bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of rituximab and cladribine (2-CDA) in newly diagnosed mantle cell lymphoma (MCL) (N0189)
Authors: Inwards D. J. , Hillman D. W. , Fishkin P. A. , White W. L. , Morton R. F. , Dakhil S. R. , Nikcevich D. A. , Wender D. B. , Fitch T. R. , Kurtin P. J.
Published: March 2020

17505

Background: A previous trial of 2-CDA as a single agent for therapy of mantle cell lymphoma demonstrated this agent to be efficacious with an overall response rate of 81% (31% complete responses) (Blood 1999 Nov 15; 94:660a). A phase II study of the addition of rituximab to 2-CDA was conducted by the North Central Cancer Treatment Group based on improved outcomes achieved by the addition of rituximab to other regimens active in MCL. Methods: This one-stage phase II study was designed to determine the complete response (CR) or complete response/unconfirmed (CRu) rate. Central pathology confirmation of cyclin D1 positive mantle cell lymphoma was required. No previous therapy for lymphoma was allowed, with the exception of splenectomy. The shedule was rituximab 375 mg/m2 IV day 1; 2-CDA 5 mg/m2/d IV days 1–5 of a 4-week cycle. After 2 of the first 6 patients developed grade 4 neutropenia, subsequent patients received either pegfilgrastim or filgrastim support. Patients received 2–6 cycles of therapy, depending on response. Patients were required to achieve at least a PR after 2 cycles of therapy to continue on protocol therapy. Results: Patient characteristics of all 29 eligible pts: median age: 70 (range: 41–86); 21 male, 8 female; PS 0 (55.2%), PS 1 (41.4%), PS 2 (3.5%); stage II (6.9%), stage III (3.5%), stage IV (89.7%); prior splenectomy (20.7%). The only grade 4 adverse event occurring more than once was neutropenia (20.7%). One patient died of cerebral ischemia in the setting of pneumonia without neutropenia. Response has been determined in 26 pts with 50.0% (95% CI: 30.0–70.0%) achieving a CR, none of whom have relapsed to date. Three patients progressed early at 17, 45, and 46 days, two of whom have died, and a fourth relapsed day 222. 10 pts (34.0%) went on to receive further therapy off study, 5 in less than a PR after 2 cycles, 2 in PR after study therapy, and 1 who went off study for a rash. At last contact, 26 (89.7%) were alive (median follow-up 10.7 months; range: 1–28). Conclusions: Rituximab and cladribine were well tolerated for the treatment of MCL in a group including elderly patients. The response rate may have been underestimated due to the study design, which required at least a PR after 2 cycles to continue therapy. Despite this, 50% achieved a complete remission.

[Table: see text]
Detection of rearranged immunoglobulin DNA in plasma
Authors: Lin L. , Gocke C. , Ambinder R. F.
Published: March 2020

17518

Background: Tumor DNA is increasingly recognized as a marker in plasma or serum. B cells are characterized by immunoglobulin heavy chain rearrangements (IgH-R)and B cell malignancies by clonal IgH-R. We hypothesized that detection of clonal IgH-R DNA (a DNA spike) might reflect the presence of malignancy. Methods: We used a PCR and capillary electrophoresis. DNA from plasma of 6 healthy donors, 5 patients treated with rituximab, 5 persons with AIDS (PWA) but not lymphoma, 5 patients with AIDS-related lymphoma (ARL) and 5 patients with Hodgkin’s lymphoma (HL) was studied. In some cases matched peripheral blood mononuclear cells (PBMC) and followup specimens were available. Results: In plasma from healthy donors there was a normal (bell-shaped) distribution of IgH-R. In patients treated with rituximab (including a patient with an autoimmune disorder but no malignancy), IgH-R in plasma decreased by at least 100-fold. In PWA, there was a normal distribution of IgH-R. In pretreatment plasma from 2 of 5 patients with ARL, a DNA spike was detected superimposed on the background of IgH-R. The DNA spike was not detected in PBMC. In both ARL patients the spikes disappeared with therapy. However, in 1 it reappeared, and shortly thereafter the patient relapsed. Clinical relapse was associated with an increase in spike amplitude. The spike disappeared again with salvage chemotherapy. Identity of the pretreatment and relapse spikes was confirmed by sequencing. In 1 of 5 patients with HL a pretreatment DNA spike was detected in plasma. It decreased in serial specimens during the first month of combination chemotherapy. Conclusions: A normal distribution of rearranged Ig DNA is readily detected in plasma from healthy donors and patients. This normally distributed rearranged Ig DNA consistently disappears with rituximab therapy. A DNA spike can be detected in the plasma of some patients with B lineage lymphoma even when that spike is not evident in PBMC consistent with the possibility that this DNA is not derived from circulating tumor cells. The reappearance of a DNA spike may presage relapse. Further investigation will be required to determine the sensitivity and specificity of detection of such Ig DNA spikes and to confirm a tumor origin.

