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Objective: Aiming at the assistance of women with breast cancer, quality of life indicators can help in clinical practice, guide therapeutic intervention strategies, and evaluate the success of intervention after surgery and cancer treatment, in addition to defining parameters for actions. This perspective study is about the quality of life of patients treated for breast cancer at the Institution. However, as soon as the pandemic started, the need to readapt the way of filling out the questionnaires to an online model emerged. Our objective is to share the facilities and difficulties of online model research. Methods: Through the selection of patients for research that aimed to analyze the quality of life of patients with breast cancer, they were contacted by their registered e-mails in the institution system. Each patient received an explanation of the project through e-mail and the Free and Informed Consent Term (TCLE). After agreement, the survey link of the REDCap system directing the selected instrument to be filled in was sent. The analysis included a general questionnaire composed of demographic and clinical aspects (collected by electronic medical record data) and specific questionnaires. Results: In all, 477 e-mails were sent, 52 patients signed the TCLE (but 2 did not answer the research), 36 answered the questionnaires completely, and 14 incompletely. A total of 12 e-mails were returned (wrong e-mail address). Conclusion: During the pandemic period, new tools were incorporated in order to obtain data and maintain research. Moving to an online way brought the chance to keep studies, giving new possibilities to answer research remotely, but difficulties were added to this new kind of research. E-mail data, lack of explanation face-to-face, and the number of complete responses mainly in long questionnaires were some of the most tricky parts of this new way of study. Online strategy is a real option, but the success of the process depends on many variables.

The unavoidable progression of EGFR-mutated NSCLC on EGFR-TKIs forces us to discover solutions for further therapies. Herein, we discuss the necessity of accurate genomic mapping of progressive disease illustrated by a patient case. Tumor rebiopsies at progression are strongly needed to characterize acquired resistance to EGFR-TKI. The necessary data, however, may be reliably obtained only by deep targeted next generation sequencing (NGS) of both DNA and RNA. The reported case is a patient with EGFR-mutant NSCLC, who progressed during second line Osimertinib with subsequent targeted treatment determined by the detection of an acquired intergenic ANK3-RET-fusion with concomitant PTEN-mutation and MDM2-amplification. These three acquired gene alterations represent potential mechanisms of TKI-resistance, not previously reported on second line Osimertinib. Yet, while PTEN-mutations and MDM2-amplification are currently undruggable, the ANK3-RET fusion allowed further personalized treatment by combining continuation of Osimertinib with the RET-TKI Pralsetinib, which resulted in objective partial response, so far for 7 months, and significant clinical improvement. Hence, complementary DNA- and RNA-based targeted NGS may be of importance in clinical routine to better reveal the current molecular state of the disease and contribute to the identification of further targeted therapy strategies. Indeed, further cases with acquired RET-fusions, including ANK3-RET, should be investigated to fully determine the effectiveness of RET-TKI-Osimertinib combinations.

OBJECTIVES: To evaluate diagnostic accuracy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) compared to contrast-enhanced CT in assessment of inguinal lymph node (ILN) metastases, distant metastases and synchronous cancers in patients with penile squamous cell carcinoma (pSCC).PATIENTS AND METHODS: During a 4-year period, patients with pSCC were scheduled for FDG PET/CT prior to surgical treatment at two referral centres that manage all penile cancers in Denmark. The primary endpoint was diagnostic accuracy of FDG PET/CT and of CT alone with histopathology or Response Evaluation Criteria In Solid Tumors (RECIST) as reference.RESULTS: We evaluated 171 patients for distant metastases and synchronous incident cancers and examined 286 groins in 143 patients for LN metastases by FDG PET/CT. Six groins disclosed false negatives. FDG PET/CT sensitivity was 85.4% per patient. In 135 patients (270 groins), CT images were evaluated separately and 22 groins disclosed false negatives. CT sensitivity was 47.5% per patient. FDG PET/CT detected pSCC distant metastases in seven patients. Distant metastases from other cancers were newly detected in three patients. In eight patients, an incidental synchronous cancer was detected. Seven out of the 18 distant malignancies detected depended on FDG PET information.CONCLUSION: This study underlines the increased diagnostic accuracy of FDG PET/CT compared to CT alone in the evaluation of ILN status. In patients with palpable LNs, the advantage of FDG PET/CT over CT is less pronounced. FDG PET/CT may play a role in penile cancer evaluation.

