Brain Metastases as Inaugural Sign of Non-Small Cell Lung Carcinoma: Case Series and Review of Literature.

In the era of immune checkpoint inhibitors (ICI), managing non-oncogene driven non-small cell lung cancer (NSCLC) with brain metastases (BM) is challenging, especially when brain involvement is the initial sign. Patients with newly diagnosed brain metastatic NSCLC without epidermal growth factor receptor (EFGR) nor anaplastic lymphoma kinase (ALK) alterations were retrospectively included. Twenty-five patients were analyzed; 15 (60%) had symptomatic BM as the first sign (group 1), while 10 (40%) had BM discovered during complementary examinations (group 2). Fourteen patients (56%) had concomitant extracerebral metastases, primarily in group 2. Eight (32%) had oligometastatic disease, with seven in group 1. Over half received chemotherapy and pembrolizumab as first-line treatment. BM surgical resection occurred in twelve (80%) patients in group 1 and one in group 2. Median cerebral progression-free survival was 10 months: 12 in group 1 and 5 in group 2. Median overall survival was 25 months: not reached in group 1 and 6 months in group 2. This case series highlights survival outcomes for patients with inaugural BM, a demographic underrepresented in pivotal trials. Oligometastatic disease and symptomatic BM as initial signs seem associated with better prognosis due to increased use of multimodal local approaches. Combining local approaches with first-line ICI+/- chemotherapy appears to improve survival in brain metastatic NSCLC. A literature review was conducted to explore key questions regarding upfront ICI alone or in combination with systemic drugs or local approaches in brain metastatic NSCLC.

A single chemotherapy administration induces muscle atrophy, mitochondrial alterations and apoptosis in breast cancer patients.

BACKGROUND: Breast cancer patients are commonly treated with sequential administrations of epirubicin-cyclophosphamide (EC) and paclitaxel (TAX). The chronic effect of this treatment induces skeletal muscle alterations, but the specific effect of each chemotherapy agent is unknown. This study aimed to investigate the effect of EC or TAX administration on skeletal muscle homeostasis in breast cancer patients. METHODS: Twenty early breast cancer patients undergoing EC followed by TAX chemotherapies were included. Two groups of 10 women were established and performed vastus lateralis skeletal muscle biopsies either before the first administration (pre) of EC (50 ± 14 years) or TAX (50 ± 16 years) and 4 days later (post). Mitochondrial respiratory capacity recording, reactive oxygen species production, western blotting and histological analyses were performed. RESULTS: Decrease in muscle fibres cross-sectional area was only observed post-EC (-25%; P < 0.001), associated with a reduction in mitochondrial respiratory capacity for the complex I (CI)-linked substrate state (-32%; P = 0.001), oxidative phosphorylation (OXPHOS) by CI (-35%; P = 0.002), CI&CII (-26%; P = 0.022) and CII (-24%; P = 0.027). If H2 O2 production was unchanged post-EC, an increase was observed post-TAX for OXPHOS by CII (+25%; P = 0.022). We found a decrease in makers of mitochondrial content, as shown post-EC by a decrease in the protein levels of citrate synthase (-53%; P < 0.001) and VDAC (-39%; P < 0.001). Despite no changes in markers of mitochondrial fission, a decrease in the expression of a marker of mitochondrial inner-membrane fusion was found post-EC (OPA1; -60%; P < 0.001). We explored markers of mitophagy and found reductions post-EC in the protein levels of PINK1 (-63%; P < 0.001) and Parkin (-56%; P = 0.005), without changes post-TAX. An increasing trend in Bax protein level was found post-EC (+96%; P = 0.068) and post-TAX (+77%; P = 0.073), while the Bcl-2 level was decreased only post-EC (-52%; P = 0.007). If an increasing trend in TUNEL-positive signal was observed post-EC (+68%; P = 0.082), upregulation was highlighted post-TAX (+86%; P < 0.001), suggesting activation of the apoptosis process. CONCLUSIONS: We demonstrated that a single administration of EC induced, in only 4 days, skeletal muscle atrophy and mitochondrial alterations in breast cancer patients. These alterations were characterized by reductions in mitochondrial function and content as well as impairment of mitochondrial dynamics and an increase in apoptosis. TAX administration did not worsen these alterations as this group had already received EC during the preceding weeks. However, it resulted in an increased apoptosis, likely in response to the increased H2 O2 production.