No significant financial relationships to disclose.
Safety and efficacy of retreating follicular non-Hodgkin’s lymphoma (NHL) with 90Y ibritumomab tiuxetan
Authors: Shah J. , Harrough D. , Saville W. , Mueh J. , Lister J. , Jasthy S. , Gregory M. , McKay C. , Krumdieck R. , Forero A.
Published: March 2020

17528

Background: There is no data regarding safety and efficacy of treating follicular NHL patients with a second course of 90Y ibritumomab tiuxetan (Zevalin). Methods: Patients with follicular NHL who received 2 courses of Zevalin therapy were identified nationally, and data was retrospectively collected. Results: 10 patients (pts) (mean age 62.5 years, 48–91) were identified. Prior to the first Zevalin, all pts received chemotherapy (mean 2.4 courses, 1–5), 3/10 auto-PBSCT, and 4/10 external beam radiotherapy(ebRT). After the initial course of treatment, the mean time to nadir for the anemia was 7.9 weeks (wks)(4–13), neutropenia was 6.7 wks (4–10); and thrombocytopenia was 5.2 wks (4–8). 1 pt required growth factor support and transfusions; 2 had an incomplete recovery of platelet count at 23 and 30 wks (76,000 and 126,000/μl). Hematologic toxicity and grades are in the table below. Prior to the second course of Zevalin 2 pts received ebRT, 1 received 131I tositumomab, and 3 received chemotherapy (1–5 regimens). The median time to the second Zevalin course was 613 days (183–1,300). After the second course of Zevalin, the mean time to nadir for the anemia was 8.2 wks (2–25); neutropenia was 6.7 wks (4–10); and thrombocytopenia was 5.5 wks (4–7). 4/10 pts required growth factor support, 2 required transfusions, 3 had incomplete recovery of platelet count and early progression, 2 pts had a maximum recovery of their platelet count at 29 and 40 wks (143,000 and 144,000/μl). There were no infectious or bleeding complications with either course of Zevalin. No secondary myelodysplastic syndrome or acute leukemia were reported. Conclusions: Retreating patients with follicular NHL with a second course of Zevalin is tolerable with substantial evidence of clinical efficacy. This data warrants further evaluation of Zevalin retreatment in a clinical trial.

[Table: see text]

[Table: see text]
Pharmacokinetics and efficacy of pegfilgrastim as hematopoietic support for dose-dense every-2-week chemo-immunotherapy with R-CHOP as first-line therapy in elderly patients with diffuse large B cell lymphoma
Authors: Mey U. J. , Maier A. , Kleinschmidt R. , Ziske C. , Forstbauer H. , Banat G. A. , Gorschlueter M. , Popp H. , Schmidt-Wolf I. G. , Glasmacher A. G.
Published: March 2020