Anaplastic lymphoma-kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is prone to developing heterogeneous, only partly known mechanisms of resistance to ALK-tyrosine-kinase-inhibitors (ALK-TKIs). We present a case of a 38-year old male, who never smoked with disseminated ALK-rearranged (EML4 (20) – ALK (20) fusion variant 2) lung adenocarcinoma, who received four sequentially different ALK-TKIs and two lines of chemotherapy in-between. We observed significant clinical benefit by the first three ALK-TKIs (Crizotinib, Ceritinib, Alectinib) and chemotherapy with Pemetrexed, resulting in overall survival over 3 years. Longitudinal assessment of progressions by rebiopsies from hepatic metastases showed different mechanisms of resistance to each ALK-TKI, including secondary ALK-mutations and the downstream p.V600E BRAF-mutation that had not been linked to second-generation ALK-TKIs before. Ultimately, in connection with terminal rapid progression and resistance to Alectinib and Lorlatinib, we identified phenotypical epithelial-mesenchymal transition (EMT) of newly occurred metastatic cells, a phenomenon not previously related to these two ALK-TKIs. This resistance heterogeneity suggests a continuously changing disease state. Sequential use of different generation’s ALK-TKIs and combination therapies may yield prolonged responses with satisfactory quality of life in patients with advanced ALK-positive NSCLC. However, the development of EMT is a major hurdle and may explain rapid disease progression and lack of response to continued ALK-inhibition.

Introduction The purpose of this study was to evaluate the safety and efficacy of PET and MRI guided re-irradiation of recurrent high-grade glioma (HGG) and to assess the impact of radiotherapy dose, fractionation and irradiated volume. Material and methods Patients with localized, recurrent HGG (grades III-IV) and no other treatment options were eligible for a prospective phase I trial. Gross tumor volumes for radiotherapy were defined using T1-contrast enhanced MRI and 18F-fluoro-ethyl tyrosine PET. Radiotherapy was delivered using volumetric modulated arc therapy with a 2-mm margin. The dose prescription of four consecutive groups was (1) 35 Gy/10fr., (2) 42 Gy/10fr., (3) 29.5 Gy/5fr. and (4) 35 Gy/10fr. to larger tumor volumes (100–300 cm3), respectively. Results Thirty-one patients were treated of which 81% had glioblastoma. The median progression-free survival was 2.8 months (95%CI: 2.1–3.5) and the median overall survival was 7.0 months (95%CI: 3.5–10.5). Early side effects were mild and included headache and fatigue. Seven patients were progression-free beyond 10 weeks and were evaluable for late toxicity. Among these patients, three (43%) suffered late adverse events which included radionecrosis and irreversible white matter changes. Conclusion Re-irradiation showed limited efficacy and 43% of patients achieving disease control suffered late toxicity that was manageable but not negligible. (Less)

Background and purpose To evaluate the patterns of failure following clinical introduction of amino-acid O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET)-PET-guided target definition for radiotherapy (RT) of glioblastoma patients. Materials and methods The first 66 consecutive patients with confirmed histology, scanned using FET-PET/CT and MRI were selected for evaluation. Chemo-radiotherapy was delivered to a volume based on both MRI and FET-PET (PET vol ). The volume of recurrence (RV) was defined on MRI data collected at the time of progression according to RANO criteria. Results Fifty patients were evaluable, with median follow-up of 45months. Central, in-field, marginal and distant recurrences were observed for 82%, 10%, 2%, and 6% of the patients, respectively. We found a volumetric overlap of 26%, 31% and 39% of the RV with the contrast-enhancing MR volume, PET vol and the composite MRPET vol , respectively. MGMT-methylation ( p =0.03), larger PET vol ( p p vol overlap. Conclusion The combined MRPET vol had a stronger association with the recurrence volume than either of the modalities alone. Larger overlap of PET vol and RV was observed for patients with MGMT-methylation, less extensive surgery, and large PET vol on the RT-planning scans.