Primary resistance to ALK inhibitors in KLC1/ALK-rearranged pleural metastatic lung adenocarcinoma: a case report.

Background: Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to second- and third-generation ALK inhibitors, which have become the standard of care for ALK-positive non-small cell lung carcinoma (NSCLC). However, primary resistance to these inhibitors remains a rare and poorly understood phenomenon, especially in cases involving kinesin light chain 1 (KLC1)/ALK-rearranged metastatic NSCLC. Case Description: In this report, we present a unique and challenging case of primary resistance to second- and third-generation ALK tyrosine kinase inhibitors (TKIs) attributed to KLC1/ALK gene fusion partners in a patient with ALK-positive pleural metastatic NSCLC. The patient's disease progression was rapid and unresponsive to multiple lines of ALK-targeted therapies, including alectinib, brigatinib, and lorlatinib, underscoring the need for a deeper understanding of primary resistance mechanisms in such cases. Conclusions: The occurrence of primary resistance to ALK inhibitors in metastatic NSCLC with ALK rearrangement is an infrequent occurrence, and its underlying mechanisms remain elusive. This case emphasizes the importance of further research to elucidate the specific mechanisms of primary resistance to ALK TKIs in non-canonical ALK fusion partners like KLC1. Developing targeted therapies for such rare cases is a clinical challenge that warrants continued investigation and innovation in the field of precision oncology.

Anaplastic Lymphoma Kinase Inhibitor-Induced Neutropenia: A Systematic Review.

Lung cancers with ALK rearrangement represent less than 5% of all lung cancers. ALK inhibitors are currently used to treat first-line metastatic non-small cell lung cancer with ALK rearrangement. Compared to chemotherapy, ALK inhibitors have improved progression-free survival, overall survival, and quality of life for patients. The results of several phase 3 studies with a follow-up of over 6 years suggest that the life expectancy of these patients treated with targeted therapies is significantly higher than 5 years and could approach 10 years. Nevertheless, these treatments induce haematological toxicities, including neutropenia. Few data are available on neutropenia induced by ALK inhibitors and on the pathophysiological mechanism and therapeutic adaptations necessary to continue the treatment. Given the high efficacy of these treatments, managing side effects to avoid treatment interruptions is essential. Here, we have reviewed the data from published clinical studies and case reports to provide an overview of neutropenia induced by ALK inhibitors.

Acquired L718V/TP53 co-mutation and discordant molecular pattern between plasmatic and cerebrospinal fluid in a bone and meningeal metastatic L858R+ non-small cell lung cancer: a case report.

Background: Osimertinib is approved in first line metastatic epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). Acquired EGFR L718V mutation is a rare mechanism of resistance towards osimertinib in L858R+ NSCLC with potential sensibility to afatinib. This case reported an acquired EGFR L718V/TP53 V727M resistance co-mutation to osimertinib with discordant molecular pattern between plasmatic and cerebral fluid in a leptomeningeal and bone metastatic EGFR L858R mutant NSCLC. Case Description: A 52-year-old female, diagnosed with a bone metastatic EGFR L858R-mutated NSCLC, was treated with osimertinib as second line treatment for a leptomeningeal progression. She developed an acquired EGFR L718V/TP53 V272M resistance co-mutation after seventeen months of treatment. Discordant molecular status was observed between plasmatic (L718V+/TP53+/L858R+) and cerebrospinal fluid (CSF) (L718V-/TP53+/L858R+). Afatinib as third line did not prevent neurological progression. Conclusions: Acquired EGFR L718V mutation mediate a rare mechanism of resistance to osimertinib. Some cases reported sensibility to afatinib in patients with EGFR L718V mutation. In this described case, afatinib had no efficacy against neurological progression. This could be explained by the absence of EGFR L718V mutation in CSF tumor cells and concomitant TP53 V272M mutation as negative survival prognostic. Identify resistance mechanisms against osimertinib and develop specific therapeutic approaches remain a challenge in clinical routine.