17531

Background: Recently, 6 cycles of R-CHOP-14 have been recommended as reference standard for elderly patients with diffuse large B cell lymphoma (Pfreundschuh, 2004). Pegfilgrastim as a pegylated form of G-CSF has been shown to provide rapid neutrophil recovery and facilitate dose dense chemotherapy schedules with a single administration per chemotherapy cycle. The aim of this study was to analyze pharmacokinetics of a single fixed dose of 6 mg of pegfilgrastim per cycle in a homogenous group of elderly patients with diffuse large B cell lymphoma treated with R-CHOP as first-line therapy in two-weekly intervals. Methods: Ten patients with diffuse large B cell lymphoma between the age of 60 and 80 years received a single subcutaneous injection of 6 mg pegfilgrastim 24 h after the administration of R-CHOP chemo-immunotherapy, repeated for 6 to 8 cycles in two-weekly intervals. Pegfilgrastim plasma levels as well as absolute neutrophil counts were measured every other day during the first treatment cycle and twice weekly during all consecutive cycles. Incidence and duration of grade 3/ 4 neutropenia, depth of neutrophil nadir and incidence of febrile neutropenia were assessed. Results: Median age was 73.4 years. A single 6 mg injection of pegfilgrastim 24 h after the administration of CHOP was effective to allow neutrophil recovery in 69 of 70 (98.6%) two-weekly treatment cycles. Median absolute neutrophil nadir was 0.38 G/l on day 9. Grade 3/ 4 granulocytopenia occurred in all ten patients. Mean duration of grade 3/4 neutropenia (< 1.0 G/l) was two days. Febrile neutropenia occurred in one patient. Plasma levels of pegfilgrastim remained elevated during the neutropenic phase. At the start of hematologic recovery, plasma concentrations of pegfilgrastim decreased rapidly as a result of clearance by the neutrophils. Median pegfilgrastim trough plasma level was 0.43 ng/ml on the day preceding the next application. Conclusions: A single fixed dose of 6 mg of pegfilgrastim given once per cycle of R-CHOP-14 is effective in supporting neutrophil recovery to safely allow two-weekly drug administration in previously untreated elderly patients with diffuse large B cell lymphoma.

[Table: see text]
Primary cutaneous lymphomas in Peru
Authors: Beltran B. , Carrasco A. , Vera L. , Salinas E. , Ticona M. , Portugal K.
Published: March 2020

17566

Background: The clinicopathologic characteristics of malignant lymphomas vary according to geography. The aim of this study was to determine the relative frequency of cutaneous lymphomas and to examine the clinical relevance of the new WHO/EORTC classification in Peruvian cases of cutaneous lymphoma. Methods: We conducted a clinicopathologic retrospective study of a collection of 68 primary cutaneous lymphomas, diagnosed from 1997 to 2004 in a National General Hospital. The clinical records, haematoxylin & eosin-stained slides and immunohistochemical stains from 67 patients with malignant lymphomas of the skin were reviewed. HTLV-1 serology was made using ELISA and Western Blot methods. The statistical method was descriptive and survival was calculated using the Kaplan-Meier method. Results: Mean age at presentation was 62 years and the female/male ratio 1.5:1. T cell lymphomas were 88.6% and 11.4% were B-cell lymphomas. The most frequent cutaneous lymphoma was mycosis fungoides (MF) 30/67 (44.7%), Adult T-cell leukemia/lymphoma (ATLL) 13/67 (19.4%), unspecified peripheral T-cell lymphoma 4/67 (6%), lymphomatoid papulosis 2/67 (3%), leg-type diffuse large B-cell lymphoma 2/67 (3%), diffuse large B-cell lymphoma 2/67 (3%), subcutaneous panniculitis-like T-cell lymphoma 2/67 (3%), anaplastic large cell lymphoma 1/67 (1.4%), Sézary síndrome 1/67 (1.4%), nasal type extranodal NK/T-cell lymphoma 1/67 (1.4%), marginal zone B-cell lymphoma 1/67 (1.4%), follicle center lymphoma 1/67 (1.4%), intravascular lymphoma 1/67 (1.4%) and unclassifiable 5/67 ( 7.4%). Clinical stages of MF were: 60% stage I; 30% stage II; 3% stage III and 7% stage IV. 5-year survival was 77%. In ATLL group, 3 had smouldering type and 10 had cutaneous type. 5-year survival was 18%. Conclusions: In this retrospective analysis, cutaneous T cell lymphomas were prevalent; both MF and ATLL had the most frequency among primary cutaneous lymphomas in our hospital. ATLL had a poor 5-year survival.

