bluuebunny/crossref_metadata_2025 huggingface dataset:
Presence of survivin-specific cytotoxic T-lymphocytes (CTLs) in pancreatic cancer patients, and specific killing of human pancreatic carcinoma cells in vitro by survivin-specific CTLs
Authors: Chang D. Z. , Zhu K. , Kopetz S. , Voo K. , Li Y. , Hwu P. , Radvanyi L. , Abbruzzese J. L.
Published: March 2020

3070

Background: The apoptosis inhibitor protein Survivin is an attractive target for a cancer vaccine because of its differential overexpression by most human tumors, its importance for tumor survival, and its demonstrated immunogenicity. To examine Survivin’s potential as a vaccine target for pancreatic cancer (PC), we evaluated the presence of Survivin-specific cytotoxic T-lymphocytes (CTLs) in PC patients and assessed the specific killing of HLA-A*0201+ human pancreatic carcinoma cell lines in vitro by Survivin-specific CTL. Methods: Mononuclear cells from the peripheral blood (PBMC) of PC patients and normal donors and Survivin peptides were used to generate Survivin-specific CTLs in vitro. The presence of Survivin-specific CTLs was evaluated by IFN-γ ELISPOT analysis. Recognition of human PC cell lines (e.g., Panc-1 and CF-Pac-1) was analyzed by 51Cr release assays. Results: Multiple CTL lines were generated from different donors against a number of Survivin 9-mer and 10-mer peptides, including Sur5–14, Sur95–104, and Sur96–104 and altered forms of these peptides with enhanced HLA-A*0201 binding. Sur5–14 (TLPPAWQPFL) and new modified mSur95–104 (ELMLGEFLKL) peptides could generate specific CTL from the PBMC of most donors, and the resulting CTL showed cytotoxicity against Survivin peptide-pulsed Panc-1 and CF-Pac-1 in an HLA-A2-dependent manner. We found for the first time that mSur95–104 could elicit CTL activity that cross-reacted with wild-type peptide and 9-mer Sur96–104 in IFN-γ ELISPOT assays. In our preliminary analysis, we detected Survivin peptide-specific CTLs in four of five PC patients for Sur5–14 and three of five for mSur95–104. All five PC patients had a positive response to a pool of A2 peptides as positive controls, indicating their immune competence. Conclusions: CTLs specific for human Survivin peptide Sur5–14 and the modified peptides mSur95–104 were detected in majority of the PC patients tested. Further, Survivin-specific CTLs killed pancreatic carcinoma cell lines in vitro. Our results suggest that these two peptides are potential vaccines for the treatment of PC.

No significant financial relationships to disclose.
Discovery of TH-302: An achiral hypoxia-activated cytotoxic prodrug
Authors: Hart C. P. , Ammons S. , Duan J. X. , Jung D. , Wang J. , Jiao H. , Meng F. , Lan L. , Evans J. W. , Matteucci M.
Published: March 2020

3515

Background: Selective targeting of the hypoxic compartment of the tumor microenvironment is both a challenge and an opportunity for discovering and developing new cancer therapeutics. Chronic and transient hypoxia underlie resistance to chemotherapeutics and radiation. We have taken a modular design approach to synthesize hypoxia-activated prodrugs. Different nitro-containing heterocyclic triggers were linked to bis alkylating phosphorous mustard toxins and profiled in in vitro and in vivo assays predictive of compound efficacy and pharmacokinetics (PK). Methods: Drug candidates were synthesized and characterized using standard synthetic methods. In vitro efficacy was assessed with cancer cell line cytotoxicity and clonogenic assays. In vivo efficacy was assessed with xenograft models in monotherapy and combination therapy modes. Results: Screening trigger-toxin combinations in H460 lung cancer cell proliferation assays under anoxic, hypoxic, and aerobic conditions yielded structure-activity relationships (SAR) and identified TH- 302, a 2-nitroimidazole triggered bromo analog of ifosfamide, as a potent and selective molecule. TH-302 exhibits in vitro proliferation IC50 values of 0.2, 5, and 90μM and clonogenic IC90 values of 0.1, 5, and 30μM under conditions of 0%, 0.6%, and 21% O2, respectively. In vitro profiling showed sufficient solubility, plasma and microsomal stability, resistance to drug efflux mechanisms, and PK. In vivo efficacy was assessed with the H460 ectopic xenograft model. TH-302 administered alone (100mpk, ip, Q3Dx5) or in combination with cisplatin (6mpk, iv, Q7Dx2) showed mean tumor volume growth delays to 500mm3 (TGD500) of 10 days for TH-302 alone, 4 days for cisplatin alone, and 20 days for the combination. These results have been confirmed and extended using different tumor models, dosing regimens, and combinations which included Taxol and 5-FU. TH-302 demonstrates dose-proportional PK in multiple species. Conclusions: TH-302, a novel hypoxia-activated cytotoxic prodrug, has promising preclinical in vitro and in vivo efficacy and selectivity and has entered IND-enabling studies. Acute and subchronic toxicology is underway in rats and dogs. We expect to file an IND for clinical studies of TH-302 this year.

No significant financial relationships to disclose.
Prediction of response to temozolomide (TMZ)-based therapy by loss of MGMT expression in patients with advanced neuroendocrine tumors (NET)
Authors: Kulke M. H. , Frauenhoffer C. S. , Hooshmand S. M. , Ryan D. P. , Enzinger P. C. , Meyerhardt J. A. , Clark J. W. , Hornick J. , Fuchs C. S. , Redston M. S.
Published: March 2020

4505

Background: TMZ, an oral alkylating agent, has recently been shown to be active in a subset of patients with NETs. In other tumor types, methyl-guanine methyl transferase (MGMT) expression is associated with TMZ resistance through its ability to remove methyl/alkyl groups from the O6 -position of guanine, thereby preventing TMZ-induced DNA damage. Methods: To better define NET pts who benefit from TMZ, we performed a retrospective analysis of 76 NET pts treated with TMZ-based regimens at 3 institutions, identified using IRB-approved observational and clinical trial databases. Immunohistochemical MGMT expression was measured in a subset of pts with available paraffin-embedded archival tissue specimens in a blinded fashion, utilizing mouse monoclonal antibodies to MGMT. Nuclear MGMT expression was scored as either present or absent in tumor cells and correlated with tumor type and treatment outcome. Results: Of 76 pts, 30 received TMZ/thalidomide and 46 received TMZ/bevacizumab. Both regimens incorporate oral TMZ, administered at a dose of 150 mg/m2 qd for 7d, every other week. 63 pts were enrolled on phase II studies, and 13 pts were treated outside a formal study protocol. Pt characteristics were: M:F=42:34; median age 57.5 (20–75); tumor type carcinoid (38), pancreatic NET (35), paraganglioma/pheochromocytoma (3). PR or CR (as measured by RECIST) was observed in 11/35 (31%) pancreatic NETs and 0/38 carcinoid pts (P<0.001), as well as 1/3 pts with paraganglioma/pheo. In 21 pts with available specimens, complete absence of MGMT expression was observed in 5/8 pancreatic NET and 0/13 carcinoid tumors (P<0.01). In this pt subset, absence of MGMT expression was associated with response to TMZ ( Table 1 ). Conclusions: Treatment with TMZ is associated with radiologic response in approximately one third of pts with pancreatic NET, but not in pts with carcinoid tumors. Absence of MGMT expression appears to define pts with pancreatic NET who achieve significant benefit from TMZ.

[Table: see text]

No significant financial relationships to disclose.
Management of clinical stage (CS) I and II patients with non-seminomatous germ cell tumors of the testis (NSGCTT) avoiding upfront retroperitoneal lymph node dissection (RPLND)
Authors: Flechon A. , El Karak F. , Salas C. , Rivoire M. , Droz J.
Published: March 2020

5090

Background: CS I, Is, IIa and IIb may be treated by either upfront RPLND or upfront medical management followed by RPLND in selected cases. We retrospectively analyzed the later approach. Methods: From 1993 to 2003, 225 NSGCTT patients CS I and Is, IIa, IIb were treated at our center. In total, 148 patients with CS I were managed by surveillance followed by CT and surgical exeresis of residual disease in case of relapse and 77 with CS Is, IIa and IIb underwent upfront chemotherapy and RPLND in case of residual masses. Median follow-up was 52 months for all patients (0.16–165 months). Results: In CS I: 47/148 (32%) patients relapsed: 22/42 (52%) patients with microvascular involvement versus 25/106 without (24%). The median time to relapse was 5 months (0.16–79 months). All relapsing patients received CT except one for whom we have no information. Twenty-two patients (46%) had RPLND. Two patients died, one probably of haemorrhage one month after RPLND and one in a car accident. In CS II: 4 (5%) patients had CS Is, 40 (52%) CS IIa and 33 (43%) CS IIb. Respectively 71 (92%), 5 (6.5%) and 1 (1,5%) patients had good, intermediate or poor prognosis according to the IGCCCG. All patients received cisplatin-based chemotherapy. Forty-one (53%) patients had RPLND after CT and one refused surgery for residual disease. Histological review showed a teratoma in 22 cases (54%), necrosis in 16 (39%) and residual active disease in 3 (7%). Six patients (8%) relapsed: 1 of them had a growing teratoma. One patient died of disease and all others are alive with no evidence of disease. In total, after medical management of CS I and II, avoiding primary RPLND, only 124 (55%) and 63 (28%) patients had eventually CT and RPLND respectively. Ninety-nine percent patients were cured. Conclusions: Upfront medical treatment of CS I and CS II NSGCTT is a good option which allows to avoid unnecessary CT and RPLND indications.

[Table: see text]

No significant financial relationships to disclose.
Sequential therapy with carboplatin (C) followed by paclitaxel (P) as first-line chemotherapy in 105 patients with advanced ovarian cancer (AOC): Results of a multicenter phase II study of the Northeastern German Society of Gynecological Oncology
Authors: Oskay-Oezcelik G. , Mustea A. , Sommer H. , Keil E. , Höckel M. , Pfisterer J. , Camara O. , Hindenburg H. J. , Lichetenegger W. , Sehouli J.
Published: March 2020

5533

Background: For the adjuvant setting of AOC after primary radical surgery the combination of paclitaxel and platinum in a three weeks schedule has emerged as the current standard. Exposition duration of the drug is important for cell death. In animal model additional anti-angionetic effects of low dose paclitaxel infusion was observed. A sequential schedule of these agents can potentially yield in an improved therapeutic index. Methods: In this multicenter-phase II trial after primary radical surgery 4 cycles of Carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles weekly paclitaxel at a dose of 80mg/m2 (d1/q7d) was applied. All patients with haemoglobin levels < 12mg/dl get primary erythropoietin. No primary use of other growth factors were allowed. Eligibility criteria were: AOC (FIGO IIb-IV), ECOG performance status 0–2, normal organ functions. Results: Between 07/2003 and 05/2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (23–80). FIGO-stages were: II: 11.4%, III: 67.6%, IV: 14.2%. 1,441 cycles were analyzed and in median 16 courses were applied (range 0–16). The incidence of non-hematological toxicities was very low. 25 % of all patients experienced alopecia (grade 1–2). Neurotoxicity and nausea/vomiting (grade III-IV) occurred in no patients. Grade 3–4 hematological toxicity (% of all pts) included: thrombocytopenia (16 %), anemia (3%), leucopenia (22%), neutropenic fever (0%). 96% received erythropoietin. Thromboembolic events (5%) were not increased in patients who received erythropoietin. After a median follow-up interval of 10 months (range: 1–27 months) 20 patients died, the median overall survival is already not reached. The progression free survival is 19 months (range:10–23 months). Conclusions: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted. (Supported by Bristol Myers Squibb Germany and Ortho Biotech Germany)

No significant financial relationships to disclose.
Molecular targeting in acute myeloid leukemia (AML) therapy: APcK110 is a new inhibitor of c-Kit activity in AML blasts
Authors: Faderl S. , Bornmann W. , Maxwell D. , Peng Z. , Van Q. , Liu Z. , Verstovsek S. , Ferrajoli A. , Kantarjian H. M. , Estrov Z.
Published: March 2020

7019

Background: Tyrosine kinases (TK) are important for most cellular functions and require stringent control and regulation. C- Kit, a TK and transmembrane receptor for stem cell factor, plays a crucial role in hematopoiesis. Mutations of c-Kit can contribute to AML pathophysiology and have been associated with shorter survival and higher relapse risk following standard AML therapy. On the other hand, responses have been observed following TK inhibitor therapy such as imatinib. Identification of c-Kit or its pathways in AML leukemogenesis and development of new compounds targeting these mutations may therefore hold promise for therapy. Methods: APcK110 is the result of a structure-based design of c-Kit inhibitors and was derived of a set of compounds with favorable IC50 values in a c-Kit kinase assay. Here we present results of the activity and mechanism of action of APcK110. We used the mastocytosis cell line HMC1.1 carrying an activating c-Kit mutation and two AML lines (OCIM2 and OCI/AML3) as well as primary samples from patients with AML. Results: We demonstrate that: (1) APcK110 inhibits proliferation of all three cell lines in a dose dependent fashion using an MTT assay. Inhibition of proliferation is most significant in the SCF-dependent cell line OCI/AML3; (2) inhibition of OCIM2 cells (SCF-responsive) by APcK110 can be enhanced when adding SCF suggesting recruitment of c-Kit-dependent signaling components and increased activity of the c-Kit inhibitor under these circumstances; (3) APcK110 is a more potent inhibitor of OCI/AML3 proliferation than imatinib and dasatininb; (4) using Western immunoblotting, APcK110 decreases levels of phospho-Akt, phospho-Stat3 and 5 in a time- and dose-dependent fashion demonstrating activity of APcK110 on c-Kit downstream signaling pathways; (5) APcK110 induces apoptosis by cleavage of caspase 3 and PARP; (6) APcK110 inhibits proliferation of primary AML cells in a clonogenic assay, but does not affect proliferation of normal controls. Conclusions: APcK110 is a potent inhibitor of AML cell lines and primary samples from patients with AML. Activation of c-Kit or downstream pathways increases activity of APcK110. APcK110 and similar compounds should be evaluated in clinical trials of patients with AML.

No significant financial relationships to disclose.
Incorporating a FLT3 inhibitor into AML therapy
Authors: Levis M. J. , Small D.
Published: March 2020

7060

Background: Activating mutations of FLT3 occur in 30% of adults with AML and are associated with worse survival. Lestaurtinib (CEP-701), an oral FLT3 kinase inhibitor, has activity as monotherapy in relapsed/refractory AML patients with FLT3 mutations. Using the results of pre-clinical models, a trial was designed in which patients with AML and FLT3 mutations in first relapse were randomized 1:1 to receive chemotherapy alone or chemotherapy followed by treatment with lestaurtinib. The primary endpoint was complete remission (CR), with a target accrual of 220 patients. We present here correlative data from this trial. Methods: Efficacy of FLT3 inhibition was measured using the plasma inhibitory activity (PIA) assay for FLT3. This assay method has been previously published (Blood 108(10):3477–83). Prior to initiation of chemotherapy, leukemia cells of the patients randomized to lestaurtinib were tested for in vitro sensitivity to lestaurtinib using a cytotoxicity assay. Plasma samples were obtained at baseline and at trough time points on Days 15 and 42. PIA assay and in vitro cytotoxicity results were correlated with the clinical results from the first 40 patients enrolled. In addition, plasma levels of lestaurtinib and alpha-1 acid glycoprotein (AAG; the principle plasma binding protein for this drug) were measured. Results: Accrual is ongoing. Twenty-three of 35 patients treated with lestaurtinib achieved a PIA result of 85% or greater (i.e., successful FLT3 inhibition). Of the first 40 patients enrolled, all those who achieved a FLT3 PIA results of 85% or greater and whose pretreatment leukemia cells were sensitive in vitro to lestaurtinib achieved a clinical response. Conversely, patients with insensitive cells or inadequate PIA did not respond. Ten of 17 patients randomized to lestaurtinib showed response (5 CR, 3 CRp, 2 PR). Four of 17 patients randomized to receive chemotherapy alone responded (2 CR, 2 CRp). Conventional pharmacokinetic analysis showed no correlation whatsoever with response, due to the high degree to which lestaurtinib is bound to AAG. Conclusions: These results demonstrate that the PIA assay for FLT3 is able to accurately predict response to lestaurtinib, and provides important evidence that targeting FLT3 remains a valid therapeutic approach for AML with FLT3 activating mutations.

