Analysis of Survival and Response to Lenvatinib in Unresectable Hepatocellular Carcinoma

The association between radiological response and overall survival (OS) was retrospectively evaluated in patients treated with lenvatinib as a first-line systemic treatment for unresectable hepatocellular carcinoma. A total of 182 patients with Child–Pugh class A liver function and an Eastern Cooperative Oncology Group performance status of zero or one were enrolled. Radiological evaluation was performed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified Response Evaluation Criteria in Solid Tumors (mRECIST). Initial radiological evaluation confirmed significant stratification of OS by efficacy judgment with both RECIST and mRECIST, and that initial radiological response was an independent prognostic factor for OS on multivariate analysis. Furthermore, in patients with stable disease (SD) at initial evaluation, macrovascular invasion at the initial evaluation on RECIST and modified albumin–bilirubin grade at initial evaluation on mRECIST were independent predictors of OS on multivariate analysis. In conclusion, if objective response is obtained at the initial evaluation, continuation of treatment appears desirable because prolonged OS can be expected; but, if SD is obtained at the initial evaluation, one should determine whether to continue or switch to the next treatment, with careful consideration of factors related to the tumor and hepatic reserve at the initial evaluation.

A Support Vector Machine Based on Liquid Immune Profiling Predicts Major Pathological Response to Chemotherapy Plus Anti-PD-1/PD-L1 as a Neoadjuvant Treatment for Patients With Resectable Non-Small Cell Lung Cancer

The biomarkers for the pathological response of neoadjuvant chemotherapy plus anti-programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) (CAPD) are unclear in non-small cell lung cancer (NSCLC). Two hundred and eleven patients with stage Ib-IIIa NSCLC undergoing CAPD prior to surgical resection were enrolled, and 11 immune cell subsets in peripheral blood were prospectively analyzed using multicolor flow cytometry. Immune cell subtypes were selected by recursive feature elimination and least absolute shrinkage and selection operator methods. The support vector machine (SVM) was used to build a model. Multivariate analysis for major pathological response (MPR) was also performed. Finally, five immune cell subtypes were identified and an SVM based on liquid immune profiling (LIP-SVM) was developed. The LIP-SVM model achieved high accuracies in discovery and validation sets (AUC = 0.886, 95% CI: 0.823–0.949, P < 0.001; AUC = 0.874, 95% CI: 0.791–0.958, P < 0.001, respectively). Multivariate analysis revealed that age, radiological response, and LIP-SVM were independent factors for MPR in the two sets (each P < 0.05). The integration of LIP-SVM, clinical factors, and radiological response showed significantly high accuracies for predicting MPR in discovery and validation sets (AUC = 0.951, 95% CI: 0.916–0.986, P < 0.001; AUC = 0.943, 95% CI: 0.912–0.993, P < 0.001, respectively). Based on immune cell profiling of peripheral blood, our study developed a predictive model for the MPR of patients with NSCLC undergoing CAPD treatment that can potentially guide clinical therapy.

First experiences with 177Lu-PSMA-617 therapy for recurrent or metastatic salivary gland cancer

Background Advanced salivary gland cancers become difficult to treat when they are technically irresectable and radiotherapy limits are exceeded. There is also an unmet need to improve palliative systemic therapy. Salivary glands depict the Prostate-Specific Membrane Antigen (PSMA) on 68Ga-PSMA-PET/CT, a transmembrane protein that is targeted for diagnosis and treatment of advanced prostate cancer. Some salivary gland carcinomas also express PSMA. Methods This study aimed to retrospectively evaluate the effectiveness of 177Lu-PSMA-617 therapy for recurrent or metastatic salivary gland cancers, as a last resort treatment. Patients with serious tumour-related discomfort for whom no regular option was available were selected and critically re-assessed by the tumour board. Radionuclide therapy eligibility was confirmed when tumour targeting was greater than liver SUVmax on 68Ga-PSMA-PET/CT. The protocol aimed at four cycles of 6.0–7.4 GBq 177Lu-PSMA-617 every 6–8 weeks. Clinical response was evaluated by questionnaires and radiological response by 68Ga-PSMA-PET/CT. Results Six patients were treated with 177Lu-PSMA: four adenoid cystic carcinomas, one adenocarcinoma NOS and one acinic cell carcinoma. In two patients, radiological response was observed, showing either stable disease or a partial response, and four patients reported immediate relief of tumour-related symptoms. Most reported side effects were grade 1–2 fatigue, nausea, bone pain and xerostomia. Four patients prematurely discontinued therapy: three due to disease progression and one due to demotivating (grade 1) side-effects. Conclusions Palliative 177Lu-PSMA therapy for salivary gland cancer may lead to rapid relief of tumour-associated discomfort and may even induce disease stabilization. It is safe, relatively well tolerated and can be considered when regular treatment options fail.

