HA was rendered. The rarity of this histologic variant and lack of long-term follow-up records in the literature challenges the clinician to predict its biological behavior. Hence, further research is required to understand the same.

In the evolving world of Cyber Attacks, this research presents an innovative approach aimed at fortifying user authentication within the Application Programming Interfaces (APIs) Ecosystem. We employ a groundbreaking synthesis of Context-Based fingerprinting attributes alongside the Random Forest algorithm, assessing their efficacy in enhancing security in how the user is authenticated. The study emphasizes the model’s potential to advance the precision of identifying legitimate login attempts, positioning it as a superior alternative to conventional methods. A model evaluation investigates the capacity of the Random Forest algorithm, augmented with these attributes, to discern the authenticity of user login attempts. Results unveil an exceptionally accurate model with 99.5 % accuracy, showcasing elevated F1 scores, precision, recall, and a notable MCC. The paper’s insights underscore the Random Forest algorithm’s potential as a robust tool for user authentication using the user’s historical profile, significantly contributing to the domain of Cyber Security. As the digital landscape continues to evolve, this research endeavours to provide a pioneering solution, ensuring robust API security and endorsing the broader adoption of this groundbreaking model.

Despite the high activity of selective RET inhibitors in RET-driven NSCLC, resistance eventually develops and there is unmet need to better define therapeutic options for patients. This is a case of a patient initially thought to have no targetable alterations, then found to have a RET fusion, and subsequently HER2 amplification on three distinct biopsies. She was treated initially with chemotherapy and immune therapy, then switched to selpercatinib, and eventually had fam-trastuzumab deruxtecan added to selpercatinib. She also developed neuroendocrine differentiation at time of progression in the context of a p53 mutation, which is a known factor that can lead to small cell transformation. This patient’s case highlights the need for comprehensive molecular testing at both diagnosis and progression, as unexpected resistance mechanisms may be identified particularly for patients with uncommon driver mutations.

Abstract Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova‐T) is an antibody‐drug conjugate that targets delta‐like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova‐T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova‐T in patients with previously treated extensive‐stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova‐T over 30 minutes, administered 6 weeks apart. Forty‐six patients received at least one dose of Rova‐T. At the geometric mean Rova‐T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia‐corrected QT (QTcF) interval; the upper limit of the 2‐sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova‐T administration. All patients experienced a treatment‐emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac‐related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova‐T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.

Immunotherapy has transformed lung cancer care in recent years. In addition to providing durable responses and prolonged survival outcomes for a subset of patients with heavily pretreated non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs)— either as monotherapy or in combination with other ICIs or chemotherapy—have demonstrated benefits in first-line therapy for advanced disease, the neoadjuvant and adjuvant settings, as well as in additional thoracic malignancies such as small-cell lung cancer (SCLC) and mesothelioma. Challenging questions remain, however, on topics including therapy selection, appropriate biomarker-based identification of patients who may derive benefit, the use of immunotherapy in special populations such as people with autoimmune disorders, and toxicity management. Patient and caregiver education and support for quality of life (QOL) is also important to attain maximal benefit with immunotherapy. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). This CPG represents an update to SITC’s 2018 publication on immunotherapy for the treatment of NSCLC, and is expanded to include recommendations on SCLC and mesothelioma. The Expert Panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for lung cancer and mesothelioma, including diagnostic testing, treatment planning, immune-related adverse events, and patient QOL considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers using immunotherapy to treat patients with lung cancer or mesothelioma.

Introduction: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. Methods: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a “pick a winner” design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. Results: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%–54.1 %) and 40.4 % (95 % CI: 26.4%–54.5 %), respectively (p = 0.93). The progression-free survival in arms A and B was as follows: hazard ratio of B versus A equals to 1.06, 95 % CI: 0.68–1.66, p value equals to 0.84, and median progression-free survival of 5.8 months and 4 months, respectively. The overall survival was as follows: hazard ratio of B versus A equals to 1.04, 95 % CI: 0.63–1.74, p value equals to 0.85, and median overall survival of 15.5 months and 14 months, respectively. Conclusions: Additional evaluation of either sequence in a phase 3 trial is not warranted.