No significant financial relationships to disclose.
Clinical findings in a large cohort of adult patients (pts) with Hodgkin’s disease (Hd) in Argentina: A report from two institutions
Authors: Morgenfeld E. L. , Dragosky M. , Alcaraz S. , Annetta I. , Calmet R. , Luchetta P. , Marquez M. , Gil Deza E. , Rivarola E. , Gercovich F. G.
Published: March 2020

17570

Background: More than 20,000 new cases of HD are diagnosed each year all over Europe, Canada and the United States. Nevertheless, there are few reports in current literature showing data from large series in developing countries. Methods: The medical records of adult pts with an oncohaematologic diagnosis in two large oncological centers (HMC and IOHM) were reviewed. A period spanning the past 10 years was considered with the objective of measuring the incidence of HD. Oncologists in charge were asked to fill a form with the relevant clinical data. Results: Three hundred and fifty eight out of 1,884 medical records of pts with HD (19%) were retrieved (M: 55.2%/F: 44.8%). Seven pts were HIV positive. Bulky disease was present in 7,4%. The following table shows the main topics (See table ): Conclusions: Incidence of HD in our serie was similar to the published report. However, two important differences arose: it was not possible to notice neither the double curve described nor the usual histological subtype distribution (more MC than the expected frequency). According to previous reports, prevalence of NS was associated with mediastinal locations and younger pts. Actuarial survival must be presented.

[Table: see text]

No significant financial relationships to disclose.
Efficacy and safety of epoetin beta 30,000 IU once weekly in patients with solid tumors and chemotherapy-induced anemia
Authors: Heras P. , Hatzopoulos A. , Karagiannis S.
Published: March 2020

18620

Background: Anemia is common in patients receiving chemotherapy, causing a multitude of symptoms which have a major impact on quality of life (QoL). Epoetin beta rapidly increases hemoglobin (Hb) levels and improves QoL in anemic patients with a variety of tumors. In patients with lymphoid malignancies, once-weekly epoetin beta 30,000 IU has comparable efficacy to the three-times weekly 10,000 IU regimen (Cazzola et al. Br J Haematol 2003; 122: 386–393). Methods: This was a randomized, double-blind, dose-finding study assessing the efficacy and safety of once-weekly epoetin beta in patients with solid tumors receiving chemotherapy. Adult patients with anemia (Hb levels <11 g/dl) were randomized to receive epoetin beta 30,000 IU or 20,000 IU once weekly for 12 weeks. All patients received oral iron supplementation. Hb levels, transfusion need and QoL (Functional Assessment of Cancer Therapy-fatigue subscale score [FACT-fatigue]) were assessed at regular intervals. Results: Fifty patients were randomized; 30 patients received epoetin beta 30,000 IU once weekly and 20 received 20,000 IU once weekly. Mean (± SD) increase in Hb from baseline to week 12 was 1.75 ± 2.15 g/dl in the 30,000 IU group (p = 0.008 vs baseline) and 1.04 ± 1.75 g/dl in the 20,000 IU group (p = non-significant). Hb response (increase in Hb level ≥2 g/dl from baseline) was observed in 78.3% of patients receiving epoetin beta 30,000 IU and 66.7% receiving epoetin beta 20,000 IU. Improvements in FACT-fatigue were significantly (p < 0.001) correlated with increases in Hb level. Transfusion use was low during the study in both groups. Both epoetin beta regimens were well tolerated and there were no dose-dependent adverse events. Conclusion: Epoetin beta 30,000 IU once weekly is an effective and well-tolerated treatment of anemia in patients with solid tumors.

No significant financial relationships to disclose.
Imatinib mesylate therapy in advanced gastrointestinal stromal tumors—A Regional cancer centre experience
Authors: Patel K. M. , Shah P. M. , Shukla S. N. , Parikh B. J. , Anand A. S. , Shah S. A. , Talati S. S. , Panchal H. P. , Pandey R.
Published: March 2020