Rare, disseminated Kaposi sarcoma in advanced HIV with high-burden pulmonary and skeletal involvement

We describe the case of a 30-year-old man who presented to our institution with hypoxia and widespread pulmonary infiltrates managed initially as COVID-19 before receiving a new diagnosis of HIV-associated Kaposi sarcoma (KS) with widespread pulmonary and skeletal involvement. Initial differential diagnoses included Pneumocystis jirovecii pneumonia, disseminated mycobacterial infection and bacillary angiomatosis. A bone marrow biopsy showed heavy infiltration by spindle cells, staining strongly positive for human herpes virus-8 (HHV-8) and CD34, suggesting symptomatic, disseminated KS as the unifying diagnosis. The patient commenced cytotoxic therapy with weekly paclitaxel, with a clinical and radiological response. To our knowledge, this case is among the most severe described in the literature, which we discuss, along with how COVID-19 initially hindered developing a therapeutic allegiance with the patient.

Radiological progression of extremity soft tissue sarcoma following preoperative radiotherapy predicts for poor survival

Objectives: To determine if radiological response to preoperative radiotherapy is related to oncologic outcome in patients with extremity soft tissue sarcomas (STS). Methods: 309 patients with extremity STS who underwent preoperative radiation and wide resection were identified from a prospective database. Pre-and post-radiation MRI scans were retrospectively reviewed. Radiological response was defined by the modified Response Evaluation Criteria in Solid Tumours (RECIST).Local recurrence-free (LRFS), metastasis-free (MFS) and overall survival (OS) were compared across response groups. Results: Tumour volume decreased in 106 patients (34.3%; PR- Partial Responders), remained stable in 97 (31.4%; SD- Stable Disease), increased in 106 (34.3%; PD- Progressive Disease). The PD group were older (p = 0.007), had more upper extremity (p = 0.03) and high grade tumours (p < 0.001). 81% of myxoid liposarcomas showed substantial decrease in size. There was no difference in initial tumour diameter (p = 0.5), type of surgery (p = 0.5), margin status (p = 0.4), or complications (p = 0.8) between the three groups. There were ten (3.2%) local recurrences with no differences between the three response groups (p = 0.06). Five-year MFS was 52.1% for the PD group versus 73.8 and 78.5% for the PR and SD groups respectively (p < 0.001). OS was similar (p < 0.001). Following multivariable analysis, worse MFS and OS were associated with higher grade, larger tumour size at diagnosis and tumour growth following preoperative radiation. Older age was also associated with worse OS. Conclusion: STS that enlarge according to RECIST criteria following preoperative radiotherapy identify a high risk group of patients with worse systemic outcomes but equivalent local control. Advances in knowledge: Post radiation therapy, STS enlargement may identify patients with potential for worse systemic outcomes but equivalent local control. Therefore, adjunct therapeutic approaches could be considered in these patients.

Mutational status of plasma exosomal KRAS predicts outcome in patients with metastatic colorectal cancer

Liquid biopsy has become a useful alternative in metastatic colorectal cancer (mCRC) patients when tissue biopsy of metastatic sites is not feasible. In this study we aimed to investigate the clinical utility of circulating exosomes DNA in the management of mCRC patients. Exosomes level and KRAS mutational status in exosomal DNA was assesed in 70 mCRC patients and 29 CRC primary tumor and were analysed at different disease steps evaluating serial blood samples (240 blood samples). There was a significant correlation between the extension of disease and exosomes level and the resection of primary localized tumor was correlated with a decrease of KRAS G12V/ D copies and fractional abundance in metastatic disease. CEA expression and liver metastasis correlated with a higher number of KRAS G12V/D copies/ml and a higher fractional abundance; in the subgroup of mCRC patients eligible for surgery, the size of tumor and the radiological response were related to exosomes level but only the size was related to the number of KRAS WT copies; both KRAS wild-type and mutated levels were identified as a prognostic factor related to OS. Finally, we found that 91% of mutated mCRC patients became wild type after the first line chemotherapy but this status reverted in mutated one at progression in 80% of cases. In a prospective cohort of mCRC patients, we show how longitudinal monitoring using exosome-based liquid biopsy provides clinical information relevant to therapeutic stratification.