No significant financial relationships to disclose.
Erlotinib for first line treatment in unselected patients (p) with advanced or metastatic non-small cell lung carcinoma (NSCLC)
Authors: Jimenez U. , Gurpide A. , Isla D. , Garcia-Campelo R. , Firvida J. , Vinolas N. , Jaen A. , Montalar J. , Regueiro P. , Massuti B.
Published: March 2020

7639

Background: Erlotinib is an orally available selective EGFR tyrosine-kinase inhibitor. Erlotinib is approved for the treatment of patients (p) with advanced or metastatic NSCL that have progressed at least to one prior chemotherapy regimen. In certain subgroups erlotinib has demonstrated to be active when administered as first line treatment. We retrospectively analysed efficacy and safety of patients treated with erlotinib as first line included in the Target Study. Methods: The TargeT trial is a multicentric, open-label, non-randomized, phase II study carried out in 101 Spanish institutions. Eligibility criteria included chemonaive p with stage IIIB-IV NSCLC. Subjects were treated with 150 mg/day po until disease progression or unacceptable toxicity. Dose reductions were allowed. Primary end-point was survival. Results: By the time of this interim analysis, data from 437 p treated with erlotinib as first line were available. Median age 72 y (range 26–90). Demographics (%): M/F 59/41; PS0/1/2 19/51/30; pathology adeno 53; current or former smoker 63. In the evaluable population for efficacy best response was: 6 CR, 68 PR, 93 SD, 69 PD (RR 31.35%). Time to progression was 6.6 mo (95% CI 4.8–8.6/ OS 7.1). Overall survival was 7.1 mo (95% CI 5.9–9.1). Most common erlotinib-related adverse events were skin rash (61%) and diarrhea (31.2%) with no unexpected toxicities having been observed. Conclusions: Although at this moment clinical trials are ongoing trying to find the best predicitive factor of response, erlotinib first line was active and well tolerated in this analysis in an unselected population.

No significant financial relationships to disclose.
Targeted radiopharmaceutical therapy for advanced lung cancer: Phase I trial of rhenium Re188 somatostatin analogue P2045
Authors: Edelman M. J. , Clamon G. , Kahn D. , Magram M. , Line B. R.
Published: March 2020

7672

Background: Both small cell (SCLC) and non-small cell lung cancer (NSCLC) overexpress somatostatin receptors (SSTR). P2045 peptide is an 11-amino acid somatostatin analogue that binds with high affinity to SSTR. The analogue can be labeled with Tc-99m to gauge receptor prevalence, or with Re-188 for 2.1MeV beta radiotherapy. To evaluate the safety of this approach a phase I dose-escalation study of Re-188 P2045 in SSTR positive lung cancer was performed. Methods: Patients (pts) were required to have progressive advanced lung cancer, PS 0–1, and normal organ function. There were no limitations on the number of prior therapies. Tumor SSTR was detected with Tc-99m P2045. If positive, treatment with escalating doses of Re-188 P2045 was instituted. Three doses were evaluated, 30 mCi/m2, 60 mCi/m2 and 90 mCi/m2. A single dose of Re-188 P2045 was allowed. Dose limiting toxicity was defined as ≥ grade 3 non-hematologic toxicity, grade 4 hematologic toxicity or projected renal radiation dose of >20 Gy. Results: 15 pts entered, 7 M, 8 F, median age 61y, 9-PS0, 6 PS1. 13 NSCLC, 2 SCLC. 14 pts had ≥ 2 prior chemotherapy regimens. 1 pt refused standard therapy. All pts were imaged with Tc-99m P2045, 8 pts received Re-188 P2045. The 7 pts who did not proceed to Re-188 P2045 were due to rapid progression (n=2) non-uptake of Tc 99m P2045 (n=2) or projected renal radiation dose above the 20 Gy limit (n=3). All pts treated with Re-188 P2045 (4 at 30 mCi/m2, 3 at 60 mCi/m2 and 1 at 90 mCi/m2) had NSCLC. The major toxicity was grade 1 or 2 lymphopenia. No dose limiting toxicities were seen. All tumors imaged by Tc-99m had uptake of Re- 188. The trial was halted at the 90 mCi/m2 level when 3 pts had projected renal radiation doses above 20Gy. No responses were seen. 5 of the 8 pts (62.5%, 95% CI: 24%, 91%) had stable disease at 8 weeks, all of whom entered with progressive disease.. Median overall survival was 11.5 mo. Conclusions: 1) Re-188 P2045 was well-tolerated. 2) Tc-99m P2045 imaging allows identification of pts who may benefit from Re-188 P2045. 3) While responses were not seen, survival for these heavily pretreated pts is encouraging. 4) Further exploration of this approach utilizing amino acid infusion to ameliorate potential renal toxicity is warranted.

No significant financial relationships to disclose.
Multicenter phase II study evaluating docetaxel (D) and cisplatin (C) as an induction regimen prior to surgery or radiochemotherapy (RCT) with D, followed by adjuvant D in chemonaive patients with NSCLC: TAX-AT1–203
Authors: Greil R. , Pfeifer W. , Vetter N. , Eckmayr J. , Burghuber O. , Hilbe W. , Schmid T. , Gastl G. , Mohn-Stauder A.
Published: March 2020

7702

Background: This phase II study evaluated operable and unresectable patients (pts) treated with induction chemotherapy with DC to assess the response rate and conversion to resectability. Furthermore, the feasibility and efficacy of radiosensitizing with D was tested in unresectable pts undergoing RCT. The feasibility of adjuvant D was investigated in all patients. Study Design: Pts with stages II, IIIA and IIIB NSCLC were treated with 3 cycles of 3-wkly neoadjuvant D (75 mg/m2 d 1) and C (40 mg/m2 d1, 2). Within 4 wk after induction, pts were either resected or treated with RCT (2 Gy × 5d for 6 wk) and D 20 mg/m2 wkly × 6 cycles. Within 4–8 wk after definitive RCT or surgery, 3 cycles of adjuvant D 75 mg/m2 q3wk were initiated. Adjuvant RT was allowed in non-R0 resected cases. The primary endpoint was response rate to induction; secondary endpoints included resectability after induction, progression-free survival, overall survival, and safety. Results: 77 pts were included: age 60 yr [46–76 yr], males 78%, stages (II/IIIA/IIIB: 8%/39%/52%), primary resectability n=22 (29%), primary unresectability n=55 (71%). 59 patients were evaluable after induction chemotherapy, of whom 66% achieved a PR, 23% had stable disease, and 10% progressed. The PR rate was 73% in initially resectable and 63% in initially unresectable pts. 67 pts were evaluable for resectability. 28/39 (72%) of PR patients were resectable. As a result of induction therapy, 19 pts (25%) became resectable, 18 (24%) remained resectable, 27 (35%) remained unresectable, and 3 (4%) became unresectable. Treatment had to be stopped in 11 pts during induction. Three pts, primarily unresectable (4%) died of toxicity. 53% of patients had a grade 3 or 4 toxicity. In evaluable pts, the median PFS was 350 [80–1495] days vs 192 [21–989] days for resectable and unresectable pts after induction, respectively, and overall survival was 491 vs 303 days. Conclusions: DC induction chemotherapy resulted in a promising PR rate and rate of secondary resectability. The toxicity is substantial. Results of efficacy and toxicity of radiosensitizing and adjuvant D are pending.

No significant financial relationships to disclose.
Percutaneous radiofrequency ablation of lung tumours: Results in first 100 consecutive patients
Authors: Zhu J. C. , Yan T. D. , Ng K. , Glenn D. , Morris D. L.
Published: March 2020

7714

Background: Treatment modalities for patients with primary and secondary lung malignancies who are not surgical candidates are limited. Radiofrequency ablation is a minimally invasive, lung sparing therapeutic alternative that may provide local disease control for these patients. The study reported our experience with first 100 consecutive patients who underwent radiofrequency ablation of their lung tumours. Methods: From November 2000 to December 2006, the clinical and treatment-related information regarding the 100 consecutive patients (58 males, mean age of 65 years) with 240 lung tumours treated by radiofrequency ablation were collected prospectively. Radiofrequency ablation was performed percutaneously under CT guidance with local anaethesiologic assistance and conscious sedation using a RITA Starbust XL electrode. The patients were hospitalized overnight and followed at one week, one month and then every three months with CT to evaluate treatment outcome and complications. Results: Five patients had primary lung carcinoma while the remaining patients had pulmonary metastases from extra-thoracic malignancies, with colorectal cancer being the most common primary site (68%), followed by renal cell carcinoma (8%) and uterine leiomyosarcoma (5%). The mean number of pulmonary lesions ablated was 2.4 per patient; the mean size of lesion ablated was 2.2 cm in diameter. Fifteen patients had second-time RFA; 4 patients underwent third- or fourth-time RFA for pulmonary recurrence. There was no post-procedural mortality and the overall morbidity rate was 42%. The most common complication was pneumothorax, which occurred in of 31% of procedures (n=39/127) with 20 (16%) requiring chest tube placement. After a median follow-up of 24 months (range 1 to 70 months), 72% of RFA treated lesions did not progress. The overall median disease-free interval was 13 months, with 1-, 3- and 5- year disease-free survival of 55%, 22% and 7% respectively. The overall median survival was 34 months with 1-, 3- and 5-year- survival of 85%, 49% and 33% respectively. Conclusions: Percutaneous radiofrequency ablation is an emerging therapy with promising results when surgical resection of pulmonary malignancy cannot be performed.

No significant financial relationships to disclose.
Positron emission tomography using 18-fluorodeoxyglucose in pre- and post-transplantation in lymphoma patients treated with autologous stem cell transplantation: Impact
Authors: Cuenca X. , Mounier N. , Deville G. L. , Brice P. , Larghero J. , Haddad A. , Ertault M. , Filmont J. , Moretti J. , Briere J. , De Kerviler E. , Hennequin C. , Gisselbrecht C.
Published: March 2020

8060

Background: The pre-transplant evaluation of lymphoma with Positron Emission Tomography (PET) scanning using 18- FluoroDeoxyGlucose may ease a decision making. The impact on patient outcome of post-transplant assessment is unknown. Methods: Between July 04 and December 05, patients (pts) who achieved tumor response and received high-dose chemotherapy plus autologous stem cell transplantation (ASCT) were explored with PET, prior and 100 days after ASCT, without knowledge of conventional imaging nor clinical history. PET results (negative or positive) were related to event-free survival (EFS) and overall survival (OS). Results: 60 pts were included. 50 had Non-Hodgkin Lymphoma (26 aggressive) and 10 Hodgkins Lymphoma. Median age was 52 [19-68]. 22 pts received front-line ASCT mainly after ACVBP (n=14) or CHOP. Platinum-based salvage chemotherapy was the most used (n=38), and most of the pts received rituximab (n=40). Prior ASCT,by clinical staging, there were 31 complete remission (CR), 23 uncertain CR and 6 partial remission. Conditioning regimen was BEAM in 39 pts; Zevalin BEAM in 11, Total Body Irradiation in 10. 75% were pre-ASCT-PET negative and 80% post-ASCT-PET negative. 6 pts (10%) converted from pre-ASCT-PET positive to post-ASCT-PET negative and 2 pts from negative to post-ASCT-PET positive. Median follow-up was 1.25 years [0.5–2]. 12 pts died (OS 80%) and 19 relapsed (EFS 68%). OS and EFS was better in pre-ASCT-PET-negative pts than in PET-positive (92% vs 53% (p=0.0009), 77% vs 35%, (p=0.0002) respectively). OS was estimated to 90% in post-ASCT-PET-negative pts vs 50% in PET-positive (p<0.0001), EFS was 79% vs 25%, respectively (p<0.0001). In multivariate analysis,including analysis by histology subtypes, the only adverse prognostic factor was PET positive either pre-ASCT (Relative Risk(RR)=4) or post-ASCT (RR=12). Conclusions: A positive PET after induction chemotherapy indicates a high risk of ASCT failure which is increased by a positive PET after ASCT. In pre-ASCT-PET-positive pts, more experimental approaches are required. In pre-ASCT-PET-negative patients, post-ASCT-PET assessment may be omitted.

No significant financial relationships to disclose.
Gamma knife radiosurgery for melanoma/renal cell carcinoma brain metastases 1 -10 lesions with optimized margin dose: Improved tumor control and survival
Authors: Fregene A. O. , Mobit P. , Zamorano L. , Diaz F. , Guthikonda M. , Syrian M. , Rakowski J.
Published: March 2020

8581

Background: Radioresistant brain metastases melanoma/renal cell carcinoma cause significant morbidity and mortality: response to whole brain external beam radiotherapy (WBXRT) is minimal, chemotherapy role is investigative, and surgery has its indications and limitations. Reports of survival with Gamma Knife Radiosurgery (GK) is mixed. Reports indicate that 80 to 90% of tumor failure following GK is in the margin: recent multivariate analyses indicate tumor control dependence on margin dose. This study evaluates the impact of better control of brain lesions and consequent reduction of CNS death on overall survival. Methods: Between 10/2002 and 12/2005, 24 consecutive patients with melanoma and renal cell carcinoma male/female radio 14/10, 20 melanoma and 4 renal cell were treated by WBXRT followed by GK radiosurgery utilizing optimized margin dose. Dose was (16 - 20 Gy) to the 50% line with adequate margin to reduce systematic and other associated errors. This was achieved by combining the separate errors associated with the procedure; extent of tumor infiltration beyond gross tumor margin; GK/procedure mechanical precision limitations; MRI image transfer spatial limitations and beam profile margin dose sensitivity. Karnofsky Performance status was 70 - 90%. Follow-up period was 52 months. Results: The mean survival period for the 24 patients with 1 - 10 lesions was 14.11 months: median survival by Kaplan-Meier was 12.0 months. This result is a significant improvement on the 5.5 months reported earlier from this institution for 1 - 5 lesions treated with non-optimized GK dosage; and data by Lavin, et al, at 8 months for predominantly solitary lesions. Conclusions: Melanoma and renal cell carcinoma brain metastases respond very well to GK radiosurgery with optimized margin dose: mean survival for these patients with 1 -3 and 4 - 10 lesions is 14.11 months and comparable to the survival of patients with brain metastases from lung and breast patients: More studies along this line are called for. Patients with multiple metastatic brain lesions from melanoma and renal cell cancers stand to benefit.

No significant financial relationships to disclose.
Increasing risk for venous thromboembolism among hospitalized cancer patients
Authors: Khorana A. A. , Francis C. W. , Culakova E. , Kuderer N. M. , Lyman G. H.
Published: March 2020

9009

Background: Venous thromboembolism (VTE) contributes to morbidity and mortality in cancer patients and is a frequent complication of anti-cancer therapy. We examined the frequency, risk factors and trends associated with VTE among hospitalized US cancer patients. Methods: We conducted a retrospective cohort study using the discharge database of the University Health System Consortium. This included all 1,824,316 hospitalizations of cancer patients between 1995 and 2003 at 133 United States medical centers. To avoid overestimation, only a single randomly chosen hospitalization was included for patients with multiple admissions. Results: Among 1,015,598 individual cancer patients, 34,357 (3.4%) were diagnosed with deep venous thrombosis and 11,515 with pulmonary embolism (PE) (1.1%) for an overall VTE rate of 4.1%. Subgroups of cancer patients with highest rates included Black ethnicity (5.1% per hospitalization) and those on chemotherapy (4.9%). Sites of cancer with the highest rates of VTE included pancreas (8.2%), kidney (5.7%), ovary (5.6%), lung (5.1%) and stomach (4.9%). Amongst hematologic malignancies, myeloma (5%), non-Hodgkin’s lymphoma (4.8%) and Hodgkin’s disease (4.6%) had the highest rates of VTE. The rate of VTE rose from 3.6% per hospitalization in 1995–96 to 4.6% in 2002–03, an increase of 28%, including a near-doubling of PE rates from 0.8% to 1.5% (P<0.0001). Among patients receiving chemotherapy, rates of VTE rose from 3.9% per hospitalization to 5.7%, an increase of 47% (P<0.0001). In contrast, patients undergoing surgery for breast, head and neck, pancreatic or spinal cancers, experienced no significant change in the rate of VTE. Use of diagnostic procedures for VTE also did not increase over the study period. Conclusions: The rate of VTE, including PE, among hospitalized cancer patients has increased significantly in recent years. Black patients, those on chemotherapy and those with certain types of cancer are disproportionately at increased risk. The rise in VTE does not appear to be attributable to an increased utilization of diagnostic procedures. Further efforts to increase thromboprophylaxis compliance during hospitalization are needed.

No significant financial relationships to disclose.
Co-morbidity is a better predictor of 5-fluorouracil pharmacokinetic than chronological age in older adults
Authors: Gusella M. , Stievano L. , Padrini R. , Ferrazzi E. , Bononi A.
Published: March 2020

9038

Background: Fifty percent of all cancers occur in elderly people and the total cancer burden is expected to rise. Data are needed to ensure the safe administration of chemotherapy in the older patient population. Aging can affect the pharmacokinetics in a number of ways and the selection of chemotherapy in the elderly is frequently and empirically determined by degree of comorbidity and the patients’ functional status. The aim of our study was to determine whether high level of comorbidity, measured using a standardized instrument, can predict 5-fluorouracil (5FU) disposition in older adults. Methods: Geriatric outpatients affected by stage 2 or 3 colorectal cancer and treated with adjuvant MAYO Clinic regimen were the study population. The evaluation was conducted on men aged 70 years old or more, with varying levels of chronic illness. All of them had a good performance status (ECOG score= 0–1). Non neoplastic disease burden was measured using the Cumulative Illness Rating Scale (CIRS) and drug disposition using area under the curve (AUC) of the drug plasma levels during 30 min immediately after 2 minute bolus administration of 5FU 375–425 mg/mq. Results: Forty men were studied, aged between 70 and 80 years old (median = 72); their CIRS scores ranged between 0 and 12 (median=3). Pharmacokinetic analysis confirmed an elevated interpatient variability: 5FU plasma AUC after bolus administration ranged between 241 and 1,140 mg × min/L. There was no correlation between age and comorbidity burden or age and 5FU AUC in that population. On the contrary with increasing comorbidity (increase in CIRS score) there was a proportional increase in 5FU AUC: patients with CIRS score from 0 to 3 (n=22), between 4 and 7 (n=11) and greater than 7 (n=7) had mean AUC of 523.5± 139.6, 637.0±124.0 and 877.4±195.0 mg × min/L respectively (p<0.0001). Conclusions: This study shows that chronological age did nor correlate with CIRS score or 5FU disposition. In older adults with varying degrees of chronic illness, administrated with the same chemotherapy doses, the comorbidity level influenced the magnitude of 5FU exposition, suggesting that the CIRS score could be used to tailor treatment doses. Funded by AIRC-Veneto

No significant financial relationships to disclose.
Identifying patient-reported anxiety and depression in older adults with cancer.
Authors: Jayani Reena , Sun Can-Lan , Charles Kemeberly , Soto Perez De Celis Enrique , Chien Leana , Roberts Elsa , Moreno Jeanine , Dale William , Mohile Supriya Gupta , Sedrak Mina S. , Koczywas Marianna , Chung Vincent , Fakih Marwan , Chao Joseph , Cristea Mihaela C. , Pal Sumanta K. , Katheria Vani , Hurria Arti , Li Daneng
Published: March 2020

11556

Background: Anxiety and depression are associated with decreased quality of life, treatment adherence, and survival in patients with cancer. Mental Health Inventory (MHI-17) is a validated screening tool for psychological well-being, but cut points for older adults with cancer are unknown. The goal of this study is to identify cut points on MHI-17 Anxiety (MHI-A) and Depression (MHI-D) subscales which correlate with patient-reported anxiety and depression in older adults with cancer. Methods: This is a secondary analysis of baseline data from a randomized controlled trial in adults aged 65+ with solid tumors starting chemotherapy. At baseline, patients completed MHI-17. MHI-A and MHI-D were calculated (range 0-100; higher scores represent better mental health). Self-reported anxiety was obtained from single-item Linear Analog Scale Assessment (0-5 = low, 6-10 = high). Self-reported depression was obtained from Yale Depression Screen, “Do you often feel sad or depressed?” The association of MHI-A and MHI-D with the patient-reported outcomes was analyzed using logistic regression. Youden’s index was used to determine the optimal cut points for MHI-A and MHI-D for identifying patients with high anxiety and depression. Results: 458 patients (median age 71 (range 65-91), 57% female, 55% non-Hispanic white) were included in this analysis. The most common cancer types were: GI (31%), breast (19%), GU (18%), and pulmonary (16%); 75% had stage IV cancer. Twenty-four percent (N = 110) reported high anxiety and 21% (N = 97) depression. Median scores for MHI-A and MHI-D were 75 (range 0-100) and 80 (range 0-100). The optimal cut point for high anxiety on MHI-A was 65; this had an accuracy of 76.1%, a sensitivity of 71.8%, and a specificity of 77.5%. The optimal cut point for depression on MHI-D was 70; this had an accuracy of 80.1%, a sensitivity of 80.4%, and a specificity of 79.8%. Conclusions: The current study identified optimal cut points for MHI-Anxiety and MHI-Depression subscales to identify older adults with cancer starting chemotherapy with self-reported anxiety and depression. In the absence of patient-reported anxiety and depression, these cut points could be used to identify older patients with cancer at risk for poor mental health.
Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline
Authors: Chiorean E. Gabriela , Nandakumar Govind , Fadelu Temidayo , Temin Sarah , Alarcon-Rozas Ashley Efrain , Bejarano Suyapa , Croitoru Adina-Emilia , Grover Surbhi , Lohar Pritesh V. , Odhiambo Andrew , Park Se Hoon , Garcia Erika Ruiz , Teh Catherine , Rose Azmina , Zaki Bassem , Chamberlin Mary D.
Published: March 2020

PURPOSE

To provide expert guidance to clinicians and policymakers in resource-constrained settings on the management of patients with late-stage colorectal cancer.

METHODS

ASCO convened a multidisciplinary, multinational Expert Panel that reviewed existing guidelines, conducted a modified ADAPTE process, and used a formal consensus process with additional experts for two rounds of formal ratings.

RESULTS

Existing sets of guidelines from four guideline developers were identified and reviewed; adapted recommendations from five guidelines form the evidence base and provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75% on all recommendations.

RECOMMENDATIONS

Common elements of symptom management include addressing clinically acute situations. Diagnosis should involve the primary tumor and, in some cases, endoscopy, and staging should involve digital rectal exam and/or imaging, depending on resources available. Most patients receive treatment with chemotherapy, where chemotherapy is available. If, after a period of chemotherapy, patients become candidates for surgical resection with curative intent of both primary tumor and liver or lung metastatic lesions on the basis of evaluation in multidisciplinary tumor boards, the guidelines recommend patients undergo surgery in centers of expertise if possible. On-treatment surveillance includes a combination of taking medical history, performing physical examinations, blood work, and imaging; specifics, including frequency, depend on resource-based setting. Additional information is available at www.asco.org/resource-stratified-guidelines .
Mary Wroth, Ovid, and the Metamorphosis of Petrarch
Authors: Sokolov Danila
Published: March 2020

The language of arboreal metamorphosis in Lady Mary Wroth’s pastoral song “The Spring Now Come att Last” from Pamphilia to Amphilanthus (1621) may invoke the myth of Apollo and Daphne. However, the Ovidian narrative so central to Petrarchan poetics celebrates the male poet by erasing the female voice. This essay instead explores parallels between Wroth’s poem and the metamorphosis of the Heliades, who turn into poplars while mourning their brother Phaeton in book 2 of the Metamorphoses. Their transformation is predicated on an act of female speech, however precarious and evanescent. This alternative Ovidian scenario offers a model of lyric that capitalizes on the brief resonance that the female voice acquires at the point of vanishing. By deploying it in her song, Wroth not only rewrites Petrarch through Ovid in order to articulate a gendered lyric voice but shows herself a poet attuned to the crucial developments in English lyric of the sixteenth and seventeenth centuries, in particular the complex relationship between the Petrarchan and the Ovidian legacies.
Addressing complex societal challenges in health education – A physiotherapy-led initiative embedding inclusion health in an undergraduate curriculum
Authors: Broderick Julie , Waugh Alice , Mc Govern Mark , Alpine Lucy , Kiernan Sinead , Murphy Niamh , Hodalova Sofia , Feehan Sorcha , Ní Cheallaigh Clíona
Published: March 2020

People who are socially excluded experience vastly poorer health outcomes compared to the general population. Inclusion Health seeks to directly address this health inequity. Despite the increased requirement for health care and the increased prevalence of complex health and social needs in socially excluded people, Inclusion Health features very little in health education curricula.

This letter has been written by a group of clinicians, academics, clinical education specialists and students with a common interest in Inclusion Health. In the absence of established guidance on how best to incorporate the broad topic of inclusion health in undergraduate education, we have developed a two-pronged approach within Physiotherapy. We are writing to highlight the following initiatives; firstly, the provision of a dedicated undergraduate clinical placement devoted to the area of Inclusion Health. Secondly, we have also initiated a step-wise process of introducing the topic of Inclusion Health into the formal undergraduate curriculum.

This letter demonstrates the need to implement strategies to incorporate Inclusion Health into the curriculum and the approaches described are applicable to diverse health professions and settings.
Developments and challenges of e-health strategies for people with inflammatory bowel disease
Authors: Avery Pearl
Published: March 2020

Technological developments have opened up new possibilities for the management of inflammatory bowel disease. Pearl Avery discusses these developments, as well as the potential benefits and challenges of e-health strategies for long-term patient care.
New rearing method, life cycle, tunneling behavior and ecological notes on the splendid ghost moth Aenetus djernaesae Simonsen, 2018 from Western Australia (Lepidoptera: Hepialidae)

Authors: KAY PAUL , HUTCHINSON PAUL M , GREHAN JOHN A
Published: March 2020

This study successfully documents, for the first time, the entire life cycle of Aenetus djernaesae Simonsen, 2018 and confirms the efficacy of using supplemental sources of fungi to feed the early instar larvae. Fresh cut pieces of the commercial mushroom Agaricus bisporus (J.E. Lange) and sections of Eucalyptus L’Her. bark were placed around the base of potted host plants –Myoporum insulare R.Br. (Scrophulariaceae) and the potential host plant Dodonea hackettiana W.Fitz. (Sapindaceae). First instar larvae were added to this matrix where they fed on the mushroom and bark. The life cycle comprised egg development of 20 days, fungal feeding of ~36 days, and host plant development (including pupal) of ~300 days. Adult emergence of reared and field collected samples occurred within a 22 day period. Larvae transferring from fungi to host plants transitioned during the night by constructing a web of silk and plant tissues within two hours and proceeding to excavate a tunnel from within. The mature larval tunnel is relatively short, up to 220 mm in length and usually extending below the entrance around which the larvae grazes on callus tissue forming after bark removal. Most adults emerged within an hour of dusk with the pupa protruding from the top of the vestibule. The rearing method described here demonstrates the feasibility of laboratory based studies of larval development in Aenetus Herrrich-Schäffer and other callus-feeding stem boring Hepialidae.  Key words: Hepialidae, Aenetus, life cycle, artificial diet, Myoporum, Dodonea, larval foodplant
Metasurface-based total internal reflection microscopy
Authors: Gortari Antu Nehuen , Bouchoule Sophie , Cambril Edmond , Cattoni Andrea , Hauke Lara , Enderlein Jörg , Rehfeldt Florian , Yacomotti Alejandro
Published: March 2020

Recent years have seen a tremendous progress in the development of dielectric metasurfaces for visible light applications. Such metasurfaces are ultra-thin optical devices that can manipulate optical wavefronts in an arbitrary manner. Here, we present a newly developed metasurface which allows for coupling light into a microscopy coverslip to achieve total internal reflection (TIR) excitation. TIR fluorescence microscopy (TIRFM) is an important bioimaging technique used specifically to image cellular membranes or surface-localized molecules with high contrast and low background. Its most commonly used modality is objective-type TIRFM where one couples a focused excitation laser beam at the edge of the back focal aperture of an oil-immersion objective with high numerical aperture (N.A.) to realize a high incident-angle plane wave excitation above the critical TIR angle in sample space. However, this requires bulky and expensive objectives with a limited field-of-view (FOV). The metasurface which we describe here represents a low cost and easy-to-use alternative for TIRFM. It consists of periodic 2D arrays of asymmetric structures fabricated in TiO2 on borosilicate glass. It couples up to 70% of the incident non-reflected light into the first diffraction order at an angle of 65° in glass, which is above the critical TIR angle for a glass-water interface. Only ∼7% of the light leaks into propagating modes traversing the glass surface, thus minimizing any spurious background fluorescence originating far outside the glass substrate. We describe in detail design and fabrication of the metasurface, and validate is applicability for TIRFM by imaging immunostained human mesenchymal stem cells over a FOV of 200 µm x 200 µm. We envision that these kinds of metasurfaces can become a valuable tool for low-cost and TIRFM, offering high contrast, low photodamage, and high surface selectivity in fluorescence excitation and detection.