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Introduction: Lobular breast cancer represents 10%–15% of breast cancers in women but is virtually nonexistent in men, related to the typical absence of the anatomic breast lobule structure in male breast tissue. We describe donor-transmitted metastatic lobular carcinoma to a male after kidney transplantation. Determining whether a post-transplant cancer is transplant associated, donor transmitted, or donor derived is significant for treatment, prognosis, and possibly management of other organ recipients. Case Report: A 74-year-old Caucasian male presented to the emergency department with lower abdominal pain and macro-hematuria. Past medical history included two renal transplantations. Computed tomography identified a 4–5-cm space-occupying lesion in the native left kidney. A left native nephrectomy was performed. Histology pathologic examination demonstrated lobular (as opposed to ductal) breast carcinoma. Fluorescent in situ hybridization probes to identify X- and Y-chromosomes showed tumor cells with an XX genotype, whereas the surrounding host cells were of XY genotype. These findings confirmed the female-sex origin (donor) of the tumor within the XY native male (current patient) tissues. Discussion/Conclusion: Due to discordance between the donor and recipient sex, fluorescent in situ hybridization as a molecular technique correctly identified the origin of an individual’s cancer in the post-transplant setting. The metastatic breast cancer behaved more indolently than usually seen. Expanded criteria donors (ECD) are those who cannot donate under standard criteria for organ transplantation; expanded criteria widen the potential organ donor pool at the expense of increased risk for post-transplant complications (e.g., graft failure, the transmission of malignancy). The case provides a potential area of future research into considering allowing ECDs with a distant history of cancer with very low transmission risk when the biochemical environment of the recipient would, in the unlikely event of transmission, induce the tumor to pursue an indolent clinical course.

Introduction: Non-small cell lung cancer (NSCLC) accounts for most lung cancers and is a leading cause of cancer-related deaths in the USA. Alterations in c-MET, a tyrosine kinase receptor, have been involved in many cases of NSCLC progression and metastasis. Crizotinib and other tyrosine kinase inhibitors (TKIs) have been used in NSCLC treatment with limited success. Methods: In this retrospective observational study, we analyzed data from patients diagnosed with lung cancer at Soroka University Medical Center between January 2015 and January 2020. We investigated patient characteristics, including disease-associated mutation type and median survival in response to different TKI treatments. Results: A total of 780 patients with lung cancer were included in the study, 134 of whom had small cell lung cancer and 646 had NSCLC. Of the NSCLC patients, 403 were diagnosed with advanced or metastatic disease, and 374 underwent molecular testing. We identified 16 patients with either c-MET mutations or amplifications who were treated with crizotinib. Of these patients, 7 expressed a c-MET exon 14 skipping mutation while the remaining 9 patients expressed c-MET amplification. Among the patients with a c-MET exon 14 skip mutation, the overall survival was 22.8 months and the median progression-free survival (PFS) on crizotinib treatment was 12.4 months. Of the patients with c-MET amplification, the median overall survival was 5.4 months and the median PFS with crizotinib treatment was 2.6 months. Discussion and Conclusions: We analyzed the data of a series of cases describing patients diagnosed with different stages of NSCLC, having either a c-MET exon 14 skipping mutation or an amplification mutation, and treated with various TKIs, including crizotinib. We investigated the characteristics of these patient groups in accordance with mutation types and compared median survival between patient groups. Crizotinib was found to be an optimal treatment for NSCLC harboring c-MET exon 14 skipping mutations.

Introduction: Approximately 10% of EGFR mutations (EGFRmuts) are uncommon (ucEGFRmuts). We aimed to collect real-world data about osimertinib for patients with ucEGFRmuts.Methods: This is a multicenter, retrospective study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC treated with osimertinib as first EGFR inhibitor. The Response Evaluation Criteria in Solid Tumors and response assessment in neuro-oncology brain metastases brain objective response rate (ORR) were evaluated by the in-vestigators. Median progression-free survival (mPFS), me-dian overall survival, and median duration of response (mDOR) were calculated from osimertinib initiation. Muta-tions found at resistance were collected.Results: A total of 60 patients were included (22 centers, nine countries), with median age of 64 years, 75% females, and 83% Caucasian. The largest subgroups were G719X (30%), L861Q (20%), and de novo Thr790Met (T790M) (15%). The ORR was 61%, mPFS 9.5 months, mDOR 17.4 months, and median overall survival 24.5 months. Regarding patients with no concurrent common mutations or T790M (group A, n 1/4 44), ORR was 60%, mPFS 8.6 months, and mDOR 11 months. For G719X, ORR was 47%, mPFS 8.8 months, and mDOR 9.1 months. For L861Q, ORR was 80%, mPFS 16 months, and mDOR 16 months. For de novo T790M, ORR was 44%, mPFS 12.7 months, and mDOR 46.2 months. Compound EGFRmut including common muta-tions had better outcome compared with only ucEGFRmut. For 13 patients with a response assessment in neuro-oncology brain metastases-evaluable brain metastases, brain ORR was 46%. For 14 patients, rebiopsy results were analyzed: four patients with additional EGFR mutation (C797S, D585Y, E709K), three with new TP53 mutation, one with c -Met amplification, one with PIK3CA mutation, and one with neuroendocrine transformation. Conclusions: Osimertinib was found to have an activity in ucEGFRmut with a high rate of disease control systemically and intracranially. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest data set of its kind.(c) 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). No funding was provided to the participating centers. Centralized data collection, statistical analysis, and figure preparation were funded by AstraZeneca. The authors thank Ana Maria Iordan (MD, MSc) and Sorin Tita-Calin for excellent data management, statistical analyses, and figure preparation (MedInteractiv Plus [Bucharest, Romania; funded by AstraZeneca]). The authors also thank Judith Elbaz, Liesbet Lodewyckx, and Nathalie Sassi (AstraZeneca) for helpful discussions.

Systemic capillary leak syndrome (SCLS) is a life-threatening disease. It is characterized by severe capillary hyperpermeability to proteins resulting in hemoconcentration, hypoalbuminemia and hypovolemic shock. Its treatment remains supportive, and the prognosis is generally poor. We report on a 51-year old male with melanoma treated with nivolumab for 1 year. 1 month following the completion of the treatment, the patient presented with signs of hypovolemic shock, anasarca, hemoconcentration and hypoalbuminemia. After excluding other diseases, a diagnosis of nivolumab-induced systemic capillary leak syndrome was made. A high dose of intravenous steroid therapy was promptly initiated without any significant clinical improvement. Intravenous immunoglobulin therapy was then administered with normalization of blood pressure, hemoconcentration and complete resolution of anasarca. Intravenous immunoglobulin should be considered a first-line treatment option for this rare phenomenon.Lay abstract Systemic capillary leak syndrome (SCLS) is a life-threatening disease with a high fatality rate. Patients present with low blood pressure, widespread edema and rapid weight gain. Labs show low albumin levels with highly concentrated blood, seen as high hematocrit and hemoglobin levels. Current treatments aim to support the acute crisis. We are presenting on a 51-year old patient with melanoma, treated with nivolumab for 1 year who developed signs of SCLS 1-month following medication discontinuation. He was first treated with high-dose steroids without symptom resolution. He was then administered immune proteins called intravenous immunoglobulins, resolving all his symptoms. Due to the patient’s complete response, we suggest intravenous immunoglobulins as the initial treatment in patients taking nivolumab presenting with SCLS.

Epithelioid hemangioma (EH) and epithelioid hemangioendothelioma (EHE) are both rare vascular tumors. EH tumors are often benign while EHE tumors have moderate malignant potential. Here, we present three unique cases at Soroka Medical Center, two featuring EH of the bone and one presenting EHE of the mediastinum. Each case demonstrates distinct treatment challenges due to the rarity of both diseases and lack of established guidelines. We propose three treatment approaches including pazopanib for salvage therapy of EH of the bone and minimally invasive surgical resection which in these cases lead to complete symptom relief and tumor stabilization upheld over time with close follow-up.

Introduction and importance: Collision tumors refer to the phenomenon where two or more different and unrelated tumors occur in the same location of an organ and form a single lesion. We present the first case of renal collision tumors composed of clear cell carcinoma (ccRCC) and collecting duct carcinoma (CDC) treated with combined therapy of nivolumab and ipilimumab. Case presentation: An 89-year-old male presented to the emergency room with back pain. Imaging studies demonstrated a large tumor in the left kidney with renal vein thrombosis. After radical nephrectomy, the histopathological report showed collision tumors with ccRCC and CDC components. The patient was included in a treatment protocol based on nivolumab (220 mg) and ipilimumab (73 mg) every 21 days, however, obtaining no clinical responses after 5 cycles of treatments. Clinical Discussion: Immune checkpoint inhibitors have become a new standard of care for patients with advanced ccRCC. However, current literatures showed inconclusive evidence on the efficacy of immune checkpoint inhibitor for metastatic CDC. As collision tumors with ccRCC and CDC components were infrequently reported in the literature, we also discuss the histological and immunohistochemical findings, clinical outcomes, and a literature review on this type of renal collision tumors. Conclusion: CDC is a rare and highly aggressive type of renal neoplasms, with limited treatment choices. More studies are needed to evaluate the efficacy of immune checkpoint inhibitors on CDC and its associated collision tumors. Highlights: Collecting duct carcinoma is a rare and highly aggressive type of renal neoplasms, with a poor clinical outcome. Radical nephrectomy alone is rarely curative. The use of immune checkpoint inhibitors for collecting duct carcinoma needs further evaluation. The use of HMWCK as a histologic marker for differential diagnosis of collecting duct carcinoma may need to be evaluated.

While immune checkpoint inhibitors (ICIs) have transformed standards of care and drastically improved patient prognoses in several malignant diseases, a range of immune related adverse events (irAEs) from ICIs have been observed. This case series describes the clinical course of three patients with unusual immune checkpoint-inhibitor (ICI) induced toxicities. These three patients developed carpal tunnel syndrome (CTS) while on ICI therapy. The first patient was a 79 year-old male who received neo-adjuvant chemo-immunotherapy and adjuvant immunotherapy (atezolizumab) for stage II-B lung adenocarcinoma, the second patient was a 70 year-old female who received immunotherapy only (nivolumab) for stage IV renal cell carcinoma and the third patient was a 71 year-old male who received adjuvant immunotherapy (nivolumab) for stage 2-A melanoma. The patients developed carpal tunnel syndrome with severe neuropathy as a result of therapy. All patients had complete symptomatic relief when treated with either corticosteroids or intravenous immunoglobulins for CTS.

In the present case report, we aimed to describe 2 cases of myocarditis occurring as serious adverse effects of immune checkpoint inhibitors (ICIs) administered as treatment for metastatic melanoma. We describe 2 female patients: an 81-year-old treated with pembrolizumab and a 55-year-old treated with a combination of nivolumab and ipilimumab. Both patients underwent resection of metastases; while under treatment, both developed myocarditis, most probably as a toxicity from pembrolizumab and nivolumab plus Ipilimumab, respectively. While they achieved complete response, the occurrence of myocarditis as a toxicity of ICIs may have been a predictive sign that the immune system was sufficiently activated by the checkpoint inhibitor therapy to induce complete remission.

Foramen of Winslow hernias form 8% of all internal hernias. They present with non-specific findings and are often diagnosed late in disease progression. Delayed diagnosis of the hernia is associated with an estimated mortality of 50%. This rare event has yet to be described in the literature as a follow-up complication to a Ladd’s procedure. Here, we present a young male patient with a surgical history of a Ladd’s procedure with a chief complaint of an acute-onset, severe abdominal pain accompanied by episodes of emesis. Prompt clinical analysis, imaging and fluid resuscitation was conducted. A computed tomography (CT) scan showed a mesenteroaxial gastric volvulus and air was identified within the Falciform Ligament. Consequently, the patient underwent an exploratory laparotomy and the foramen of Winslow hernia was identified. An excision and anastomosis procedure was performed, and the cecum was fixed in the lower left quadrant. The procedure had no complications and the patient was discharged from the hospital on the fifth post-operative day. The purpose of this case report is to present an unusual patient who experienced a foramen of Winslow hernia involving the small bowel six years following a Ladd's procedure. While a causative relation cannot be made between these two events, we theorize that gastrointestinal hypermobility, being one of the three properties leading to herniation, played a role in both pathologies. Therefore, a vigilant surgeon should keep in mind that intra-abdominal congenital malrotation can put patients at greater risk for future herniation.

Background Osimertinib is selective for both epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI) sensitizing and Thr790Met mutations. While intracranial activity of osimertinib is documented in larger trials, a prospective study focusing exclusively on patients with asymptomatic brain metastases has not been reported. Methods In this nonrandomized, phase II, open-label, 3-arm prospective proof-of-concept pilot study, 48 patients with metastatic EGFR-mutant lung adenocarcinoma (LUAD) received osimertinib 80 mg daily. Patients were either treatment naive (arm A = 20) or previously treated with an EGFR-TKI and Thr790Met positive (arm B = 18) or negative (arm C = 10). In cases of isolated intracranial progression, osimertinib dose was escalated (160 mg). The primary endpoints were intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). The secondary endpoint was intracranial progression-free survival (iPFS). This study is registered at Clinicaltrials.gov, NCT02736513. Results The iORRs were 84.2%, 66.7%, and 50% and the iDCRs were 94.7%, 94.4%, and 80% in arms A, B, and C, respectively. The median iPFS was 11.8 months (95% CI 7.7 to NA), 7.6 months (95% CI 5.3 to NA), and 6.3 months (95% CI 3.9 to NA) in arms A, B, and C, respectively. Following dose escalation, pooled iORR was 54% (arm A = 5, arm B = 4, arm C = 2). Adverse events were similar to those in previously published literature. Conclusion Osimertinib demonstrated high efficacy on brain metastases. All trial arms displayed a significant decrease in the number and diameter of target lesions. These findings indicate that osimertinib is effective for Thr790Met-positive and -negative LUAD patients with asymptomatic brain metastases. Therefore, osimertinib should be considered a viable option for EGFR-mutant patients with brain involvement regardless of their Thr790Met mutation status.

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal–epithelial transition ( MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48–91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47–69), whereas it was 68% (95% CI, 50–82) in treatment-naïve and 50% (95% CI, 35–65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7–14.3), whereas it was 10.6 months (95% CI, 5.5–15.7) in first-line and 9.1 months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2–23.1). In patients with measurable brain metastases ( n = 11), the intracranial ORR was 46% (95% CI, 17–77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.

PURPOSE OF REVIEW The recently published large-scale NELSON trial showed a reduction in lung cancer (LC) mortality with the use of low-dose computed tomography (LDCT) in high-risk patients. This is the first such European-based trial to mirror the results of the US National Lung Screening Trial (NLST). The NLST was responsible for nationwide implementation of LC screening protocols which has shown a decrease in LC mortality. However, the implementation of such screening in Europe has been challenging. With the findings from the NELSON trial, implementation of LC screening throughout Europe should once again be evaluated. RECENT FINDINGS This review article further elaborates on the advantages of LDCT in LC screening. It also discusses promising future approaches that can supplement the current LC screening guidelines. SUMMARY Implementation of LC screening with LDCT should again be evaluated throughout Europe as it could substantially decrease LC-related mortality.

Highlights • NUT carcinoma is a rare but aggressive solid tumor that can be diagnosed by presence of the BRD4-NUT fusion. • This series presents 31 cases of solid tumors that harbor BRD4-NUT but often carry other diagnoses such NSCLC—NOS and NSCLC-SCC. • Despite lack of PD-L1 expression and a low tumor mutational burden, two index cases responded to either nivolumab or atezolizumab+chemotherapy with partial response or better with 4–5 month duration of response. • The unexpected response to checkpoint inhibitors could be explained by a very high affinity of the fusion peptide at the junction of BRD4 and NUT to the MHC complex as recently suggested for an exceptional response to an immune checkpoint inhibitor in a fusion bearing low TMB, low PD-L1 expression head and neck carcinoma., Background The translocation t(15:19) produces the oncogenic BRD4-NUT fusion which is pathognomonic for NUT carcinoma (NC), which is a rare, but extremely aggressive solid tumor. Comprehensive genomic profiling (CGP) by hybrid-capture based next generation sequencing of 186+ genes of a cohort of advanced cancer cases with a variety of initial diagnoses harboring BRD4-NUT may shed further insight into the biology of these tumors and possible options for targeted treatment. Case presentation Thirty-one solid tumor cases harboring a BRD4-NUT translocation are described, with only 16% initially diagnosed as NC and the remainder carrying other diagnoses, most commonly NSCLC—NOS (22%) and lung squamous cell carcinoma (NSCLC-SCC) (16%). The cohort was all microsatellite stable and harbored a low Tumor Mutational Burden (TMB, mean 1.7 mut/mb, range 0–4). In two index cases, patients treated with immune checkpoint inhibitors (ICPI) had unexpected partial or better responses of varying duration. Notably, four cases – including the two index cases - were negative for PD-L1 expression. Neo-antigen prediction for BRD4-NUT and then affinity modeling of the peptide-MHC (pMHC) complex for an assessable index case predicted very high affinity binding, both on a ranked (99.9%) and absolute (33 nM) basis. Conclusions CGP identifies BRD4-NUT fusions in advanced solid tumors which carry a broad range of initial diagnoses and which should be re-diagnosed as NC per guidelines. A hypothesized mechanism underlying responses to ICPI in the low TMB, PD-L1 negative index cases is the predicted high affinity of the BRD4-NUT fusion peptide to MHC complexes. Further study of pMHC affinity and response to immune checkpoint inhibitors in patients with NC harboring BRD4-NUT is needed to validate this therapeutic hypothesis.

The COVID-19 pandemic, caused by the SARS-CoV2 virus, has infected millions worldwide with cancer patients demonstrating a higher prevalence for severe disease and poorer outcomes. Recently, the BNT162b2 mRNA COVID-19 vaccine was released as the primary means to combat COVID-19. The currently reported incidence of local and systemic side effects was 27% in the general public. The safety of the BNT162b2 mRNA COVID-19 vaccine has not been studied in patients with an active cancer diagnosis who are either ongoing or plan to undergo oncologic therapy. This single center study reviewed the charts of 210 patients with active cancer diagnoses that received both doses of the BNT162b2 mRNA COVID-19 vaccine. The development of side effects from the vaccine, hospitalizations or exacerbations from various oncologic treatment were documented. Type of oncologic treatment (immunotherapy, chemotherapy, hormonal, biologic, radiation or mixed) was documented to identify if side effects were related to treatment type. The time at which the vaccine was administered in relation to treatment onset (on long term therapy, within 1 month of therapy or prior to therapy) was also documented to identify any relationships. Sixty five (31%) participants experienced side effects from the BNT162b2 mRNA COVID-19 vaccine, however most were mild to moderate. Treatment protocol was not linked to the development of vaccine related side effects (P = .202), nor was immunotherapy (P = .942). The timing of vaccine administered in relation to treatment onset was also not related to vaccine related side effects (P = .653). Six (2.9%) participants were hospitalized and 4 (2%) died. The incidence of side effects in cancer patients is similar to what has been reported for the general public (31% vs 27%). Therefore, we believe that the BNT162b2 mRNA COVID-19 vaccine is safe in oncologic patients undergoing numerous cancer treatments.

Pembrolizumab is an immune checkpoint inhibitor used in many different cancers. Several immune-related adverse events (irAEs) have been associated with pembrolizumab, including toxic epidermal necrolysis. Here, we are presenting a patient with non-small cell lung cancer that developed toxic epidermal necrolysis 3-days following initiation of pembrolizumab. Following high-dose steroid therapy, intravenous immunoglobulin 2 g/kg was initiated and resulted in complete resolution of all his irAEs. To our knowledge, this is the first reported case of total re-epithelialization and resolution of immune checkpoint inhibitor-induced toxic epidermal necrolysis following the use of intravenous immunoglobulin.

BACKGROUND: The Dako PD-L1 immunohistochemistry (IHC) 22C3 pharmDx and the Dako 28-8 IHC pharmDx assays were approved by the US Food and Drug Administration, as a companion diagnostic test for pembrolizumab (Keytruda, Merk, Kenilworth, NJ, USA) and a complementary diagnostic test for nivolumab (Opdivo, Bristol Meyer Squibb, New York, NY, USA) in non-small cell lung cancer (NSCLC), respectively. Increased PD-L1 expression levels can be associated with greater therapeutic efficacy of pembrolizumab relative to other anti-PD-1 agents. However, in treatment decision making, little is known about which tissue (primary or metastatic lesion) should be stained by 22C3 antibody. We investigated the relationship between PD-L1 expression in primary tumors and paired metastatic lymph nodes using the 22C3 assay, and evaluated the concordance between the 22C3 and 28-8 assays. METHODS: PD-L1 expression was evaluated in cells from primary tumors and paired metastatic lymph nodes using the 22C3 and 28-8 IHC assays. Total 35 patients with primary tumor and paired metastatic lymph node were enrolled into this study, and all samples were surgically resected, formalin-fixed, and paraffin-embedded NSCLC tissues. Tumor cells exhibiting complete or partial membrane staining, were considered as PD-L1 positive. On the basis of tumor proportion score (TPS), all samples were classified as no expression (TPS

Background: The COVID-19 pandemic, caused by the SARS-CoV2 virus, has infected millions worldwide with cancer patients demonstrating a higher prevalence for severe disease and poorer outcomes. Recently, the BNT162b2 mRNA COVID-19 vaccine was released as the primary means to combat COVID-19. The currently reported incidence of local and systemic side effects was 27% in the general public. The safety of the BNT162b2 mRNA COVID-19 vaccine has not been studied in patients with an active cancer diagnosis who are either ongoing or plan to undergo oncologic therapy. Methods: This retrospective single center study reviewed the charts of 210 patients with active cancer diagnoses that received both doses of the BNT162b2 mRNA COVID-19 vaccine. The development of side effects from the vaccine, hospitalizations or exacerbations from various oncologic treatment were documented. Type of oncologic treatment (immunotherapy, chemotherapy, hormonal, biologic, radiation or mixed) was documented to identify if side effects were related to treatment type. The time at which the vaccine was administered in relation to treatment onset (on long term therapy, within one month of therapy or prior to therapy) was also documented to identify any relationships. Results: 65 (31%) participants experienced side effects from the BNT162b2 mRNA COVID-19 vaccine, however most were mild to moderate. Treatment protocol was not linked to the development of vaccine related side effects (p =.202), nor was immunotherapy, specifically, (p =.942). The timing of vaccine administered in relation to treatment onset was also not related to vaccine related side effects (p =.653). 6 (2.9%) participants were hospitalized and 4 (2%) died. Conclusions: The incidence of side effects in cancer patients is similar to what has been reported for the general public (31% vs 27%). Therefore, we believe that the BNT162b2 mRNA COVID-19 vaccine is safe in oncologic patients undergoing numerous cancer treatments. Legal entity responsible for the study: A. Yakobson. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Cardiomyopathy can be defined as a structural and functional myocardial disorder that is commonly genetic rather than due to coronary artery, valvular or congenital heart disease. It can be subcategorized into dilated, hypertrophic, restrictive, unclassified, and arrhythmogenic right ventricular cardiomyopathy/dysplasia. They can be further subdivided into primary and secondary cardiomyopathy. Primary includes genetics (HOCM, ARVC/D), mixed (DCM, RCM) or acquired (stress-induced, myocarditis) causes; while secondary cardiomyopathy is derived from the involvement of other organ systems. Cardiomyopathies can be identified by echocardiogram to display the anatomic and functional changes related to each subtype including systolic or diastolic dysfunction. In certain instances, cardiac-MRI or CT are used to further elucidate its specific characteristics such as fatty infiltration and focal hypertrophy. Treatment is very diverse and catered to each individual case. This will all be further elaborated on in the following chapter.

Background Resistance mechanisms following 1st line therapy with osimertinib in EGFR + NSCLC have become focus of investigation. This retrospective study aims to deepen the understanding and clarify possible mechanisms of osimertinib 1st line resistance in comparison to the 2nd line by examining NGS results of 30 patients who developed resistance to osimertinib. Furthermore, we followed clinical outcomes of select patients who received combined therapy following EGFR resistance, a novel strategy not yet widely tested. Methods Liquid biopsy technique (Guardant360) was used to monitor tumor dynamics in patients who were treated with osimertinib as 1st-line therapy (Group A, N = 15) and patients who received osimertinib as 2nd-line therapy (Group B, N = 15). Results At the time of progression under osimertinib all but one patient preserved the primary EGFR mutation. While the C797S mutation was relatively common in the 2nd-line osimertinib setting (5/15), it did not develop in group A patients. TP53 was the most common detected mutation among all patients accounting for 11/15 in group A (73.33 %) and 10/15 in group B (66.67 %). In group A MET amplification was found in 3/15 patients (20 %) whereas MET mutation appeared in only one patient from group B. The outcomes of different treatment approaches post osimertinib resistance is reported including chemotherapy with/without osimertinib for maintaining control of brain metastases, drug combination such as osimertinib with crizotinib, chemo-immunotherapy and others. Overall survival in this cohort ranged from 12 to80 months. Conclusions Mechanisms of resistance to osimertinib as 1st-line therapy differ from those which develop in the 2nd-line setting and commonly include MET amplification. C797S is not a main resistance mechanism in the 1st-line setting, whereas it is more common in the 2nd-line setting. Combined therapy was effective and well tolerated, making it an acceptable choice in patients for whom there is a reasonable rationale for such treatment, however this approach deserves further investigation.

Medulloblastoma (MB) is an aggressive, primitive neuroectodermal tumor mainly affecting pediatric patients and with frequent involvement of the posterior fossa and extraneural metastasis. MB has a low incidence in adults (< 1% of adult brain tumors) and treatment protocols for adult patients have been adapted from pediatric oncology.1,2 PTCH13 tumor suppressor gene functions as an inhibitor of smoothened (SMO) and downstream sonic hedgehog (SHH) signaling. SHH ligand connects to the receptor on PTCH1, which results in SMO suppression (Fig 1). PTCH1 germline inactivating mutations are associated with Gorlin syndrome, which is associated with a high incidence of basal cell carcinoma (BCC) and predisposition to MB.4-6 This association is strengthened because somatic mutations that inactivate PTCH1 are frequently found in the sporadic forms of these types of cancers. Genomic analyses of MB have identified PTCH1 a mutation incidence of 3%-7% of MB cases. On the basis of gene expression profiling, four molecular subgroups of MB have been identified: WNT, SHH, group 3, and group 4.7 The prognosis for patients within the SHH subgroup MB differs greatly upon TP53 mutation status, wherein patients with wild-type TP53 have a significantly better 5-year overall survival rate (76%) compared with those with TP53 mutation (41%).8 Open in a separate window FIG 1. Graphic representation of sonic hedgehog (SHH) pathway. (1) HH ligand binding to PTCH1. (2) Binding of HH to PTCH1 releases SMO. (3) Showing the inhibition of SMO by vismodegib, which leads to inhibition of the whole pathway.

Background Osimertinib is a selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with increased penetration across the blood–brain barrier compared with previous EGFR-TKIs, and thus, a 52% reduction in the risk of intracranial disease progression is seen when it is used as a first line of therapy compared with gefitinib and erlotinib. It is also efficient as second-line therapy for patients who developed the T790M resistance mutation following treatment with previous generation TKIs. Here, we report 11 patients who were treated by an increasing dose of osimertinib from 80 mg to 160 mg QD orally following intracranial progression in either first- or second-line setting. Methods This is a subcohort analysis from a larger nonrandomized, phase 2, open-label trial, evaluating the efficacy of osimertinib dose escalation from 80 mg to 160 mg in EGFR-mutated advanced non-small-cell lung cancer (NSCLC) patients with intracranial progression in either first- (arm A) or second-line setting (arm B for T790M+ and C for T790M−). Results Eleven patients, 5 in arm A, 4 in arm B, and 2 in arm C were reported in this study. The mPFS of osimertinib before dose escalation was 11.4 ± 8.9 (6.6–30.7) months for arm A, 8.7 ± 1.8 (6.3–11.2) for arm B, and 14.5 ± 7.8 (6.7–22.3) for arm C. Intracranial response rate to dose escalation was 54% (6 of 11) with 2 of 11 having intracranial stability. Median iPFS was 4.3 ± 7.4 (0.7–25.5) months; 3.8 ± 6.4 (1.8–18.9), 5.6 ± 9.7 (0.7–25.5), and 7.0 ± 2.7 (4.3–9.6) for arms A/B/C, respectively. Dose escalation was well tolerated with diarrhea and paronychia as the main dose-limiting symptoms. Conclusions Osimertinib 160 mg is feasible and may offer a therapeutic alternative for patients with isolated intracranial progression on osimertinib standard (80 mg) dose. Further studies on CNS osimertinib pharmacokinetics are needed to test this hypothesis.

Pembrolizumab is a humanized monoclonal antibody that blocks the programmed death 1 receptor (PD-1) and has antitumor activity in advanced non-small-cell lung cancer (NSCLC). The phase 1 trial first published in 2015, included a total of 495 advanced NSCLC patients. The patients received pembrolizumab at a dose of either 2 or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks with progression-free survival (PFS) of 3.7 months and median duration of response (DOR) of 12.5 months. Among all patients, the median overall survival (OS) was 12.0 months. In patients with a PD-L1 immunohistochemistry [tumor proportion score (TPS)] score of at least 50% the median PFS was 6.3 months and the response rate was 45.2%, thus, the median OS was not reached (1).

As guest editors, we are thrilled to present this specially curated issue of Precision Cancer Medicine ( PCM ), wherein we have invited leading experts from around the globe to discuss currently evolving paradigms and controversies in the field of lung cancer.

Recent years have witnessed a revolution in the era of immune checkpoint inhibitors (ICIs). It has greatly impacted the oncological field and especially advanced non-small cell lung cancer (NSCLC) treatment. Here, we summarized the 3 main treatment protocols for a specific population of NSCLC with strong PD-L1 staining (PD-L1 ≥50%); which include ICI (e.g., pembrolizumab) monotherapy, ICI in combination with chemotherapy or combination ICIs. To date, it is uncertain whether there is a therapeutic difference amongst the PD-L1 TPS ≥50% group in comparison to other PD-L1 subdivisions. The findings reviewed here show that the combination ICI with chemotherapy yields the best response rate in comparison to other treatment protocols. Crucially, this treatment protocol is highly suggested for patients with high disease burden, especially for those with liver or brain involvement.