19505

Background: The treatment of gastrointestinal stromal tumors has been revolutionised by the advent of Imatinib, a specific tyrosine kinase inhibitor. Post operative local and metastatic recurrences of this tumor have been effectively managed by Imatinib. Here we present our experience of Imatinib in recurrent locally advanced/metastatic gastrointestinal stromal tumors (GIST). Methods: From Nov 2001 to Sep 2005, 33 patients with metastatic and / or locally advanced inoperable CD-117 positive GIST were offered imatinib mesylate therapy at 400 mg/day p.o. A total of 21 patients were evaluable for tumor response. Follow up period ranged from 4 months to 38 months with median follow up period being 18 months. Median age is 58 yrs, M:F ratio is 6:4. ECOG performance status was 0–1 in 70% (23 patients) and 2 in 30% (10 patients). 70% patients had post surgery recurrence. 2 patients (6%) had received adjuvant chemotherapy prior to recurrence. 30% (10 patients) had local recurrence, 40% (13 patients) had metastatic disease while 30% (10 patients) had local recurrence as well as metastatic disease. Results: Response evaluation was done by RECIST criteria. 15% (5 patient) showed CR while PR rates were 30% (10 patients). The overall major response (CR+PR) was 45%. The overall progression free survival was as high as 80%. All the patients who had a progression free survival also had a significant improvement in quality of life. Conclusions: Imatinib mesylate therapy shows significant survival benefits in locally advanced inoperable/metatstatic gastrointestinal stromal tumors. It will be a very long time before PET scan for evaluation and follow up becomes feasible in developing country setting.

No significant financial relationships to disclose.
Frequency of histopathologic types of soft tissue sarcoma (STS) reported from a large community-based hospital over a 20 year period
Authors: Nair S. G. , Amadio C. H. , Scarlato M. , Forman D. A.
Published: March 2020

19507

Background: Soft Tissue Sarcomas (STS) are rare tumors primarily of mesenchymal origin. The World Health Organization recognizes more than 50 subtypes of STS. Previously reported frequencies of histopathologic types of STS come from a handful of large cancer centers. The incidence of tumor types seen at large cancer treatment centers do not necessarily reflect the histologies seen at community hospitals. We sought to determine the frequency of histopathologic types of adult STS seen at our large community-based hospital. Methods: We performed a search of our tumor registry from the year 1984 through 2004 looking for histologic types of non-GIST STS involving the peripheral nervous system, autonomic nervous system, retroperitoneum, peritoneum, other connective and soft tissue locations. Our tumor registry is certified through the American College of Surgeons. Our pathologist are board certified, highly skilled, and commonly refer pathologic specimens for second opinion if a histologic diagnosis is in doubt. The 10 most common histologies diagnosed are reported. Results: Our hospital diagnosed and treated 250 STS over this 20 year period. The histologic type of sarcoma by number and percent of total cases is as follows: Malignant fibrous histiocytoma 60 (24%), Liposarcoma 51 (20%), Leiomyosarcoma 38(15%), Sarcoma N.O.S. 18(7%), Hemangiosarcoma 15 (6%), Synovial Sarcoma 10 (4%), Rhabdomyosarcoma 9 (4%), Fibrosarcoma 9 (4%), Spindle Cell Sarcoma 7 (3%), and Giant Cell Sarcoma 3 (3%). Conclusions: The frequency of the most common histologic types of soft tissue sarcoma seen at our community hospital is quite consistent with that previously reported in the literature from large referral-based cancer centers. There does not appear to be an influence of selection bias in previous reports of relative frequency of histopathologic types of STS.

No significant financial relationships to disclose.
Changes in serum P1NP, BAP, CTX-1, and YKL-40 following hormonal treatment for metastatic prostate carcinima are related to survival
Authors: Brasso K. , Iversen P. , Johansen J. , Teisner B. , Garnro P. , Pri Ce P. , Christensen I. J.
Published: March 2020

20002

Background: Previously it has been demonstrated that elevated P1NP, BAP, CTX-1, and YKL-40 levels at the time of diagnosis in patients with metastatic prostatic carcinoma were associated with survival. This study presents a follow-up to evaluated the prognostic value of thes biomarkers in a time-dependent analysis. Methods: Serum P1NP, BAP, CTX-1, and YKL-40 were determined in 106 patients with newly diagnozed metastatic prostatic carcinoma following start of either total androgen ablation or parenteral estrogen theraphy. Results: After 6 months of treatment significant decreases in P1NP, BAP, and YKL-40 were found. Univariate Cox analysis demonstrated that 6 month levels of P1NP, BAP, and CTX-1 were significantly associated with survival. In a multivatiate analysis using tumormarker levels at 6 months after start of treatment demonstrated that Soloway score (HR=3.9), WHO grade (HR=3.9), and P1NP (HR=2.2) all were significant predictors of survival. When using the biomarkers mentioned above as time-dependent co-variates in univariate COX regression analysis it could be shown that increasing levels og P1NP, BAP, and YKL-40 alle were significant predictors of early death. Conclusions: Serial monitoring of serum P1NP, BAP, CTX-1, and YKL-40 in patients with metastatic prostatic carcinoma during hormonal treatment provide information on prognosis.

No significant financial relationships to disclose.
Risk assessment in high grade sarcoma patients during neoadjuvant chemotherapy using multiple tracer PET
Authors: Eary J. F. , Conrad E. , Link J. , Cizik A. , Mankoff D. , Krohn K.
Published: March 2020

20006

Background: Patients with high grade soft tissue sarcomas are treated with neoadjuvant chemotherapy. Sarcomas have biological features that may predict for poor outcome. Some of these features are tumor proliferation rate, level of tumor hypoxia, and upregulation of tumor drug resistance mechanisms. Methods: We have a group of specific PET imaging agents to quantify the level of activity of these tumor processes. Patients with soft tissue sarcomas receive [C-11]Thymidine (TdR) to assess cellular proliferation, [O-15] Water to quantify tumor blood flow and to serve as the input function for quantification of the other tracers, [C-11]Verapamil to assess drug resistance mechanism activity, and [F-18]Fluoromisonidazole) FMISO to quantify changes in tumor hypoxic volume in response to treatment. These studies are performed in a single PET imaging session prior to neoadjuvant chemotherapy, after the second of four cycles of therapy and in the week prior to resection. Results: An example of this complex study result, is demonstrated by a recent patient with a high grade soft tissue sarcoma. The tumor showed increased TdR uptake, a moderate hypoxic volume, and [C-11] verapamil uptake prior to initiation of neoadjuvant adriamycin based chemotherapy. After 2 cycles of therapy, there was a significant decrease in the maximum level and volume of TdR uptake and a large reduction in tumor hypoxic volume. Conclusions: These data would imply a high risk soft tissue sarcoma due the presence of increased cellular proliferation, a significant hypoxic volume and the absence of p-glycoprotein activity determined by the presence of [C-11]Verapamil uptake. However, early response is also suggested by the findings above. Patient outcome will be assessed and correlated with these tumor parameters to further understand what tumor biological risk factors can be quantified non-invasively and repeated throughout the clinical course in soft tissue sarcoma patients. Supported by NIH NCI PO1 42045–18 and S10 RR017229–01

[Table: see text]

No significant financial relationships to disclose.
Phase I clinical and pharmacokinetic (PK) trial of the kinesin spindle protein (KSP) inhibitor MK-0731 in cancer patients
Authors: Stein M. N. , Rubin E. H. , Scott P. D. , Fernandez R. , Agrawal N. G. , Hsu K. , Walker A. , Holen K. , Wilding G.
Published: March 2020

2001

Background: KSP is essential for the separation of spindle poles during mitosis and inhibition results in mitotic arrest. Function is thought to be limited to mitosis and inhibitors should not cause the peripheral neuropathy seen with other mitotic-inhibitors. MK-0731 is a potent inhibitor of KSP, with an IC50 of 2.2 nM, and >20,000 fold selectivity against other kinesins. MK-0731 causes mitotic arrest with an EC50 in several tumor cell lines of 3−5 nM. Methods: Phase I study to determine the safety and tolerability, MTD, and PK of MK-0731 administered IV over 24 hrs every 21 (Q21) ds. Results: Eight pts with solid tumors (M/F 6/2), median age 55 yrs (45–72 yrs), were treated at doses of 6 to 48 mg/m2/24hrs. Prolonged (≥5 ds) Grade 4 neutropenia was observed in 2 pts at 48 mg/m2/24 hrs leading to expansion of cohorts at lower dose levels. Other drug related toxicities include diarrhea, alopecia, nail changes, nausea/vomiting, mucositis, abdominal pain, anorexia, phlebitis. PK results suggest that steady-state concentrations may not be achieved by the end of the 24 hr infusion and MK-0731 concentrations appear to decline monoexponentially or biexponentially following the infusion with terminal t1/2 from ∼4 to 11 hrs. Median values at the 48 mg/m2/24 hrs dose level were Cmax = 1223 nM, AUC∞ = 26.585 μM · hr, and CL=122 mL/min. AUC, exposures, and end of infusion concentrations appear to increase proportionally with dose. Conclusions: This is the first study of MK-0731. The MTD was exceeded at 48 mg/m2/24 hrs Q21. Further evaluation will continue at lower doses.