Objectives: Fibro-osseous lesions (FOLs) of the jaws exhibit an overlapping histomorphologic spectrum with respect to nature of calcifications. Sometimes these calcifications may be difficult to characterize as bone and cementum on routine Hematoxylin and Eosin (H&E) staining. This causes difficulty in assessing the origin and diagnosis of these lesions. Thus the study aimed to characterize bone, cementum, and hard tissue components in FOLs using special stains. Method: The study included a histochemical evaluation of 20 samples of bone and cementum and 12 cases each of fibrous dysplasia (FD) and ossifying fibroma (OF). Three consecutive sections of each tissue were stained with H and E, modified Gallego's iron fuschin stain and Van Gieson stain. H and E and modified Gallego's iron fuschin stained sections were analyzed under light microscope whereas Van Gieson stained section was analyzed under polarizing microscope. Results: It was found that cementum stained red and bone stained greenish-yellow in color. The calcifications seen in fibrous dysplasia stained greenish-yellow in color. Three cases of OF showed greenish-yellow calcifications and nine cases showed reddish calcifications. Polarization study of bone showed lamellar pattern and tooth cementum showed quilt pattern. Four cases of FD showed lamellar pattern and eight cases showed haphazard pattern. In OF, three cases showed lamellar pattern and nine cases quilt pattern. Conclusion: Calcifications having lamellar pattern and greenish-yellow color suggest their osteogenic origin thus having aggressive nature and requiring aggressive treatment. Calcifications having quilt pattern and reddish color suggest periodontal ligament origin thus having less aggressive behavior and less extensive treatment.

Aim Gunshot wounds (GSW) to the penis represent a rare type of traumatic injury in the civilian United States population. Although small, single‐center studies have reported results of care for these types of injured patients, no national analyses have examined this group. Methods A cohort of patients with GSW to the penis was identified using the 2017 American College of Surgeons Trauma Quality Programs database, a comprehensive national database of 753 accredited trauma centers. Results Gunshot wounds to the penis occurred in 722 patients, which represents 1.7% of all GSW patients (n = 41,017). Gunshot wounds from altercations with law enforcement or accidental discharge of a firearm were rare; the vast majority (n = 655, 90.7%) occurred as a result of assault, intentional self‐harm, attempted suicide, or attempted homicide. Patients with a major concomitant non‐genitourinary injury comprised 119 (16.5%) patients of the cohort. Most patients (n = 499, 69.1%) underwent a genitourinary procedure during their trauma admission. Penile salvage was successful in most cases, with only 13 (1.8%) patients requiring completion penectomy. Most patients (87.8%) required admission with a median length of stay of 49.8 h. Most patients were treated at the initial trauma center without requiring transfer to another center, and complications during admission were rare. Conclusions This analysis, the first national examination of care of patients with GSW to the penis, reveals overall favorable outcomes. Admission and surgical intervention were required in most patients, but penectomy was rare and length of stay was generally short. These results will guide resource utilization and quality improvement efforts in this patient cohort.

Body composition refers to the proportional content of body fat mass and lean body mass that can lead to a continuum of different phenotypes ranging from cachectic/sarcopenic state to obesity. The heterogenetic phenotypes of body composition can contribute to formation of some cancer types and can sometimes lead to disparate outcomes. Both of these extremes of the spectrum exist in patients with non-small cell lung carcinoma (NSCLC). The discovery of new pathways that drive tumorigenesis contributing to cancer progression and resistance have expanded our understanding of cancer biology leading to development of new targeted therapies including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) that have changed the landscape of NSCLC treatment. However, in the new era of precision medicine, the impact of body composition phenotypes on treatment outcomes and survival is now being elucidated. In this review, we will discuss the emerging evidence of a link between body composition and outcomes in patients with NSCLC treated with TKI and ICI. We will also discuss suggested mechanisms by which body composition can impact tumor behavior and anti-tumor immunological response.

AIM: To evaluate the cytotoxic potential of endophytic fungi isolated from A. blanchetii. MATERIALS AND METHODS: Endophytic fungi were isolated from A. blanchetii using surface sterilization methods, grown in different types of media to ascertain their suitability for growth. Mass culture was prepared using suitable media and extracts using several solvents were prepared and dried. These extracts were later evaluated using MTT assay for their cytotoxic potential. RESULTS: Hydroalcoholic extract of Phomopsis species exhibited better cytotoxicity (80 μg/ml) when compared ethyl acetate extract of the same 160 μg/ml. Similarly, ethyl acetate extract of Phomopsis species, ethyl acetate extract of Alternaria aff. raphani J. W. Groves and Skolko also demonstrated cytotoxicity of 160 μg/ml in MTT assay against MCF 7 cell line. CONCLUSION: Both the species of Phomopsis and Alternaria have shown significant cytotoxicity in MTT assay.