68Ga-DOTATOC PET in Extracranial Hepatic and Bone Metastasis of Atypical Refractory Meningioma: A Case Report.

ABSTRACT: A falcine meningioma was diagnosed in a 66-year-old woman and was treated by surgery and 2 times by radiotherapy during 9 years of follow-up with the diagnosis of atypical meningioma. Three months after the last radiotherapy, incidental liver lesions were detected on chest CT realized for suspected pneumonia. In view of the predisposing factors for meningioma metastases, 68Ga-DOTATOC hepatic and cerebral PET/MRI was performed and completed by total body PET/CT demonstrating a somatostatin receptor 2 overexpression of the multiple liver lesions and several bone lesions. Biopsies from the liver and iliac bone confirmed the metastatic origin of meningioma.

Development of skeletal muscle atrophy and intermuscular adipose tissue in patients with early breast cancer treated with chemotherapy.

Chemotherapy is a common therapy to treat patients with breast cancer but also leads to skeletal muscle deconditioning. Skeletal muscle deconditioning is multifactorial and intermuscular adipose tissue (IMAT) accumulation is closely linked to muscle dysfunction. To date, there is no clinical study available investigating IMAT development through a longitudinal protocol and the underlying mechanisms remain unknown. Our study was dedicated to investigating IMAT content in patients with early breast cancer who were treated with chemotherapy and exploring the subsequent cellular mechanisms involved in its development. We included 13 women undergoing chemotherapy. Muscle biopsies and ultrasonography assessment were performed before and after chemotherapy completion. Histological and Western blotting analyses were conducted. We found a substantial increase in protein levels of three mature adipocyte markers (perilipin, +901%; adiponectin, +135%; FABP4, +321%; P < 0.05). These results were supported by an increase in oil red O-positive staining (+358%; P < 0.05). A substantial increase in PDGFRα protein levels was observed (+476%; P < 0.05) highlighting an increase in fibro-adipogenic progenitors (FAPs) content. The cross-sectional area of the vastus lateralis muscle fibers substantially decreased (-21%; P < 0.01), and muscle architecture was altered, as shown by a decrease in fascicle length (-15%; P < 0.05) and a decreasing trend in muscle thickness (-8%; P = 0.08). We demonstrated both IMAT development and muscle atrophy in patients with breast cancer who were treated with chemotherapy. FAPs, critical stem cells inducing both IMAT development and skeletal muscle atrophy, also increased, suggesting that FAPs likely play a critical role in the skeletal muscle deconditioning observed in patients with breast cancer who were treated with chemotherapy.

Chemotherapy impairs skeletal muscle mitochondrial homeostasis in early breast cancer patients.