Background and purpose Positron emission tomography (PET) provides quantitative metabolic information and potential biomarkers of treatment outcome. We aimed to determine the prognostic value of early 18 F-fluoroethyl-tyrosine ( 18 F-FET) PET scans acquired during re-irradiation for recurrent high-grade glioma (HGG). Material and methods A phase I clinical trial of re-irradiation of HGG was carried out. MRI and 18 F-FET PET were used for target delineation and follow-up. Images were acquired at baseline, during radiotherapy and 4weeks post-treatment and compared by measuring the metabolically active biological tumor volume (BTV) and maximal activity ( T max / B ). Correlations with outcomes were assessed by multivariate Cox regression analysis. Results Thirty-one patients were included and all patients have died. The median overall survival was 7.0 mos. Both baseline BTV and baseline MRI volume (necrotic/cystic cavities subtracted) were prognostic for overall survival (OS) in multivariate analysis (HR=1.3 p p T max / B were observed but they carried no independent prognostic information. Conclusions Baseline biological tumor volume (BTV) defined by 18 F-FET PET was prognostic for OS in multivariate analysis, as was MRI volume (necrotic/cystic cavities subtracted). Tumor volume may aid in identifying patients whose life expectancy is too short to warrant re-irradiation.

Patients with epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer (NSCLC) obtain substantial clinical benefit from EGFR tyrosine-kinase inhibitors (TKIs), but will ultimately develop TKI-resistance resulting in median progression-free survival of 9-15 months during first-line TKI-therapy. However, type and timing of TKI-resistance cannot be predicted and several mechanisms may simultaneously/subsequently occur during TKI-treatment. In this respect, we present a 49 year-old Caucasian male ex-smoker with metastatic pulmonary adenocarcinoma (ADC) that concomitantly harbored an EGFR exon 19-mutation (p.E746_A750delELREA) and a previously unreported 2bp frame-shift microdeletion in the fibroblast growth factor receptor 3 (FGFR3; p.D785fs*31) gene. Interestingly, FGFR3-mutations have previously been described in other cancer types of Caucasian patients and may represent an alternative pathway to EGFR-signaling. The patient received first-line erlotinib but after only 7 weeks showed metastatic pleural effusion, in which transformation to small cell lung cancer (SCLC) that retained the EGFR- and FGFR3-mutations was identified. Consequently, standard carboplatin-etoposide regimen for SCLC combined with erlotinib continuation was implemented obtaining significant objective response. However, after completing 6 cycles of this combination, new pulmonary and hepatic metastases appeared and showed persistence of the original EGFR- and FGFR3-mutated ADC phenotype together with acquisition of the erlotinib-resistant T790M EGFR-mutation. The patient rapidly deteriorated and deceased. Thus, this advanced EGFR-mutated NSCLC displayed very rapid onset and heterogeneous genetic and phenotypic mechanisms of TKI-resistance occurring at different times and locations of metastatic disease: concomitant FGFR3-mutation before and during TKI-treatment as potential intrinsic mechanism for the rapid progression; transformation to SCLC at first progression during TKI-therapy; acquired T790M EGFR-mutation at second progression. Our case also underlines that, when achievable, rebiopsies of progressive sites during TKI-treatment are important for identifying heterogeneous histopathological and molecular resistance mechanisms and better defining possible treatment modifications.

We sought to assess the impact of amino-acid (18)F-fluoro-ethyl-tyrosine (FET) positron emission tomography (PET) on the volumetric target definition for radiation therapy of high-grade glioma versus the current standard using MRI alone. Specifically, we investigated the influence of tumor grade, MR-defined tumor volume, and the extent of surgical resection on PET positivity.Fifty-four consecutive high-grade glioma patients (World Health Organization grades III-IV) with confirmed histology were scanned using FET-PET/CT and T1 and T2/fluid attenuated inversion recovery MRI. Gross tumor volume and clinical target volumes (CTVs) were defined in a blinded fashion based on MRI and subsequently PET, and volumetric analysis was performed. The extent of the surgical resection was reviewed using postoperative MRI.Overall, for ∼ 90% of the patients, the PET-positive volumes were encompassed by T1 MRI with contrast-defined tumor plus a 20-mm margin. The tumor volume defined by PET was larger for glioma grade IV (P.001) and smaller for patients with more extensive surgical resection (P = .004). The margin required to be added to the MRI-defined tumor in order to fully encompass the FET-PET positive volume tended to be larger for grade IV tumors (P = .018).With an unchanged CTV margin and by including FET-PET for gross tumor volume definition, the CTV will increase moderately for most patients, and quite substantially for a minority of patients. Patients with grade IV glioma were found to be the primary candidates for PET-guided radiation therapy planning.

OBJECTIVES: The aim of this prospective multicenter study was to evaluate and compare the diagnostic performance of PET/CT, MRI and transvaginal two-dimensional ultrasound (2DUS) in the preoperative assessment of endometrial cancer (EC). METHODS: 318 consecutive women with EC were included when referred to three Danish tertiary gynecological centers for surgical treatment. Preoperatively they were PET/CT-, MRI-, and 2DUS scanned. The imaging results were compared to the final pathological findings. This study was approved by the National Committee on Health Research Ethics. RESULTS: For predicting myometrial invasion, we found sensitivity, specificity, PPV, NPV, and accuracy for PET/CT to be 93%, 49%, 41%, 95% and 61%, for MRI to be 87%, 57%, 44%, 92%, and 66% and for 2DUS to be 71%, 72%, 51%, 86% and 72%. For predicting cervical invasion, the values were 43%, 94%, 69%, 85% and 83%, respectively, for PET/CT, 33%, 95%, 60%, 85%, and 82%, respectively, for MRI, and 29%, 92%, 48%, 82% and 78% for 2DUS. Finally, for lymph node metastases, the values were 74%, 93%, 59%, 96%, and 91% for PET/CT and 59%, 93%, 40%, 97% and 90% for MRI. When comparing the diagnostic performance we found PET/CT, MRI and 2DUS to be comparable in predicting myometrial invasion. For cervical invasion and lymph node metastases, however, PET/CT was the best. CONCLUSIONS: None of the modalities can yet replace surgical staging. However, they all contributed to important knowledge and were, furthermore, able to upstage low-risk patients who would not have been recommended lymph node resection based on histology and grade alone.

The purpose of this study was to investigate and assess the correlation and reproducibility of multiparametric imaging in head and neck cancer patients. Methods: Twenty-one patients were included in this prospective scan–rescan study. All patients were scanned twice on an integrated PET and MRI scanner. Gross tumor volumes were defined on T2-weighted MR images, and volumes of interest were defined on diffusion-weighted MRI and 18F-FDG PET (VOIDWI, VOIPET). Overlap between volumes was assessed as a percentwise overlap. 18F-FDG uptake and diffusion were measured using SUV and apparent diffusion coefficient, and correlation was tested across and within patients and as a voxel-by-voxel analysis. Results: Seventeen patients were available for correlation analysis, and 12 patients were available for assessment of tumor overlap. The median tumor overlap between VOIDWI and VOIPET was 82% (VOIDWI in VOIPET) and 62% (VOIPET in VOIDWI) on scan 1 and scan 2, respectively. Across patients, the correlation between SUV and apparent diffusion coefficient was weak and nonsignificant. However, in individual patients a weak but significant correlation was identified on a voxel-by-voxel basis. Conclusion: In multiparametric imaging with the integrated PET/MR scanner, the VOIs from DWI and 18F-FDG PET were both within the target volume for radiotherapy and overlapped substantially although not completely. No correlation between 18F-FDG uptake and DWI could be found across patients, but within individual patients a statistically significant, but weak, voxel-by-voxel correlation was found. The findings suggest that information on glucose uptake and diffusion coefficient carries complementary information of interest that may be relevant for radiotherapy treatment planning.

Positron emission tomography (PET) provides quantitative metabolic information and potential biomarkers of treatment outcome. We aimed to determine the prognostic value of earlyA phase I clinical trial of re-irradiation of HGG was carried out. MRI andThirty-one patients were included and all patients have died. The median overall survival was 7.0 mos. Both baseline BTV and baseline MRI volume (necrotic/cystic cavities subtracted) were prognostic for overall survival (OS) in multivariate analysis (HR=1.3 p0.01 and HR=1.3 p0.01, respectively). Early changes in BTV and TBaseline biological tumor volume (BTV) defined by

To the Editor,Concomitant radio-chemotherapy is the standard treatment for locally advanced non-small cell lung cancer (NSCLC), with a five-year survival of only approximately 15–20% [1]. Several c...

We present the findings on F FDG PET/CT in connection with iatrogenic venous air embolism. The patient was referred for a posttreatment evaluation PET/CT for peripheral T-cell lymphoma. On the PET images, an intense FDG-uptake was seen in the injected vein. Simultaneous non-contrast-enhanced CT showed air bubbles of various sizes within the affected veins. Because no intravenous contrast was administered, we conclude that the source of venous air embolism was either the insertion of the peripheral intravenous cannula and/or the injection of F FDG, via a power injector, 1 hour before the scan.

Objectives To estimate the diagnostic accuracy of sentinel node biopsy (SNB) combined with preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) for inguinal lymph node (LN) evaluation in patients with invasive penile squamous cell carcinoma (PSCC) with no clinical evidence of inguinal metastases (cN0) at two tertiary centres with complete clinical follow-up. Patients and Methods From April 2010 in Centre one and from January 2013 in Centre two, we prospectively enrolled patients diagnosed with invasive PSCC and scheduled for SNB at the only two university centres treating penile cancer in Denmark. All patients had FDG PET/CT before SNB. The sentinel LNs were preoperatively located by planar lymphoscintigraphy in 134 groins (68 patients) and by single-photon emission CT/CT in 120 groins (61 patients). The primary endpoints were the sensitivity, specificity, and false-negative rate of SNB combined with FDG PET/CT. The secondary endpoint was SNB-related morbidity. Results We examined 254 groins in 129 patients by SNB combined with FDG PET/CT. The median (interquartile range, IQR) follow-up of survivors was 23 (14–35) months. Of 201 LN-negative groins, two were false negatives, and despite radio-chemotherapy treatment, both patients died from penile cancer. Four of 23 radiotracer-silent groins, had a FDG PET/CT-positive LNs and were surgically explored. In one of four of the explored groins, a positive LN was found. Combined FDG PET/CT-SNB sensitivity was 94.4% (95% confidence interval [CI] 81–99%) per groin. The false-negative rate was 5.6% (95% CI 1–19%) per groin. In 15 patients (11.6%) there were 25 SNB-related complications of Clavien–Dindo grades I–IIIa. The only Clavien–Dindo IIIa complication was an inguinal lymphocele treated by aspiration. Conclusion In this study, we present a favourable SNB false-negative rate of 5.6% in a national cohort of clinically LN-negative patients with invasive PSCC with a pre-SNB FDG PET/CT scan. The combination of FDG PET/CT and SNB seems to be a promising diagnostic approach. Even so, a false-negative SNB was fatal in two of two cases and we are determined to continue the development of our SNB technique. The SNB-related morbidity was limited.

PURPOSE: To evaluate if post-surgical magnetic resonance imaging (MRI) in combination with positron emission tomography (PET) is a better predictor for localization of treatment failure than MRI alone in patients with high grade gliomas. METHODS: Twenty-one patients with primary glioblastoma WHO grade IV were included in this retrospective study. Post-surgical, contrast-enhanced MRI was used to define the gross tumor volume (GTV-MR). In addition, 18F-fluoro-ethyltyrosine (FET) PET was performed, and the FET-positive volume was semi-automatically determined by including tissue with an uptake exceeding 1.6 times the uptake in normal appearing gray matter, and subsequently manually edited to exclude non-tumor. We defined GTV-MR in combination with FET as GTV-MRPET. Clinical target volume (CTV) was defined by adding a two centimeter margin to GTV-MR and modified to include the FET-volume. Patients were treated with surgery and subsequent chemo-radiation (RCX) to 60 Gy in 30 fractions to the CTV plus concurrent and adjuvant temozolomide (TMZ). Treatment failure volume (TFV) was defined as the earliest radiological evidence of residual or recurrent disease on post-therapeutic MRI. The maximum distances from GTV-MR and GTV-MRPET to encompass TFV, and the sensitivity as well as specificity between TV and TFV, were calculated and pairwise compared (Wilcoxon). RESULTS: The maximum distance to encompass TFV was significantly higher (p < 0.001) for GTV-MR (12.7 mm [3.20-73.6]) compared to GTV-MRPET (11.4 mm [3.15-73.6]). GTV-MRPET was significantly more sensitive in predicting the location of TFV (p < 0.001), however the specificity was significantly lower (p < 0.001). CONCLUSION: GTV-MRPET required smaller margin to encompass the TFV, was more sensitive but less specific than GTV-MR.

METHODS: The study population comprised of 54 pts with high grade glioma treated with RT and Temozolomide. CT and MRI images were fused in a radiation therapy treatment planning software. GTV was delineated as a contrast-enhancing tumor plus the operation cavity, defined by a radiologist blinded to the results of FET/PET. The CTV was generated by the geometric expansion of GTV plus 20 mm and the PTV was achieved by an additional margin to the CTV by 2 mm. The FET-PET volume was determined by SUV of 1.6. On corresponding axial slices, FET uptake was compared to contrast enhancement in T1-weighted MR. Intensity modulated arc therapy (IMAT) with steep dose-gradients was delivered using daily image-guidance and 6D patient positioning. Pts received 60 Gy in 30 fractions. RESULTS: Five pts had no postoperative FET-PET uptake. Of 49 pts, 5 pts were diagnosed with PET positive areas outside the GTV plus 20 mm. In 40% of the cases there was a similarity between GTV defined by MRI and FET/PET, respectively. CONCLUSION: In this retrospective study of 54 pts, pretreatment FET-PET appears to identify areas of tumor activity outside the MRI-GTV, with the majority placed in the CTV. With stereotactic radiotherapy and a steeper gradient it is important with better imaging technique to define the tumor. With an unchanged CTV margin and by including FET PET for GTV definition, the irradiated volume will tend to increase moderately for most patients, and quite substantially for a minority of patients. Prospective radiation therapy trials could determine if the GTV-to-CTV margin can be adjusted with FET-PET.

BACKGROUND: Surgery followed by radiotherapy and concomitant and adjuvant temozolomide is standard therapy in newly diagnosed glioblastoma multiforme (GBM). Bevacizumab combined with irinotecan produces impressive response rates in recurrent GBM. In a randomized phase II study, we investigated the efficacy of neoadjuvant bevacizumab combined with irinotecan (Bev-Iri) versus bevacizumab combined with temozolomide (Bev-Tem) before, during and after radiotherapy in newly diagnosed GBM.MATERIAL AND METHODS: After surgery, patients were randomized to Bev-Iri or Bev-Tem for eight weeks, followed by standard radiotherapy (60 Gy/30 fractions) and concomitant Bev-Iri or Bev-Tem followed by adjuvant Bev-Iri or Bev-Tem for another eight weeks. Bev-Iri: Bevacizumab and irinotecan were given every 14 days before, during and after radiotherapy. Bev-Tem: Bevacizumab was given as in Bev-Iri and temozolomide was given for five days every four weeks before and after radiotherapy and once daily during radiotherapy. The primary endpoint was response after neoadjuvant chemotherapy and a pre-specified response rate of 30% or more was considered of interest for future studies. Secondary endpoints were progression-free survival (PFS) and toxicity.RESULTS: The response rate was 32% (95% CI 17-51%) for Bev-Tem (n = 32) and 23% (95% CI 9-44%) for Bev-Iri (n = 31) (p = 0.56). Median PFS was 7.7 and 7.3 months for Bev-Tem and Bev-Iri, respectively. Hematological toxicity was more frequent with Bev-Tem including one death from febrile neutropenia whereas non-hematological toxicity was manageable.CONCLUSIONS: Only the Bev-Tem arm met the pre-specified level of activity of interest. Our results did not indicate any benefit from Bev-Iri in first-line therapy as opposed to Bev-Tem in terms of response and PFS.

Background Anaplastic lymphoma kinase-positive non-small cell lung carcinoma patients are generally highly responsive to the dual anaplastic lymphoma kinase and MET tyrosine kinase inhibitor crizotinib. However, they eventually acquire resistance to this drug, preventing the anaplastic lymphoma kinase inhibitors from having a prolonged beneficial effect. The molecular mechanisms responsible for crizotinib resistance are beginning to emerge, e.g., in some anaplastic lymphoma kinase-positive non-small cell lung carcinomas the development of secondary mutations in this gene has been described. However, the events behind crizotinib-resistance currently remain largely uncharacterized. Thus, we report on an anaplastic lymphoma kinase-positive non-small cell lung carcinoma patient with concomitant occurrence of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations upon development of crizotinib-resistance. Case presentation A 61-year-old Caucasian never-smoking male was diagnosed with anaplastic lymphoma kinase -positive pulmonary adenocarcinoma, stage T4N3M1b. Treatment with crizotinib initially resulted in complete objective response in the thorax and partial response in the abdomen, but after 8 months of therapy the patient acquired resistance and progressed. Biopsies from new metastases revealed development of epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations concomitant with the original anaplastic lymphoma kinase gene rearrangement and without signs of anaplastic lymphoma kinase fusion gene amplification or secondary anaplastic lymphoma kinase mutations. Conclusion To our knowledge, this is the first report of an anaplastic lymphoma kinase-positive pulmonary adenocarcinoma, which upon emergence of crizotinib resistance acquired 2 new somatic mutations in the epidermal growth factor receptor and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog genes, respectively, concomitant with the original anaplastic lymphoma kinase rearrangement. Thus, these 3 driver mutations, usually considered mutually exclusive, may coexist in advanced non-small cell lung carcinoma that becomes resistant to crizotinib, presumably because heterogeneous tumor clones utilize epidermal growth factor receptor and/or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog signaling to circumvent the inhibition of anaplastic lymphoma kinase-mediated signaling by crizotinib. The identification of new targetable somatic mutations by tumor re-biopsy may help clarify the mechanism behind the development of the acquired crizotinib resistance and pave the way for combined strategies involving multiple targeted therapies.

Learning Objectives After completing this course, the reader will be able to: Compare the diagnostic performances of 18F-FDG PET/CT and conventional CT with respect to their ability to detect primary tumor sites in carcinoma of unknown primary patients with extracervical metastases.Describe the rate of identification of primary tumor sites using 18F-FDG PET/CT and conventional CT. CME This article is available for continuing medical education credit at CME.TheOncologist.com Background. The aim of the present study was to evaluate prospectively the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and conventional CT regarding the ability to detect the primary tumor site in patients with extracervical metastases from carcinoma of unknown primary (CUP) site. Patients and Methods. From January 2006 to December 2010, 136 newly diagnosed CUP patients with extracervical metastases underwent 18F-FDG PET/CT. A standard of reference (SR) was established by a multidisciplinary team to ensure that the same set of criteria were used for classification of patients, that is, either as CUP patients or patients with a suggested primary tumor site. The independently obtained suggestions of primary tumor sites using PET/CT and CT were correlated with the SR to reach a consensus regarding true-positive (TP), true-negative, false-negative, and false-positive results. Results. SR identified a primary tumor site in 66 CUP patients (48.9%). PET/CT identified 38 TP primary tumor sites and CT identified 43 TP primary tumor sites. No statistically significant differences were observed between 18F-FDG PET/CT and CT alone in regard to sensitivity, specificity, and accuracy. Conclusion. In the general CUP population with multiple extracervical metastases 18F-FDG PET/CT does not represent a clear diagnostic advantage over CT alone regarding the ability to detect the primary tumor site.