Background: Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral and maxillofacial region. The diagnosis in most cases is made at advanced stages with lymph node metastases and thus has a poor prognosis. Evidence suggests that detection of molecular abnormalities might be useful in screening for early malignancy. Cytokeratins (CKs) are part of the epithelial cytoskeleton. In malignancy, some CK filament fragments might be released in the serum. CK19 fragment Cyfra 21-1 is useful tumor marker for squamous cell carcinoma, but its clinical value in OSCC has not been confirmed. Hence, the aim was to investigate the diagnostic value of serum Cyfra 21-1 in OSCC patients. Materials and Methods: The preoperative serum Cyfra 21-1 concentration of forty OSCC patients and forty healthy controls was detected by enzyme-linked immunosorbent assay (ELISA) using a commercial Cyfra 21-1 ELISA kit Xema Co., Ltd., Moscow, Russia. All statistical analyses were performed on STATISTICA statistical software (Windows version 6.0). Results: There was a statistically significant difference (P < 0.001) of mean serum Cyfra 21-1 levels (ng/mL) between OSCC cases (1.76 ± 0.81) and healthy controls (0.43 ± 0.14). The difference between controls and Stage III and Stage IV was also statistically significant (P < 0.001). The mean serum Cyfra 21-1 level was lower in histopathological Grade I cases (1.72 ± 0.78) than Grade II (2.04 ± 1.13), but the difference was not statistically significant (P = 0.459). Conclusion: It could thus be conjectured from the present study that increased serum Cyfra 21-1 level can be used as an adjunctive serological marker for the OSCC disease staging.

Granulomatosis is any condition characterized by the formation of multiple nodules or granulomas in the soft tissues. Differential diagnosis for orofacial region includes a wide spectrum of diseases, but most of these lesions present histopathologically as noncaseating granulomas, giving a nonspecific depiction and leading to a diagnostic impasse. In the absence of any diagnosable entity, the disease is labelled as “orofacial granulomatosis”. A nine-year-old girl child reported with recurrent gingival enlargement and persistent macrochelia which histopathologically presented as noncaseating granulomas. The disease was progressive raising the suspicion of being oral manifestation of a systemic disorder such as Sarcoidosis or Crohn's disease. This paper throws some light on this rare entity and reports rarer features of this disease, like eye involvement and staphylococcal mucositis in the case report.

In India, tuberculosis (TB) is a prevalent systemic disease and number of people who die with TB is increasing year by year. TB can be life-threatening, and there is a high mortality rate of systemic infection with TB. Although extrapulmonary TB (EPTB) is a rare form of TB, its prevalence is increasing day-by-day. Reported here is a case of a 28-year-old female patient with a painless swelling bilaterally in the submandibular region. She was diagnosed with bilateral submandibular tuberculous lymphadenitis. Tuberculous lymphadenitis, when occurring in the cervical region, continues to be a common cause of EPTB. Thorough knowledge of this condition is important as it can help in early diagnosis leading to prompt treatment of the patient and prevent further complications.

High grade mucinous urothelial carcinoma is a rare pathological variant. There is still controversy as to its nomenclature and classification. We report the case of a 64 year old female with history of pelvic pain who was incidentally discovered to have a left upper pole renal mass. Left nephroureterectomy was performed and histopathological examination revealed high grade mucinous urothelial carcinoma. Accurate diagnosis of this distinct pathological entity will allow for better understanding of phenotypic behavior and inform best treatment strategies.

Introduction: Adolescent girls constitute a more vulnerable group particularly in developing countries where they are traditionally married at an early age and exposed to the risk of reproductive morbidity and mortality. So, the present study was planned to find out prevalence of anemia and associated epidemiological factors in relation to anemia among rural adolescent girls. Material and method: It is a community‑ based cross‑ sectional, descriptive observational study was conducted in the rural field practice areas of tertiary rural hospital. All the villages coming under field practice area of tertiary rural hospital were included in the study. A pre‑designed and pre‑tested questionnaire was used for data collection. Results: Mean age of adolescent girls was 13.77± 2.42. Among the 480 adolescent girls covered in the study 72.5% were found to be anemic. Prevalence of mild and moderate anemia among adolescent girls was 34.19% and 65.81% respectively. Study found significant association of anemia with socioeconomic status , type of family, father’s occupation, father’s education, mothers education and mothers occupation. Conclusion: The prevalence of anemia among adolescent girls was high and associated with socioeconomic status, type of family, father’s occupation, mothers education.