BACKGROUND: Chemotherapy is extensively used to treat breast cancer and is associated with skeletal muscle deconditioning, which is known to reduce patients' quality of life, treatment efficiency, and overall survival. To date, skeletal muscle mitochondrial alterations represent a major aspect explored in breast cancer patients; nevertheless, the cellular mechanisms remain relatively unknown. This study was dedicated to investigating overall skeletal muscle mitochondrial homeostasis in early breast cancer patients undergoing chemotherapy, including mitochondrial quantity, function, and dynamics. METHODS: Women undergoing (neo)adjuvant anthracycline-cyclophosphamide and taxane-based chemotherapy participated in this study (56 ± 12 years). Two muscle biopsies were collected from the vastus lateralis muscle before the first and after the last chemotherapy administration. Mitochondrial respiratory capacity, reactive oxygen species production, and western blotting analyses were performed. RESULTS: Among the 11 patients, we found a decrease in key markers of mitochondrial quantity, reaching -52.0% for citrate synthase protein levels (P = 0.02) and -38.2% for VDAC protein levels (P = 0.04). This mitochondrial content loss is likely explained by reduced mitochondrial biogenesis, as evidenced by a decrease in PGC-1α1 protein levels (-29.5%; P = 0.04). Mitochondrial dynamics were altered, as documented by a decrease in MFN2 protein expression (-33.4%; P = 0.01), a key marker of mitochondrial outer membrane fusion. Mitochondrial fission is a prerequisite for mitophagy activation, and no variation was found in either key markers of mitochondrial fission (Fis1 and DRP1) or mitophagy (Parkin, PINK1, and Mul1). Two contradictory hypotheses arise from these results: defective mitophagy, which probably increases the number of damaged and fragmented mitochondria, or a relative increase in mitophagy through elevated mitophagic potential (Parkin/VDAC ratio; +176.4%; P < 0.02). Despite no change in mitochondrial respiratory capacity and COX IV protein levels, we found an elevation in H2 O2 production (P < 0.05 for all substrate additions) without change in antioxidant enzymes. We investigated the apoptosis pathway and found an increase in the protein expression of the apoptosis initiation marker Bax (+72.0%; P = 0.04), without variation in the anti-apoptotic protein Bcl-2. CONCLUSIONS: This study demonstrated major mitochondrial alterations subsequent to chemotherapy in early breast cancer patients: (i) a striking reduction in mitochondrial biogenesis, (ii) altered mitochondrial dynamics and potential mitophagy defects, (iii) exacerbated H2 O2 production, and (iv) increased initiation of apoptosis. All of these alterations likely explain, at least in part, the high prevalence of skeletal muscle and cardiorespiratory deconditioning classically observed in breast cancer patients.

Immune-Related Cerebellar Ataxia: A Rare Adverse Effect of Checkpoint Inhibitor Therapy.

Immune checkpoint inhibitors (ICIs) have led to a revolution in cancer management, mainly due to lasting long-term durable responses in a subset of patients with metastatic solid tumours (Gettinger et al. in JCO 36(17):1675-1684, 2018). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological immune-related adverse events (irAEs) has increased (2). Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs (Johnson et al. in J Immuno Cancer 7(1):134, 2019; Wang et al. in JAMA Oncol 4(12):1721, 2018). Small-cell lung cancer (SCLC) is common cause of neurologic paraneoplastic syndrome (Sebastian et al. in J Thorac Oncol 14(11):1878-1880, 2019). Nevertheless, the distinction between neurologic iRAEs and paraneoplastic neurological syndromes (PNSs) in patients with SCLC treated by ICIs remains challenging (Williams et al. JAMA Neurol 73(8):928, 2016). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological autoimmune adverse events has increased. Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs and have yet to be fully understood. We report a case of an immune induced cerebellar ataxia in a 47 year-old small-cell neuroendocrine carcinoma patient undergoing checkpoint blockade by atezolizumab, a programmed cell death-1 ligand (PDL-1) inhibitor. After 4 cycles of immunotherapy, the patient presented with kinetic and static cerebellar syndrome leading to the diagnosis of TRIM9-Abs ICI-related cerebellar irAE. Therapeutic management was discussed in multidisciplinary meetings in the lack of therapeutic guidelines. There was no clinical improvement. Because of high morbidity and no treatment evidence, neurologic symptoms developing under ICI require early diagnosis and may indicate the need for definitive treatment discontinuation.

High risk of recurrence for grade II meningioma: a 10-year multicenter analysis of prognosis factors.

BACKGROUND: Atypical meningioma is a variant of meningioma with a high risk of recurrence. Gross total resection is the standard of treatment, while no consensus on optimal adjuvant management has been found. METHODS: Between 2008 and 2018, a retrospective search identified 216 grade II meningiomas treated in six centers. Clinical, histological, and therapeutic data were analyzed to determine the prognostic factors of recurrence and survival. RESULTS: In total, 216 patients underwent surgical resection. Among these, 122 patients (56%) underwent gross total resection, and 21% of the patients received adjuvant radiotherapy. Univariate analysis reported subtotal resection, high Ki-67, negative progesterone receptor (PR) and histological grade evolution as unfavorable prognosis factors. According to multivariate analysis, the Ki-67 proliferative index (cut-off value of 17.5%) was the only prognostic factor of recurrence (HR 1.1; 95% CI, 1.0-1.2, P=0.048). Gross total resection improved progression-free survival (PFS) (P=0.03) but without impact on overall survival (OS) (P=0.2). Median PFS and OS times were longer for patients receiving adjuvant radiotherapy than those who did not receive adjuvant radiotherapy. PFS (P=0.3) and OS (P=0.7) were associated with adjuvant RT by trend only. After a median follow-up time of 6.7 years, 99 (46%) patients relapsed. Median progression-free and OS rates were 4.5 (95% CI, 3.5-5.5) and 14.7 years (11.4-NA), respectively. CONCLUSIONS: In this study, Ki-67 proliferative index was significantly associated with recurrence. Gross total resection significantly improved PFS without impacting OS. Adjuvant radiotherapy delayed recurrence and improved OS, but a longer follow-up time is needed to distinguish a statistically significant difference. Large prospective studies are needed to determine postoperative treatment guidelines.

18F-FDG PET/CT Monitoring of Tumor Response to Tyrosine Kinase Inhibitors and Alkylating Drugs in an SDH-Deficient GIST.

ABSTRACT: Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are associated with loss of function of SDH complex and represent 5% to 7.5% of GISTs. SDH-deficient GISTs usually develop in the stomach of children and young adults, and could be part of Carney triad or Carney-Stratakis syndromes including paraganglioma. SDH-deficient GISTs are often indolent despite the high rate of distant metastasis, and overall unresponsive to tyrosine kinase inhibitors. However, epigenetic inactivation of MGMT leads to potential effectiveness of alkylating agents. We report the 18F-FDG PET/CT results for monitoring response to TKI and alkylating drugs in a patient with refractory SDHB-deficient GIST.

Usefulness of 18F-FDOPA PET for the management of primary brain tumors: a systematic review of the literature.

Contrast-enhanced magnetic resonance imaging is currently the standard of care in the management of primary brain tumors, although certain limitations remain. Metabolic imaging has proven useful for an increasing number of indications in oncology over the past few years, most particularly 18F-FDG PET/CT. In neuro-oncology, 18F-FDG was insufficient to clearly evaluate brain tumors. Amino-acid radiotracers such as 18F-FDOPA were then evaluated in the management of brain diseases, notably tumoral diseases. Even though European guidelines on the use of amino-acid PET in gliomas have been published, it is crucial that future studies standardize acquisition and interpretation parameters. The aim of this article was to systematically review the potential effect of this metabolic imaging technique in numerous steps of the disease: primary and recurrence diagnosis, grading, local and systemic treatment assessment, and prognosis. A total of 41 articles were included and analyzed in this review. It appears that 18F-FDOPA PET holds promise as an effective additional tool in the management of gliomas. More consistent prospective studies are still needed.

Metabolomic Profile of Aggressive Meningiomas by Using High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance.

Meningiomas are in most cases benign brain tumors. The WHO 2016 classification defines three grades of meningiomas. This classification had a prognosis value because grade III meningiomas have a worse prognosis value compared to grades I and II meningiomas. However, some benign or atypical meningiomas can have a clinical aggressive behavior. There are currently no reliable markers which allow distinguishing between the meningiomas with a good prognosis and those which may recur. High-resolution magic angle spinning (HRMAS) spectrometry is a noninvasive method able to determine the metabolite profile of a tissue sample. We retrospectively analyzed 62 meningioma samples by using HRMAS spectrometry (43 metabolites). We described a metabolic profile defined by a high concentration for acetate, threonine, N-acetyl-lysine, hydroxybutyrate, myoinositol, ascorbate, scylloinositol, and total choline and a low concentration for aspartate, glucose, isoleucine, valine, adenosine, arginine, and alanine. This metabolomic signature was associated with poor prognosis histological markers [Ki-67 ≥ 40%, high histological grade and negative progesterone receptor (PR) expression]. We also described a similar metabolomic spectrum between grade III and grade I meningiomas. Moreover, all grade I meningiomas with a low Ki-67 expression and a positive PR expression did not have the same metabolomic profile. Metabolomic analysis could be used to determine an aggressive meningioma in order to discuss a personalized treatment. Further studies are needed to confirm these results and to correlate this metabolic profile with survival data.

Ceritinib-related interstitial lung disease improving after treatment cessation without recurrence under either crizotinib or brigatinib: a case report.

Anaplastic lymphoma kinase inhibitors (ALKi) like ceritinib are considered standard for front-line treatment of non-small cell lung cancers (NSCLC) harboring a translocation of the anaplastic lymphoma kinase (ALK) gene. We report herein a case of interstitial lung disease (ILD) that developed following a 7-month ceritinib treatment without recurrence under either crizotinib or brigatinib, two others ALKi.

Grade III meningioma with gastro-intestinal tract and brain metastases: case report and review of the literature.

BACKGROUND: Meningioma is the most common adult primary intracranial tumor. Malignant meningioma is a rare variant of meningioma. The prognosis for the patients with these tumors is poor, due to the tumor's capacity for relapse and to develop distant metastases. These tumors can present the same evolutionary course as aggressive carcinoma. CASE DESCRIPTION: We report the case of distant brain and gastro-intestinal tract (GIT) metastases. A 78-year-old patient developed malignant meningioma with a Ki-67 proliferative index of 40%. According to guidelines, surgery followed by postoperative radiotherapy (RT) was performed. Three months after the end of RT, he presented histologically proven meningioma distant brain and GIT metastases. CONCLUSIONS: To our knowledge, this is the first case of meningioma GIT metastases. Also, we report the difficulty to confirm the diagnosis of meningioma metastases. Indeed, malignant meningioma has the same histopathological features as melanoma or carcinoma. The standard of care for the management of malignant meningioma is gross total surgery followed by postoperative radiotherapy. Metastatic meningioma is uncommon and no guidelines for the management of recurrent or metastatic meningioma have yet been published. However, several studies reported systemic therapeutic options such as antibody against VEGF, somatostatin analogs, PDGF-R, and VEGF-R tyrosine kinase inhibitors, in the case of recurrent or metastatic meningioma. We also made a review of the actual literature of systemic treatment options for metastatic meningioma.

Comparison of pediatric and adult hospice patients using electronic medical record data from nine hospices in the United States, 2008-2012.

BACKGROUND: Most pediatric hospice patients receive services from agencies typically oriented to adults. Information regarding how pediatric hospice patients differ from adult hospice patients is lacking. OBJECTIVE: We aim to assess differences between pediatric and adult hospice patients regarding patient characteristics and outcomes. METHODS: We compiled a retrospective inception cohort of patients enrolled at nine hospices in the CHOICE network (Coalition of Hospices Organized to Investigate Comparative Effectiveness) between August 1, 2008 and June 30, 2012. Measurements included patient characteristics and outcomes, including discharge from hospice and site of death. RESULTS: Among 126,620 hospice patients, 986 (0.8%) were 18 years of age or younger. Pediatric patients were less likely to have an admitting diagnosis of cancer (odds ratio [OR] 0.62; 95% confidence interval [CI]: 0.54-0.72). Although children were less likely to use oxygen at enrollment (OR 0.31; 95% CI: 0.26-0.37), they were more likely to have an enteral feeding tube (OR 4.04; 95% CI: 3.49-4.67). Pediatric patients were half as likely as adults to have a do-not-resuscitate order (DNR) order upon hospice enrollment (OR 0.52; 95% CI: 0.46-0.59). The average hospice length of stay for pediatric patients was longer than that of adults (103 days versus 66 days, p<0.001). Children were more likely to leave hospice care (OR 2.59; 95% CI: 2.00-3.34), but among patients who died while enrolled in hospice, pediatric patients were more likely to die at home (OR 3.25; 95% CI: 2.27-3.88). CONCLUSIONS: Pediatric hospice patients differ from adult patients in their broader range of underlying diagnoses and their use of hospice services.

The "comfortable dying" measure: how patient characteristics affect hospice pain management quality scores.

BACKGROUND: All hospices were required by the Centers for Medicare and Medicaid Services (CMS) to collect the "Comfortable Dying" measure in 2012 (National Quality Forum measure #0209). However, it is not known how scores on this measure are affected by patient characteristics. It is important to identify these characteristics so that a hospice's case mix can be taken into account when interpreting its scores. OBJECTIVE: Our aim was to describe the implementation of the NQF #0209 measure in 10 hospices and to identify patient characteristics associated with scores. METHODS: We conducted an electronic health record (EHR)-based retrospective cohort study of patients in 10 hospices in the United States. The main outcome measure was the proportion of patients with pain that made them uncomfortable whose pain was controlled within 48 hours. RESULTS: A total of 4157 patients were eligible for an initial pain assessment. Of those who reported pain (n=1992), 1152 (58%) reported having their pain controlled on the follow-up assessment. In a multivariable regression model, clustered by hospice, six variables were independently associated with pain control. These included age (adjusted odds ratio [OR] 1.02; 95% confidence interval [CI] 1.02-1.03, p=0.003), a cancer diagnosis (OR 1.37; 95% CI 1.20-1.53, p=0.008), initial care in an inpatient unit (OR 1.28; 95% CI 1.08-1.47, p=0.031), presence of a Foley catheter (OR 1.40; 95% CI 1.15-1.59, p=0.038), use of opioid medication (OR 1.34; 95% CI 1.03-1.74, p=0.027), and higher Palliative Performance Scale (PPS) score (OR 1.02; 95% CI 1.01-1.03, p<0.001). Presence of a Stage 2 pressure ulcer was independently associated with worse pain control (OR 0.63; 95% CI 0.31-0.96, p=0.012). CONCLUSIONS: Several patient characteristics are associated with #0209 pain scores. As hospices are increasingly required to report quality measures, it will be essential to understand how their scores are affected by case mix.

uPAR-targeted optical imaging contrasts as theranostic agents for tumor margin detection.

Complete removal of tumors by surgery is the most important prognostic factor for cancer patients with the early stage cancers. The ability to identify invasive tumor edges of the primary tumor, locally invaded small tumor lesions, and drug resistant residual tumors following neoadjuvant therapy during surgery should significantly reduce the incidence of local tumor recurrence and improve survival of cancer patients. In this study, we report that urokinase plasminogen activator (uPA) and its receptor (uPAR) are the ligand/cell surface target pair for the development of targeted optical imaging probes for enhancing imaging contrasts in the tumor border. Recombinant peptides of the amino terminal fragment (ATF) of the receptor binding domain of uPA were labeled with near infrared fluorescence (NIR) dye molecules either as peptide-imaging or peptide-conjugated nanoparticle imaging probes. Systemic delivery of the uPAR-targeted imaging probes in mice bearing orthotopic human breast or pancreatic tumor xenografts or mouse mammary tumors led to the accumulation of the probes in the tumor and stromal cells, resulting in strong signals for optical imaging of tumors and identification of tumor margins. Histological analysis showed that a high level of uPAR-targeted nanoparticles was present in the tumor edge or active tumor stroma immediately adjacent to the tumor cells. Furthermore, following targeted therapy using uPAR-targeted theranostic nanoparticles, residual tumors were detectable by optical imaging through the imaging contrasts produced by NIR-dye-labeled theranostic nanoparticles in drug resistant tumor cells. Therefore, results of our study support the potential of the development of uPAR-targeted imaging and theranostic agents for image-guided surgery.