Meta-Analysis of Neoadjuvant Immunotherapy for Patients with Resectable Non-Small Cell Lung Cancer

Purpose: Immunotherapy has created a paradigm shift in the treatment of metastatic non-small cell lung cancer (NSCLC), overcoming the therapeutic plateau previously achieved by systemic chemotherapy. There is growing interest in the utility of immunotherapy for patients with resectable NSCLC in the neoadjuvant setting. The present systematic review and meta-analysis aim to provide an overview of the existing evidence, with a focus on pathological and radiological response, perioperative clinical outcomes, and long-term survival. Methods: A systematic review was conducted using electronic databases from their dates of inception to August 2021. Pooled data on pathological response, radiological response, and perioperative outcomes were meta-analyzed where possible. Results: Eighteen publications from sixteen studies were identified, involving 548 enrolled patients who underwent neoadjuvant immunotherapy, of whom 507 underwent surgery. Pathologically, 52% achieved a major pathological response, 24% a complete pathological response, and 20% reported a complete pathological response of both the primary lesion as well as the sampled lymph nodes. Radiologically, 84% of patients had stable disease or partial response. Mortality within 30 days was 0.6%, and morbidities were reported according to grade and frequency. Conclusion: The present meta-analysis demonstrated that neoadjuvant immunotherapy was feasible and safe based on perioperative clinical data and completion rates of surgery within their intended timeframe. The pathological response after neoadjuvant immunotherapy was superior to historical data for patients who were treated with neoadjuvant chemotherapy alone, whilst surgical and treatment-related adverse events were comparable. The limitations of the study included the heterogenous treatment regimens, lack of long-term follow-up, variations in the reporting of potential prognostic factors, and potential publication bias.

Evaluating the Clinical Utility of Staged Bronchoalveolar Lavage (BAL) Fluid Analysis in Adolescent and Adult Acute Leukemia and Lymphoma Patients with Febrile Neutropenia and Lung Infiltrates

Introduction: Lung infiltrates(LI) are seen in 30-45% of the patients with Febrile neutropenia(FN) in haematological malignancies.In FN patients with LI, accurate/probable microbiological diagnosis is possible in only 30 % with conventional blood culture and serological tests. BAL increases the microbiological diagnostic yield. The battery of microbiological tests done in BAL fluid analysis is not uniform.We evaluated a staged approach while analysing the BAL fluid sample, in the first stage we performed the routine cultures and antigen-based tests and in patients with negative results, we performed Polymerase Chain Reaction(PCR) tests guided by the radiological findings. Methods: This was a prospective observational study initiated after Institutional ethics committee approval and conducted at Tata memorial centre,Mumbai between November 2018 and June 2020.BAL testing was done as per a standard protocol(Sampsonas et al.) in hemodynamically stable patients with Spo2 more than 90% and platelet count above 300x10 9/L.Samples were sent for gram stain & bacterial cultures, ziehl neelsen stain and cultures, fungal stain and cultures and Galactomannan (ELISA) and an extra sample was preserved in an EDTA vacutainer at 10-20 degree C. If none of the initial reports were positive, then stored BAL sample was sent for PCR testing guided by the radiology and clinical picture i.e., with nodular infiltrates(Bacteria,Nocardia,Aspergillus,Mucor,P.Jiroveci,Mycobacterium TB,Atypical Mycobacterium TB) and with diffuse micronodular infiltrates Viruses,Legionella,mycoplasma PCR tests were sent. The causal association of the isolated organism was defined as per AGIHO guidelines(G. Maschmeyer et al.) The Primary objective is proportion of patients with a confirmed microbiological diagnosis using staged BAL analysis. The Secondary Objectives are proportion of patients who had a change in antimicrobial therapy,Feasibility of doing a Bronchoscopy and Proportion of Patients who develop Major or Minor complications during procedure and the 4 and 12weeks Clinical and Radiological Outcomes. A sample size of 130 patients was required for incidence of 50%(40-60%) positivity with 10% variation at 95% confidence interval. Results: A total of 172 patients were eligible of which 50 patients are not enrolled due to physician discretion in 37 patients,9 lost for followup and 2 refused consent and one patient expired and one palliated and 122 patients are enrolled and of these BAL couldn't be done in 20 patients due to hypoxia,low platelets,poor GCS at the time of performing BAL and finally BAL is feasible in 83.6%(n=102/122) patients. Baseline characteristics of patients are mentioned in Table 1.Median age of the patients was 30 (15-65) years with 69.6% males (n=85/122). A confirmed microbiological diagnosis (G. Maschmeyer et al.) was established in 71.3%( 81 /122 ) of cases.Microbiological results are depicted in Table2. A change of antimicrobial based on BAL (addition and removal of antimicrobial) was done for 78 patients(63.8%) of which 42 had removal of antibacterial and 11 patients had removal of antifungals. Among 42 patients who had removal of antibiotics, by the end of 4weeks, 36(85.7%) had clinical response and 34 had radiological response,(4 died and 2 lost for followup). By the end of 12weeks, 31 patients had sustained clinical and radiological response (2 died, 2 lost to follow-up and 1 progressive disease). Among 11 patients with removal of antifungals 9 had clinical and radiological response by the end of 4weeks (1 died and 1 non responder) which was sustained at week 12. Complications of BAL One patient had a major complication (persistent hypoxia), while minor complications were recorded in 27/122 (22%) (Hypoxia-16, hypertension-8,tachycardia-3) during procedure and in 21/122 (17%) (Fever-8, bleeds-6, tachycardia-5,hypertension-2)upto 24 hours post procedure. Clinical and Radiological responses as per criteria( Figure 1) Conclusion: BAL fluid analysis improves the diagnostic yield in febrile neutropenia with lung infiltrates. This leads to a change in antimicrobials in a significant number of patients. It contributes to improved outcomes in this patient population. The test is feasible in a large majority, is safe and the staged approach helps in optimisation of resources. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

CTNI-02. NERATINIB FOR TREATMENT OF LEPTOMENINGEAL METASTASES FROM HER2-POSITIVE BREAST CANCER IN EXTENDED ACCESS PROGRAM: PRELIMINARY RESULTS

INTRODUCTION The aim of the study was to evaluate the activity of neratinib in LM from HER2-positive BC after the failure of multiple lines of treatment. PATIENTS AND METHODS Inclusion criteria were as follows: age ≥ 18 years; histological diagnosis of primary HER2-positive BC; newly-diagnosed LM (LANO criteria); KPS ≥ 60; coexistence of BM that have or not received radiotherapy; life expectancy ≥ 3 months; previous drugs, including capecitabine, trastuzumab, T-DM1, pertuzumab, and hormone therapy, were allowed, with the exclusion of lapatinib or other investigational agents. Neratinib was administered 240 mg daily continuously. Primary endpoint was the OS. Secondary endpoints were progression-free survival (PFS), neurological benefit, radiological response rate, and tolerability. RESULTS Nine patients with LM have been enrolled with a median age of 44 years, and a median KPS of 80. Median time since LM onset from the diagnosis of primary BC was 42 months, and patients underwent a median number of adjuvant treatments before LM of 3. Three patients developed LM alone, and other 6 had LM associated with multiple BM. Six-months and 1-year OS were 66.7% and 22.3%, respectively, with a median OS of 8 months (95%CI 3-13*). Median PFS was 3.5 months (95%CI 2-6) after the start of treatment. A neurological improvement was reported in 2/9 patients (22.2%), while in other 4/9 patients (44.5%) was achieved a neurological stabilization lasting for a median time of 5 months (95%CI 2-19). The best radiological response was a stable disease in 5/9 patients (55.6%), while no complete or partial were achieved according to LANO criteria. A CSF clearance was observed in 1 patient only (11.1%). Grade III-IV adverse events were not reported, and 2 patients only (22.2%) had mild diarrhea correlated with neratinib. CONCLUSIONS Neratinib might be a safe and effective treatment in LM from heavily pretreated HER2-positive BC.