Background: Designing and implementation of reverse logistics (RL) network which meets the sustainability targets have been a matter of emerging concern for the electronics companies in India. Objectives: The present study developed a two-phase model for configuration of sustainable RL network design for an Indian manufacturing company to manage its end-of-life and endof-use electronic products. The notable feature of the model was the evaluation of facilities under financial, environmental and social considerations and integration of the facility selection decisions with the network design. Method: In the first phase, an integrated Analytical Hierarchical Process Complex Proportional Assessment methodology was used for the evaluation of the alternative locations in terms of their degree of utility, which in turn was based on the three dimensions of sustainability. In the second phase, the RL network was configured as a bi-objective programming problem, and fuzzy optimisation approach was utilised for obtaining a properly efficient solution to the problem. Results: The compromised solution attained by the proposed fuzzy model demonstrated that the cost differential for choosing recovery facilities with better environmental and social performance was not significant; therefore, Indian manufacturers must not compromise on the sustainability aspects for facility location decisions. Conclusion: The results reaffirmed that the bi-objective fuzzy decision-making model can serve as a decision tool for the Indian manufacturers in designing a sustainable RL network. The multi-objective optimisation model captured a reasonable trade-off between the fuzzy goals of minimising the cost of the RL network and maximising the sustainable performance of the facilities chosen.

BACKGROUND:Systemic Sclerosis (SSc) is a rare connective tissue disorder associated with an increased risk of malignancy including lung cancer. METHODS:A single center review of all cases of lung cancer in patients with SSc was conducted. Clinical, radiographic, and detailed pathologic data was collected. Risk factors were compared with our center's SSc Registry. Cancer characteristics were compared with the National Cancer Institute SEER Cancer Statistics (NCI SEER) data. RESULTS:17 cases were identified; the majority were females (82%) with the lung cancers diagnosed after the onset of SSc (88%). Tobacco use was identified in 65% of cases. Serologic testing showed 50% of cases were Scl-70 positive. Twelve cases had radiographic evidence of SSc lung involvement, however only 6 had restrictive physiology on pulmonary function testing. Thirteen cases had pulmonary nodules preceding lung cancer. Thirteen of the cancers were adenocarcinoma. Ten underwent molecular mutational profiling: 2/8 had KRAS mutation and 1/10 had EGFR mutation. More of the non-small cell lung cancers were diagnosed at localized disease (56%) than in the NCI SEER database. However, 5 years survival among the stage I cases was 25% versus an expected survival of 54%. CONCLUSIONS:The high proportion of adenocarcinomas seen in our study is different from that reported in the literature. Lung cancers were diagnosed at an early stage, likely due to our center's practice of radiographic screening for SSc associated lung involvement, however this did not confer a survival advantage. A high proportion of patients who developed lung cancer had interstitial lung disease.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the industrialized world. Despite significant progress in early stage disease, survival rates for advanced disease remain low. Maintenance therapy is a treatment strategy that has been investigated extensively in NSCLC. Therapies that have been studied in this setting in randomized trials to date include chemotherapy and molecularly targeted agents. Following the development of multiple new agents that show activity in NSCLC and have a tolerable side-effect profile, there has been increasing interest in utilizing them to maintain response to initial therapy after treatment with platinum-based doublets. Two effective strategies have evolved: continuation and switch maintenance. Despite improvements in progression-free survival and often overall survival on multiple clinical trials, there remains considerable controversy around this treatment paradigm. Here, we briefly outline the evolution of this treatment strategy and examine the available data, including recently updated data from the PARAMOUNT, AVAPERL, and PointBreak maintenance trials. Ultimately, the decision to use maintenance chemotherapy requires a nuanced discussion between the patient and physician that adequately assesses benefits of prolonged therapy and impact in terms of toxicity, quality of life, and financial cost.

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non-small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%-63%) with median duration of response of 14 months (5.0-not reached) and median progression-free survival of 7.3 months (4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. SIGNIFICANCE: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.

BackgroundThe selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.MethodsPatients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).FindingsBetween May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [