bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I trial of combination therapy with 90Y ibritumomab tiuxetan and gemcitabine in patients with non-Hodgkin’s lymphoma
Authors: Borghaei H. , Smith M. , Millenson M. , Krieger K. , Rogatko A. , Schilder R.
Published: March 2020

17514

Background: Zevalin (Z) is an effective therapy in patients with relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL). Gemcitabine (gem) also is active against NHL and is a potent radiation sensitizer. We are conducting a phase I trial to assess the safety of concomitant administration of Z and gem in patients with NHL. Methods: The starting gem dose is 250 mg/m2 on days 1 and 8. Nine patients in three cohorts will be treated with 250 mg/m2 of gem with 0.2, 0.3 or 0.4 mCi/kg of Z. The next cohort can accrue after all patients in the prior cohort have hematologic toxicity has recovered to grade 2 or after 60 days from the date of the last treated patient in the previous cohort. Once it is confirmed that a Z dose of 0.4 mg/kg can be safely administered with gem 250 mg/m2, gem will be escalated according to a Bayesian based system. Response evaluation is based on the International Workshop on Standardized Response Criteria for Non-Hodgkin’s lymphomas. Eligibility criteria include: any histology of recurrent NHL (not candidates for high dose therapy), platelets ≥ 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to < 25% radiation of bone marrow and no prior bone marrow or stem cell transplant. Results: Five patients have been treated thus far, two with follicular NHL (FL) and three with diffuse large B cell (DLBCL). Median age is 75 (range 55–82). The median number of prior treatments is 2 (range 1–6). One patient with DLBCL is not evaluable. The first three patients received 0.2 mCi/kg and next two patients 0.3 mCi/kg of Zevalin. Toxicity consists of grades 2 & 3 myelosuppression in the first 3 weeks in 3 pts. due to gem and then of grade 2 in 1 pt. at 6 to 8 weeks as is usually seen with Z. One grade 3 leukopenia and one grade 2 thrombocytopenia have been observed resolving within one week. One grade 3 infection occurred, unrelated to the protocol or the study drugs. No grade 3 or 4 non-hematologic toxicity has been seen. In follow up, two patients with FL and one with DLBCL achieved CRu. One patient with DLBCL has progressed and one is not yet evaluable. Conclusions: Our preliminary findings suggest that Z can be safely combined with gem 250 mg/m2 in the treatment of patients with NHL. Dose escalation to full dose Zevalin and then of gemcitabine is continuing.

[Table: see text]
Comparison of engraftment in patients undergoing peripheral blood stem call transplantation (PBSCT) with or without support of G-CSF on day +5: A prospective cohort study results
Authors: Arpaci F. , Baskoy K. , Ataergin S. , Ozet A. , Komurcu S. , Ozturk B.
Published: March 2020

17521

Background: The role of G-CSF administration on day +5 after PBSCT in terms of hematologic engraftment and supportive treatment need has been evaluated. Methods: Forty-two consecutive patients with solid and hematological malignancies were enrolled in two cohort groups depending on G-CSF administration. Twenty-seven patients were given G-CSF (5 μg/kg/day) from day +5 after the transplantation until the achievement of neutrophil engraftment. Posttransplant G-CSF was not given to the control arm of 15 patients. A number of at least 2 × 106 CD34+ cells per kilogram collected by cytapheresis were given to all patients. Results: A significant difference was found between the two groups in favor of G-CSF receiving group, in terms of neutrophil engraftment time (10.56 ± 1.22 vs 11.93 ± 2.89 day; p = 0.04), number of days with fever (3.33 ± 2.66 vs 5 ± 2.95 day; p = 0,03) and number of the days requiring antibiotic therapy (7.07 ± 3.46 vs 11.87 ± 3.74 day; p < 0,001); whereas, no statistically significant difference was noted in terms of hospitalization period (13.30 ± 4.79 and 13.53 ± 2.56 day; p = 0.26), platelet engraftment time (12.22 ± 2.79 and 13.40 ± 3.89 day; p = 0.26) and erythrocyte transfusion need; however, platelet transfusion need was statistically significant between the groups with and without G-CSF support (1.27 ± 0.96 vs 0.56 ± 0.75, p = 0.01) Conclusions: This study reveal that starting G-CSF on day +5 may fasten the neutrophil engraftment, decrease the number of days with fever, as well as a the need for antibiotic therapy in posttransplant period.

No significant financial relationships to disclose.
A phase I study of G3139 in combination with RICE chemotherapy in relapsed non-Hodgkin’s lymphoma (NHL)
Authors: Smith S. M. , Van Besien K. , Conner K. , Gajewski T. , Kuna T. , Karrison T. , Wade Iii J. L. , Zwiebel J. , Vokes E. E.
Published: March 2020

17529

Background: Aggressive lymphomas are chemosensitive, but frequently relapse. Bcl-2 protein overexpression promotes tumor cell survival via anti-apoptosis, and is clinically correlated with shortened remission duration and decreased survival. The antisense oligonucleotide oblimersen sodium (G3139) downregulates bcl-2, has activity in NHL, and may be synergistic with chemotherapy. Methods: Pts had histologically confirmed aggressive NHL that relapsed after one prior anthracycline-based regimen. G3139 was given as a continuous infusion on Days 1–8 (168 hours) every 14 days, with stem cell collection following cycle 3. Standard RICE chemotherapy was given on Days 4–6, allowing 72 hrs pre- and 48 hrs post-chemo G3139. Dose-limiting toxicity (DLT) was defined as grade 3 or greater non-hematologic toxicity, grade 4 thrombocytopenia, duration of neutropenia <500/mL greater than 7 days despite growth factors, grade 3 hemolytic anemia, or prolonged severe anemia. Pharmacodynamic endpoints included measurement of bcl-2 protein in peripheral blood (FACS analysis) and tumor (IHC), and bcl-2 RT-PCR in blood and tumor. Results: 8 pts were enrolled. At dose level 1 (G3139 3 mg/kg/day), both enrolled pts had grade 4 thrombocytopenia. The next 6 patients were treated with G3139 2.5 mg/kg/day (Dose Level -1) without any DLT’s. There were no grade 3 or 4 non-hematologic toxicities. 7 evaluable pts had successful stem cell collections: median CD34+ 4.2 × 106/kg (range, 1.3–8.72 × 106/kg). Responses: 4 CR/CRu, 2 PR, 1 SD, 1 too early. There was no detectable decrease in bcl-2 protein in the blood using flow cytometry or RT-PCR. Conclusion: The maximum tolerated dose of G3139 given over 8 days in combination with RICE chemotherapy is 2.5 mg/kg/day. It is unlikely that this dose sufficiently suppresses bcl-2 levels. The protocol will thus be amended to shorten the G3139 infusion to 5 days with renewed efforts to escalate the dose.

No significant financial relationships to disclose.
The role of FDG-PET in low-grade non-Hodgkin lymphoma (NHL): Impact of histology
Authors: Kassar M. , Go A. , Fung H. , Venugopal P. , Ali A. , Kumar M. , Farhat M. , Batus M. , Shammo J. , Gregory S. A.
Published: March 2020

17534

Background: FDG-PET scan was proved important diagnostic and prognostic tool in patients with aggressive (NHL). The objective of this study is to investigate the correlation between the histology subtype in low-grade NHL and the sensitivity of the FDG-PET. Methods: We included all patients who presented to our institution during the period from April 2001 till April 2004 and underwent staging evaluation by FDG-PET during the course of their disease. All patients had histologically confirmed low-grade NHL. Patients with history of active malignancy, other than NHL, within the last five years were excluded. Correlation was made with the CT-scan findings. Results: 53 patients were included. Age (range 30–82, median 54), 57% of them were male. 34 patients had follicular lymphoma (FL), 9 patients had marginal zone lymphoma (MZL), and 10 patients had small lymphocytic lymphoma (SLL). 24/34 patients with FL underwent FDG-PET during the initial evaluation of their disease, and 10/34 patients underwent FDG-PET as part of their restaging assessment. 33 patients had true positive FDG-PET findings when compared to CT-scan results. One patient had negative FDG-PET with CT-scan findings suggestive of pathologic lymphadenopathy (sensitivity 97%). The highest SUV was in the range of 3.5–15 (median = 7). 8/9 patients with MZL had true positive FDG-PET findings and one had false negative FDG-PET result (sensitivity 89%). The highest SUV was in the range of 2–6.30 (median 2.6). Among the ten patients with SLL, 5 had FDG-PET during the initial evaluation and 8 patients during re-staging workup. 13 FDG-PET results were available for analysis. 5 cases were false negative, 1 case was false positive, 5 cases were true positive, and 2 cases were true negative (sensitivity 50%). The highest SUV was in the range of 1.8–6.2 (median of 2.5). Conclusion: Histology in low-grade NHL has a major impact on the sensitivity of the FDG-PET imaging results. Whereas it is a highly sensitive diagnostic method in patients with FL, and to a lesser degree in patients with MZL, it has poor sensitivity in patients with SLL.

No significant financial relationships to disclose.
A phase IV, open-label trial using bortezomib for retreatment of patients (pts) with multiple myeloma (MM) following an initial response to bortezomib
Authors: Druck M. , Walters I. B. , Carloss H. , Sood R. , Leblanc A. L. , Noga S. J.
Published: March 2020

17539

Background: Bortezomib (VELCADE; Vc) has substantial single agent activity in heavily pretreated patients. Response rates have been shown to improve when used in combination with other agents. Since some pts experience long durations of response with treatment-free periods, this open-label, single-arm study was designed to determine the utility of retreatment with Vc alone or in combination with dexamethasone, thalidomide or liposomal doxorubicin. Methods: Pts who previously responded to Vc alone or in combination are eligible for this study. Up to 78 pts will receive Vc alone or in combination at the finishing dose of their initial Vc treatment (0.7, 1.0, or 1.3 mg/m2) as a bolus, intravenous injection on days 1, 4, 8, and 11 of a 21-day treatment cycle. Responses are assessed by the investigators and also calculated from percentage reduction in serum or urine M-protein. Results: To date, 15 pts have been treated and 12 are evaluable for response (having received at least 2 cycles of therapy). 8/12 patients had dexamethasone added to their regimen. The population is representative of pts with relapsed and refractory MM: mean age, 68 years; 4 males, 8 females; median of 5 prior lines of therapy; and 67% IgG MM. Median treatment-free period between the end of first Vc treatment and the start of retreatment: 11.1 months (range 5–21 months). Investigator-assessed responses show that 50% of pts have achieved a PR or CR. Only 1 pt had progressive disease. One pt has developed new peripheral neuropathy, while pre-existing neuropathy has worsened in 4 pts. No Vc-related serious adverse events have been reported. Conclusions: Preliminary results show that retreatment with Vc alone or in combination has encouraging activity with manageable toxicity even in pts who are heavily pretreated. These data suggest that repeated use after a treatment break may achieve prolonged disease control. This is the first report of Vc retreatment for MM.

[Table: see text]
Vinorelbine-based salvage therapy for patients with aggressive leukemias and non-Hodgkin’s lymphomas
Authors: Morar S. , Larson J. , Qazi S. , Uckun F.
Published: March 2020

17563

Background: We treated 26 patients with aggressive lymphohematopoietic malignancies, including 3 chronic myeloid leukemia (CML) patients in blast crisis, 2 chronic lymphocytic leukemia (CLL) patients with rapidly progressive leukemia, 10 acute lymphoblastic leukemia (ALL) patients in therapy refractory relapse, and 11 non-Hodgkin’s lymhoma (NHL) patients (9 in relapse with progressive lymphoma) with vinorelbine-based outpatient salvage chemotherapy. Methods: Patients received vinorelbine-based salvage therapy regimens NND-I (Vinorelbine [Navelbine] 25 mg/m2 d1,d8, Mitoxantrone [Novantrone]10 mg/m2 d1, Dexamethasone [Decadron] 20 mg BID d1 through 7, or NND-II (Vinorelbine 25 mg/m2 d1, Mitoxantrone 10 mg/m2 d1, Dexamethasone 20 mg BID d1 through 7, Fludarabine 25 mg/m2 d1,d2,d3). Rituximab (Rituxan, 375 mg/m2 d1,8,15,29) was used in combination with chemotherapy in patients with CD20 antigen positive malignancies. Treatment responses were evaluated by peripheral blood and bone marrow examinations in patients with leukemia and CT/MRI-PET fusion imaging in patients with non-Hodgkin’s lymphoma using standard response criteria. Results: All patients completed their salvage therapy as an outpatient without infectious disease complications or hospitalizations. Of the 26 patients, 20 (77%) had objective responses, including 14 complete remissions (CR). All 3 CML patients and both CLL patients achieved a CR. Of the 10 ALL patients, 5 achieved a CR and one achieved a partial remission (PR). Of the 11 NHL patients, 4 achieved a CR and 5 achieved a PR. Conclusions: Taken together, these findings demonstrate that patients with high risk/poor prognosis leukemias and non-Hodgkin’s lymphomas can achieve meaningful objective responses in an outpatient setting using vinorelbine-based salvage regimens.

No significant financial relationships to disclose.
Working Formulation (WF) and Revised European-American classification of Lymphoma (REAL): Inter-observer agreement in conflicting lymphoma cases
Authors: Latifzadeh S. , Riahi T. , Entezari V.
Published: March 2020

17567

Background: Immunophenotypic and genetic studies play an increasingly important role in diagnosis and classification of lymphoid neoplasm. This study tried to re-evaluate a number of conflicting lymphoma cases which were reported by WF previously, with REAL classification and to measure the agreement between these two methods of classification. Methods: In a three year period, a panel of expert pathologists evaluated referral cases by WF. Those cases (n = 60, Mean age = 40.9 ± 16.4) whose evaluations did not reached to a definitive pathologic diagnosis or there was a discrepancy between their pathologic and clinical findings were reviewed in Keil institute of hematopathology in Germany based on REAL classification. The primary and secondary diagnoses each were classified in five subgroups with equivalent clinical risks (see Table ). Results: Disagreement was detected in 23 cases (38%), while exact kappa statistic was 0.50. Sixteen cases (70%) of difference belonged to group of low grade lymphoma (kappa = 0.35) in which 11 cases (69%) changed to aggressive lymphoma and one case changed to highly aggressive subgroups. Four cases (25%) of difference occurred in the group of low probability lymphoma in which neoplasia was documented. High grade and Hodgkin lymphoma subgroups showed a high level of agreement (kappa = 0.84 and 0.74 respectively). Conclusions: Based on this study’s results, it can be concluded that there is a moderate agreement between WF and REAL classifications in conflicting lymphoma cases. WF underestimates clinical risk of low grade lymphoma in a considerable amount of patients but in high grade lymphoma the disagreement is not so high.

[Table: see text]

No significant financial relationships to disclose.
The relevance of performing a bone marrow aspirate and biopsy in breast cancer patients with suspected bone marrow metastasis
Authors: Sobrevilla-Calvo P. , Jaramillo-Restrepo M. , Rivas-Vera S. , Avilés-Salas A. , Acosta-Barreda A. , Cervera-Ceballos E. , Labardini-Méndez J.
Published: March 2020

18605

Background: Patients with breast cancer often presents hematological abnormalities during the disease evolution, frequently it is difficult to define if these are due to bone marrow infiltartion or are due to drug toxicity or a new hematological disorder. To determine the proportion of patients with bone marrow metastasis we reviewed the bone marrow aspirates and biopsies of patients with histological proven breast cancer and an abnormal peripheral blood count referred to the Hematology Department. Methods: We reviewed the medical records of 88 patients referred to our Department from april 1998 to april 2005 with breast cancer and with bone marrow smears and biopsies. The BM smears were interpreted blindly by one of us. The BM biopsies were reviewed independently by a hematopatologist. A statistician analysed the data and estimated frequencies and rates, survival analysis was estimated by means of the Kaplan-Meier method. Results: Median age 47.7 years (range 28–80), clinical stage at diagnosis was: II, 19 (21.1%); IIIA, 19 (21.1%); IIIB, 16 (17.8%); IV, 34 (40%). The hematological abnormality that triggered the referral was: Thrombocytopenia, 61 (67.8%); anemia, 53 (58.9%); leucopenia, 47 (53.4%); thrombocytopenia and anemia, 39 (43.3%). The median time from the initial diagnosis to the BM biopsy was 12.8 months (range 1 to 176.7). Regarding the BM aspirates interpretatrion: 17 were not evaluable, 53 were negative for infiltration, 17 were positive for carcinoma and 1 with plasma cell infiltration (this patients had concurrent Breast cancer and myeloma). BM biopsies: 19 were not evaluable, 48 were negative, 20 positive and 1 with myeloma. The sensitivity of the BM aspirates was 75% (12/16) and the specificity 95% (41/43). The median survival of the patients with BM metastais was 109 months, and 104 of the patients without BM metastasis (p = 0.9767) Conclusions: Most of the patients with hematological abnormalities do not have BM infiltration, bone marrow biopsies have more sensitivity than aspirates. The presence of BM metastasis does not necessarily predicts a short survival period.

No significant financial relationships to disclose.
Prospective evaluation of clinical and biological parameters to predict clinically relevant denutrition in cancer patients undergoing surgery
Authors: Antoun S.
Published: March 2020

18611

Background: Denutrition increases surgery morbidity and mortality in cancer patients. Methods: This study aimed to compare the relative value of different scores widely used to measure denutrition. During 3 months for all of the patients requiring heavy carcinologic surgery we checked: weight loss over 10%, body mass index (BMI), serum albumin, transthyretin (Tt), Buzby index, Pronostic Inflammatory Nutritional Index (PINI), Ottery score (PG-SGA). Other data like the surgical procedure, duration of surgery, cancer status were also recorded. Morbidity was defined by infectious and non-infectious major complications (IMC, NIMC), length of stay (Ls) in hospital, and death at 1 and 6 months. Results: 275 patients from 8 French Cancer Centers were included (167 were female, median age: 58 years). In multivariate analyses albumin level (<30 g/l) is the only significant predictor of surgical morbidity, with the duration of the surgical procedure. Ottery score was the most sensitive among clinical parameters. Weight loss was significantly correlated with survival. Conclusions: Serum albumin and weight loss are useful parameters to consider in cancer patient requiring surgery; they are easy to monitor and should be part of pre-operative check-up in those patients.

[Table: see text]

No significant financial relationships to disclose.
Prevalence and characterization of the insomnia syndrome in an outpatient oncology clinic
Authors: Prommer E. E.
Published: March 2020

18612

Background: Insomnia is an often overlooked symptom. One potential reason for this neglect is that insomnia is viewed as a normal and temporary reaction to the cancer diagnosis or treatment. Patients themselves may fail to report their sleep difficulties to their physicians for similar reasons. Previous work in understanding insomnia has been limited by the lack of an operational definition of the insomnia syndrome, small sample size and varied instruments for symptom detection. Hence, the proportion of cancer patients meeting diagnostic criteria for the insomnia syndrome is not well known. Recently the diagnosis of the insomnia syndrome has been redefined using a combination of criteria derived from the International Classification of Sleep Disorders and the DSM-IV. The criteria includes)difficulty in initiating and/or maintaining sleep, whereby sleep-onset latency and/or wake after sleep onset is greater than 30 minutes; sleep efficiency (ratio of total sleep time to total time spent in bed) lower than 85%; difficulties occurring at least 3 nights per week; difficulties occurring for at least 6 months; and difficulties causing marked distress or significant impairment in daytime functioning (eg, fatigue, disturbed mood, performance deficits). Methods: 100 consecutive oncology patients were surveyed using the above criteria for the insomnia syndrome. Symptom assessment was also included. Results: The incidence of the insomnia syndrome seems to correspond to previously reported incidences.Patient have more problems staying asleep than going to sleep. Patients may have dramatic inversions of their sleep/wake cycle yet feel that they do not have insomnia. Pain is the most commonly associated symptom associated with insomnia. Conclusions: There is a great need for better tools to asssess the symptom of insomnia. Focusing on specific characteristics of insomnia and distinguishing the insomnia syndrome versus the symptom of insomnia is an effective way establish if there is a need for specific therapy. The addition of symptom assessment further improves the characterisation insomnia. Characteristics of insomnia experienced by the patient may help direct specific treatment modalities. Pain is a frequently associated symptom with insomnia.

No significant financial relationships to disclose.
Emetic potential of daily oral etoposide
Authors: Herbert S. M. , Brames M. J. , Einhorn L. H.
Published: March 2020

18618

Background: Chemotherapy agents are classified by their degree of emetogenicity. Agents with high or moderate emetogenicity are treated with a 5HT3 antagonist + dexamethasone to mitigate acute and delayed chemotherapy-induced nausea and vomiting. Intravenous etoposide (E) has low probability of nausea and/or vomiting. However, at the 2004 Perugia International Antiemetic Consensus meeting, oral E was listed as a moderately emetogenic drug (Supp Care Cancer 13:80–84, 2005). Daily oral E has been used to treat refractory germ cell cancer. We prospectively evaluated the emetic potential of daily oral etoposide in this patient (pt.) population. Methods: Between 8/03 and 12/05, 13 male pts. with refractory germ cell cancer were treated with single agent daily oral E 50 mg/M2 day × 21 days every 4 weeks. All had progressed following cisplatin combination chemotherapy and had previously received high dose chemotherapy with carboplatin + E (intraveneously) with peripheral blood stem cell transplant. Median age was 35 (range 14 to 54). No pt. received prophylactic antiemetics. Pts. completed a 6 question Multinational Association Supportive Care Cancer (MASCC) antiemetic tool each day they received E. Intensity and duration of nausea were recorded, with 0 being none and 10 being most severe. Additionally, pts. were asked if they experienced vomiting. The number of vomiting episodes as well as any antiemetic medications were recorded. Data on 25 pts. will be presented and we currently have information on 13 pts. Results: 13 pts. completed the MASCC form. Only 2 pts. required antiemetic support. 1 pt. experienced emesis × 1 on day 1 and 1 pt. experienced emesis × 1 on day 11. 1 pt. experienced nausea on days 9 through 20 with a MASCC rating of 3–6. 1 pt. documented nausea day 1 through 21 with a MASCC rating of 1–3. 2 pts. experienced a MASCC rating of 1 of their nausea, 1 pt. on day 1 and 1 pt. on day 2. Overall, 8 of 13 pts. had no nausea or vomiting despite the absence of any antiemetics and 2 other patients had only minimal nausea for a single day. Conclusions: Daily oral E has only a low probability of emesis and does not require prophylactic antiemetics.

[Table: see text]
Clinical prognostic factors in metastatic gastrointestinal stromal tumors (GIST) patients treated with Imatinib
Authors: Lopez-Pousa A. , Gallego O. , Matias-Guiu X. , Nadal R. , Villanueva R. , Quintana M. , Carrera G. , Marse R. , Artigas V. , Barnadas A.
Published: March 2020

19500

Background: Imatinib (IMT) therapy is the main successful therapy for metastatic GIST. We analyze the results of the treatment according to the clinical factors and dose of IMT. Methods: 38 patients (pts) with metastatic GIST (C-KIT positive) were treated from June 2001 to June 2005 with IMT; 11 pts received 400 mg bid and 27 pts 400 mg daily. Evaluation of c-Kit mutation on exon 11 was analyzed in 23 pts. An analysis of the clinical factors was performed. Results: The average age was 60 y. (18–78); Gender: 26 male/12 female; Primary location in small bowel 24, gastric 12, esophagus 2. ECOG 0–1 in 87% of pts. 31 pts have had radical surgery at the primary (26 R0, 5 R1). Interval to metastatic/local relapse was 10 months (2–61). Hepatic metastases were presented in 26 pts (1–5 in 12, 6–10 in 5, >10 in 9 pts); peritoneal disease in 26 pts (1–5 in 10, 6–10 in 8, >10 in 7 pts); pulmonary metastases in 2, bone in 2 and nodal in 3 pts; local tumor in 6. With a median follow-up of the 56 m, response rate was 5 complete, 21 partial responders, 7 disease stabilization. Three pts died in the first month of treatment, two due to tumoral bleeding, one due to progressive disease. Median survival (MS) was 43 (0–54) months, not achieved for pts in 400 mg, 41 months for 400 mg bid pts (p=0.61). Progression free survival (PFS) was 21 months (21 for pts in 400 mg, 20 for pts in 400 mg bid). We don’t find statistical differences regarding the number of hepatic and peritoneal metastases, neither according to the size of metastases (<10 cm was 48 m., ≥10 cm was 41 m.). MS was not achieved in 18/23 patients with exon 11 mutation vs 9 months for non-mutation patients (p 0.00). No differences were found in survival for 4/18 pts with missense mutation. Conclusions: Mutational status may predict the outcome of GIST patients treated with IMT. Dose of IMT, mass size and number of metastases were not prognostic factors for survival. Special attention would be done to the risk of bleeding at the start of treatment with IMT.

No significant financial relationships to disclose.
Postoperative radiotherapy results in soft tissue sarcomas
Authors: Aykanat A. , Yoney A. , Unsal M. , Kandemir O. , Berberoglu E. , Kucuk A. , Eskici S. , Buyukpolat Y. , Adatepe M. F. , Altin S.
Published: March 2020

19513

Background: Postoperative radiotherapy results with higher local rates than surgery alone. In this trial we have evaluated and studied factors that affects local recurrence rates. Methods: A retrospective clinical study of 125 eligible patients with soft tissue sarcoma diagnosis from SB Okmeydani Educational Hospital-Oncology Department treated between 1998–2002 years was performed. Tumor size, surgery margin histopathologic grade and type were evaluated. At subgroup analysis local recurrense rates were studied in groups with or without postoperative radiotherapy. Results: In 125 patients, 70 were tumor free, 45 were tumor positive or with suspicious margin after the surgery. Subgroup of 25 patients which have tumor size smaller than 5 cm and negative margin had no radiotherapy and had no local recurrens. In an other group of 45 patients which have tumor size larger than 5 cm and tumor negative after excision 18 patients did not have any postoperative radiotherapy and 4 of them (% 22) had local failure. The rest of the 27 patients of this group who had postoperatif radiotherapy had 2 (% 7) local failure. Among 55 patients with positive or suspicious margins; 18 had no postoperative radiotherapy and there were 6 (% 33) local recurrens while the 37 patients with radiotherapy had 7 (% 18) local recurrens rates. Conclusions: In operable soft tissue sarcomas tumor size, hystopathological grade, postoperatif surgery margins are the most important factors which affects local recurrens rates.

[Table: see text]

No significant financial relationships to disclose.
Detection of circulating lymphendothelial cells in patients with solid tumors
Authors: Fiedler W. , Suhrbier K. , Riethdorf S. , Schuch G. , Pantel K. , Bokemeyer C. , Loges S.
Published: March 2020

20010

Background: Bone marrow derived endothelial progenitor cells (ECPs) contribute to neoangiogenesis in cancer patients. Elevated numbers of circulating endothelial cells and EPCs can be detected in the peripheral blood of tumor patients. Recently, proliferating lymphatic vessels have been described in human cancers such as melanoma and head and neck tumors. Therefore, we investigated whether circulating lymphatic endothelial cells can be detected in cancer patients. Methods: We developed a sensitive immunocytochemical approach using a monoclonal antibody against the lymphendothelial specific hyaluronic receptor LYVE. After enrichment by Ficoll density gradient centrifugation, 7 × 10(5) peripheral blood mononuclear cells (PBMNCs) from 23 patients with metastatic cancer (6 gastrointestinal, 4 lung, 3 thymus, 3 thyroid, 1 mamma, 1 pancreas, 2 renal, 1 adrenal, 2 urothelial cancer, 1 PNET, 1 NET) and healthy individuals (n = 7) were spun onto glass slides. Two million PBMNs from each patient were stained for LYVE using the APAP technique. Isotype antibodies were used as controls. Cytospins were analyzed with the automated cellular imaging system (ACIS; ChromaVision Medical Systems). The method was validated with spiked blood samples. Results: Circulating LYVE+ lymphatic endothelial cells could be detected in 4 of 7 healthy subjects (57%) and in 16 of 23 patients (69%) with metastatic cancer. The mean number of lymphendothelial cells was significantly higher in cancer patients (15 cells/1 × 10(6) PBMNCs [range 0–276] vs. 1.0 cells/1 × 10(6) PBMNCs [range 0–2]). As a control, circulating tumor cells were enumerated after staining with a cytokeratin antibody (A45-B/B3). Circulating tumor cells could not be detected in healthy controls but in 13 of 23 of cancer patients (mean 1.4 cells/1 × 10(6) PBMNCs range [0–9]). Conclusion: Circulating lymphendothelial cells can be detected in patients with metastatic cancer and healthy subjects. Tumor patients have higher levels of circulating lymphendothelial cells than normal controls. These cells may participate in the generation of lymphatic vessels within tumor manifestations.

No significant financial relationships to disclose.
Effect of adjuvant treatment on the circulating CK-19 mRNA-positive tumor cells in patients with early stage breast cancer
Authors: Xenidis N. , Mavroudis D. , Apostolaki S. , Perraki M. , Stathopoulou A. , Lianidou E. , Georgoulias V.
Published: March 2020

20012

Background: To evaluate the effect of adjuvant treatment on the peripheral blood CK-19 mRNA circulating tumor cells (CTCs) in patients with early-stage breast cancer. Methods: CTCs were detected by real-time RT-PCR assay, in 119 patients with estrogen or/and progesterone receptors-positive tumors at the following time points: before the initiation and after the completion of adjuvant chemotherapy and every 3 or 6 months during the period of adjuvant tamoxifen administration. Results: Adjuvant chemotherapy failed to “eliminate” the CTCs in 17 (47%) out of 36 patients with detectable cells in pre-chemotherapy samples; in addition, adjuvant tamoxifen failed to “eliminate” the CTCs in 8 (36.4%) of 22 patients displaying detectable cells in post-chemotherapy samples. The incidence of clinical relapse was significantly (p = 0.017) higher for patients with post-chemotherapy detectable CTCs as well as for patients with persistently detectable CTCs throughout the follow-up period compared with those who did not (65.3% vs 7.3%, respectively; p < 0.001). In multivariate analysis, post-chemotherapy detection of CTCs and their persistence throughout the follow-up period were significantly associated (p = 0.001 and 0.003, respectively) with early relapse. Conclusions: The detection of CK-19 mRNA+ CTCs after adjuvant chemotherapy and during tamoxifen administration is an independent prognostic factor associated with unfavorable outcome.

No significant financial relationships to disclose.
Protein multiplex sandwich immunoassay: A reliable and objective method for complete molecular characterization of breast cancer from core needle biopsies
Authors: Sauer G. , Schneiderhahn-Marra N. , Bãuerle M. , Kurzeder C. , Koretz K. , Kreienberg R. , Jost T. , Deissler H.
Published: March 2020

20025

Background: Within the last years, protein microarrays have been developed to quantify a large number of parameters present in a given sample simultaneously. Such miniaturised and parallelised sandwich immunoassays are of general interest for all proteomic and diagnostic approaches in which several parameters have to be determined from small samples. We describe the development of a bead-based flow cytometry that represents a convenient approach for rapid multiplex detection of functional target molecules from breast cancer biopsies. Methods: Briefly, sonographically guided core needle biopsies (CNB) were performed from 120 breast cancer masses from different patients. All biopsies were carried out with an automated core biopsy device fitted with 14-gauge (22 mm excursion) needles. Tumor samples were frozen on at −70 Celsius and pulverized. Proteins were extracted, allowing the simultaneous quantification of more than hundred proteins by a bead-based multiplex sandwich immunoassay. Results: The total amount of extracted protein from tumor tissues (mean weight of 20 mg) ranged from 300 to 1000 μg. We demonstrate appropriate sensitivity, reproducibility, and robustness for this protein microarray technology to characterize clinical samples and generate reliable data sets. A set of multiplexed sandwich immunoassays based on Luminex beads were developed that identify marker proteins indicative of prognosis or response to therapeutic options. Up to almost hundred parameters were identified and quantified simultaneously of which estrogen, progesterone and HER2 status in the multiplex assay was highly significant correlated to results obtained by immunohistochemistry (IHC) (p < 0.01). Conclusions: Our results demonstrate that this new bead-based protein microarray technology rapidly and reliably characterizes tissue samples to generate data sets of molecular marker. Therefore, this technology may once replace traditional IHC in determining marker proteins indicative of prognosis or response to therapeutic options.

No significant financial relationships to disclose.
XIAP mRNA levels but not XAF1 or XIAP/XAF1 mRNA levels predict pathological response in bladder cancer patients treated with neoadjuvant chemotherapy
Authors: Pinho M. B. , Sellos J. , Costas F. , Herchenhorn D. , Peixoto F. A. , Diengsmann R. , Small I. A. , Cardoso H. , Guimarães D. P. , Ferreira C. G.
Published: March 2020

20030

Background: The relation between apoptosis-related molecules and chemosensitivity has been extensively studied. In recent years, attention has shifted to a new family of inhibitor of apoptosis proteins (IAPs). XIAP (X- linked inhibitor of apoptosis) is the most versatile and potent member of the IAP family. To date, the overexpression of XIAP has been detected in various cancers. XAF1 (X-linked inhibitor of apoptosis associated factor 1) is a new protein identified for its ability to interact with XIAP. Neither XIAP nor XAF1 or XIAP/XAF1 mRNA expression have been studied in bladder cancer patients. Methods: The expression of XIAP and XAF1 mRNA was analyzed by a real time quantitative fluorogenic PCR method in a group of 17 patients with locally advanced bladder cancer treated with a combination of neoadjuvant Gemcitabine and Cisplatin. The prognostic significance of XIAP and XAF1 mRNA expression and the correlation with several clinicopathological variables was evaluated. Results: XIAP and XAF1 mRNA expression was detected in all 17 (100%) case samples. The levels of XIAP mRNA expression showed a moderate variation among samples. In contrast, XAF1 and XIAP/XAF1 mRNA levels showed significant variation among samples. Bivariate correlation analyses revealed a significant positive Spearman direct correlation coefficient between the XIAP expression and the pathological response. No significant correlation was found for XAF1 expression as well as for the XIAP/XAF1 ratio and clinical and pathological response. Conclusions: This is first study to address the role of XIAP, its negative regulator XAF1, and the XIAP/XAF1 ratio in bladder cancer patients. The positive correlation between the XIAP mRNA expression and the pathological response is in line with a previous study from our group in which a correlation was found between XIAP expression and survival. All these observations point to a complex role of XIAP in tumor biology. XAF1 mRNA expression in bladder carcinomas did not achieve significance as an independent predictive and prognostic factor in a bivariate analysis. Further studies are necessary in order to better assess a possible clinical value for XIAP and XAF1 as predictive and prognostic markers in cancer patients.

No significant financial relationships to disclose.
Molecular profiling of circulating tumor cells in the peripheral blood of patients with primary and metastatic breast cancer
Authors: Fersis N. , Deckwart V. , Leitz A. , Weber M. , Rom J. , Böcher O. , Albert W. H. , Bastert G. , Sohn C. , Kaul S.
Published: March 2020

20033

Background: The purpose of this study was detection and expression profiling of circulating tumor cells (CTC) in breast cancer patients. Methods: Two separate probes of 5 mL peripheral EDTA-blood from patients with primary breast cancer (n=167) and metastatic disease (n=111) were used for immunomagnetic tumor cell selection. Targets for preanalytical enrichment were the antigens EpCAM and MUC-1. Separated cells were lysed and used for mRNA isolation and c-DNA synthesis. The breast carcinoma-associated transcripts EpCAM, MUC-1, HER-2, claudin7, cytokeratin 19, mammaglobin 1, prostate-specific ets factor (PSE) and survivin were amplified by three separate multiplex RT-PCR reactions. Amplicons were analysed by capillary electrophoresis with the Agilent Bioanalyzer 2100. Specificity of the RT-PCR was confirmed by examination of blood of healthy donors. Results: Sensitivity for every single transcript was adjusted to 2 tumor cells per 5 ml blood. Tumor-associated transcripts were detected in 31 of of 167 (18.5%) patients with primary breast cancer and in 46 of 111 (41%) patients with metastatic disease. The marker with the highest incidence in both groups was MUC-1, with a positivity rate of 81%. Tumor-associated transcripts were heterogenouosly expressed, however multiple markers were identified in more than 50% of the positive samples. Conclusion: Using a combination of preanalytical immunomagnetic tumor cell enrichment followed by a multigen RT-PCR approach we describe a sensitive detection system for breast carcinoma cells. In this study a panel of 8 genes overexpressed at high levels in metastatic breast cancer was selected for the identification of disseminated tumor cells in the peripheral blood of breast cancer patients. HER-2, survivin as a unique member of the inhibitor of apotosis protein family, as well as PSE identified in circulating breast cancer cells may serve as prognostic indicators of tumor progression and could represent valid targets for new individualized therapeutic interventions.

No significant financial relationships to disclose.
Differential spatial expression and activation pattern of EGFR and HER-2 in human breast cancer
Authors: Fink-Retter A. , Gschwantler-Kaulich D. , Hudelist G. , Mueller R. , Kubista E. , Czerwenka K. , Singer C.
Published: March 2020

20041

Background: Overexpression of HER family members is a well-established prognositc factor and identifies potential targets for antibody-based receptor blocking strategies. While several studies have analyzed the expression of HER-2 and other HER-family members in malignant tumors, considerably less is known about their expression and activation in non-involved breast tissue from breast cancer patients. Methods: We have therefore investigated the differential expression of EGFR, HER-2 and their tyrosinekinase activated forms (ptyr-1248 HER-2 and ptyr-845 EGFR) by using immunohistochemistry (IHC) in 64 tumor specimens containing malignant epithelium (a), non-malignant tissue located at the peritumoral margin (b), and univolved breast tissue obtained at a distance of at least more than 5 cm from the malignant tumor (c). Results: We found significantly higher HER-2 protein expression levels in malignant epithelium than in non-malignant epithelium (p = 0.000004, Fisher’s Exact Test). Stromal HER-2 was absent in any of the tissues investigated. Epithelial EGFR expression did not differ between the three tissue types, but stromal EGFR protein was significantly more common in peritumoral and non-involved distant tissues when compared to tumor tissues (p = 0.008, Fisher’s Exact Test). We only found one case of intratumoral epithelial ptyr-1248 HER-2 expression, and interestingley two cases in peritumoral and peripheral normal tissue. Furthermore, we did not observe ptyr-845 EGFR in any of the samples analyzed.We found a significant overall correlation between epithelial and stromal EGFR expression (r = 0.442; p < 0.0001; Spearman’s Rho). Furthermore, we found a significant overall correlation between stromal EGFR expression and normal tissue type (r = 0.170; p < 0.02; Spearman’s Rho), and an inverse correlation between epithelial HER-2 and normal tissue type (r = 0.492; p < 0.0001; Spearman’s Rho). Conclusion: We have found a differential expression pattern of EGFR, HER-2, and activated HER-2 that is dependent on the spatial relation to a malignant tumor. Our observation of decreased intratumoral EGFR expression and the absence of activated EGFR suggest that, in contrast to HER-2, EGFR inhibition might not be an ideal target for antibody therapy.

No significant financial relationships to disclose.
Role of metalloproteinase-7 in oxaliplatin acquired resistance in colorectal cancer cell lines
Authors: Almendro V. , Maurel J. , Augé J. , Laus G. , Domingo-Domenech J. , Fernández E. , Gascon P.
Published: March 2020

20042

Background: Mechanisms responsible for acquired resistance in colorectal cancer (CRC) tumors are not well understood. Anticancer drugs have been shown to enhance FASL expression by NF-kB induction. Additionally Metalloproteinase (MMP)-7 is over-expressed in CRC and has been shown to inhibit apoptosis by cleavage of FASL. We have previously shown in vivo that, sFASL increment was associated with acquired chemoresistance. Therefore we speculate that inhibition of MMP-7 or NF-kB can reverse chemoresistance in CRC cell lines. Methods: We generated an oxaliplatin-resistant cells (HT29R) from a p53 mutated (HT29) cell line. Both cell lines were cultured for 72h with different concentrations of oxaliplatin, BAY11–7085 (inhibitor of NF-kB activation), 0.01 mM of the MMP-7 inhibitor 1,10-Phenanthroline monohydrate (1,10-PM) and 100 ng/ml of DX2 monoclonal antibody. Different drug combinations were performed. Citotoxicity was determined by the MTS method, and cell cycle was analysed at 72h. Cell lines were characterized for MMP-7 expression (ELISA), NF-KB (Western-Blot), Fas expression (immunohistochemistry) and FasL expression (Western-Blot). Results: FAS was down-expressed in HT29R compared to HT29. The HT29R cells showed a IC50 for oxaliplatin 2-fold higher than normal cells. Treatment with 1,10-PM decrease MMP-7 levels (p < 0.005) compared with untreated cells. Additionally, inhibition of MMP-7, restore IC50 values after oxaliplatin treatment in HT29R without changes in NF-KB expression. This oxaliplatin-resistant cell line, presents also sensibility for BAY11–7085, without affecting MMP-7 levels. Finally the addition of oxaliplatin to the MMP-7 inhibitor, increase FAS-mediated apoptosis (induced by DX2 antibody), suggesting that FASL cleavage is responsable of sensitivity. Conclusions: Reversal of oxaliplatin chemo-resistance can be obtained either by MMP-7 or NF-kB inhibition. Both drugs induced sFASL decrement, by inhibiting cleavage or expression, respectively.

No significant financial relationships to disclose.
Temozolomide, irradiation and hypoxia promote homing of hematopoietic progenitor cells towards gliomas
Authors: Wick W. , Tabatabai G. , Frank B. , Weller M.
Published: March 2020

20044

Background: Temozolomide and irradiation are essential parts of the standard therapy and hypoxia is a critical aspect of the microenvironment of gliomas. IN the present study, we aimed at investigating the impact of these stimuli on the previously defined transforming growth factor beta (TGF-β)- and stromal cell-derived factor-1/CXC chemokine ligand 12 (SDF-1α/CXCL12)-dependent migration of adult hematopoietic stem and progenitor cells (HPC) towards glioma cells in vitro and the homing to experimental gliomas in vivo. Hyperthermia served as control. Methods and Results: Cerebral irradiation of nude mice at 21 days after intracerebral implantation of LNT-229 glioma induces tumor satellite formation and enhances the glioma tropism of HPC in vivo. Supernatants of temozolomide-treated, irradiated or hypoxic LNT-229 glioma cells promote HPC migration in vitro. Reporter assays reveal that the CXCL12 promoter activity is enhanced in LNT-229 glioma cells at 24 h after irradiation at 8 Gy or after exposure to 1% oxygen for 12 h. The irradiation- and hypoxia-induced release of CXCL12 depends on hypoxia inducible factor-1 alpha (HIF-1α), but not on p53. Induction of transcriptional activity of HIF-1α by hypoxia and irradiation requires an intact signaling cascade of TGF-β. Conclusions: Thus, we delineate a novel stress signaling cascade in glioma cells involving TGF-β, HIF-1α and CXCL12. Stress stimuli can be temozolomide, irradiation and hypoxia but not hyperthermia. These data suggest that the use of HPC as cellular vectors in the treatment of glioblastoma may well be combined with anti-angiogenic therapies which induce tumor hypoxia.

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