[Table: see text]
A phase I pharmacokinetic (PK) study of the Epothilone B analogue, ixabepilone (BMS-247550) in patients (pts) with advanced malignancies and varying degrees of hepatic impairment. A SWOG Early Therapeutics Committee and NCI Organ Dysfunction Working Group Trial
Authors: Takimoto C. H. , Liu P. Y. , Lenz H. , Remick S. , Mulkerin D. , Mani S. , Synold T. W. , Ramanathan R. K. , Ivy P. , Davies A. M.
Published: March 2020

2004

Background: Ixabepilone (Ix) is a semisynthetic Epothilone B derivative with antitumor activity in breast cancer pts previously treated with taxanes and in chemotherapy naïve prostate cancer pts. Because Ix is hepatically metabolized, the following study was performed to define dosing recommendations for pts with varying degrees of hepatic impairment. Methods: Pts were classified into hepatic dysfunction cohorts defined by a modified NCI Organ Dysfunction Working Group (NCI) schema. Starting doses were escalated in new pts independently in each cohort using a standard phase I design. Results: Overall, 71 pts were registered and 66 pts are evaluable for cycle 1 dose limiting toxicities (DLTs). Ix was administered at 10–40 mg/m2 as 10 minute infusions q3wks. Dose levels reached 40, 40, 30, and 20 mg/m2 for pts in Groups A, B, C and D, respectively. In group B, DLTs were observed in 2/12 pts treated at 30 mg/m2 (febrile neutropenia, grade (gr)3 mucositis, and gr3 diarrhea) and 3/8 pts at 40 mg/m2 (febrile neutropenia, gr3 nausea/vomiting, gr3 hyponatremia). In group C, DLTs were observed in 2/10 pts at 20 mg/m2 (gr3 dehydration, gr3 muscle weakness) and 2/3 pts at 30 mg/m2 (febrile neutropenia, gr 4 neutropenia). In group D, DLTs were observed in 2/9 pts at 10 mg/m2 (gr3 infection and gr3 renal failure) and 1/5 pts treated at 20 mg/m2 (gr3 infection). Otherwise, Ix was generally well tolerated. Pharmacokinetic parameters are currently being analyzed. No objective responses have been documented. Conclusions: Ix dose reduction is required in pts with moderate to severe liver dysfunction. The recommended Ix dose for group C patients is 30 mg/m2. To define the impact of mild liver impairment, Group B has been stratified further into B1 (Bili ≤ ULN and AST > ULN) and B2 (ULN < Bili ≤ 1.5 × ULN, AST any). Accrual continues to groups B1 and B2 at 40 mg/m2 and group D at 20 mg/m2.

[Table: see text]

[Table: see text]
Effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone
Authors: Goel S. , Goldberg G. , Iacono L. C. , Cohen M. , Griffin T. , Gollamudi R. , Desai K. K. , Chaudhary I. , Mani S.
Published: March 2020

2005

Background: Ixabepilone (Ixa) is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixa has shown clinical activity in a broad range of tumors. Oxidative metabolism by CYP3A4/5 appears to be a prominent route of Ixa biotransformation in vitro. As a single agent, the recommended dose is 40 mg/m2 over 3 hours once every three weeks. Methods: This was an open-label, sequential study to assess the effect of CYP3A4/5 inhibition on the pharmacokinetics (PK) and pharmacodynamics (PD) of Ixa. Ketoconazole (K) was used as a model inhibitor of CYP3A4/5. Patients were administered a single 10 (n=4), 20 (n=12), 25 (n=7) or 30 (n=4) mg/m2 intravenous (iv) infusion of Ixa with K (400 mg/d orally x 6 days) during cycle 1, and a single 40 mg/m2 iv infusion of Ixa during Cycle 2. Cycles were repeated every 21 days. Detailed PK and PD analysis was performed in cycles 1 and 2. Results: The observed adjusted geometric mean of Ixa AUC for subjects with K was 2892 vs. 1628 ng/mL*hr in subjects without K. The ratio of the geometric means of normalized Ixa AUC and Cmax in Cycle 1/Cycle 2 were 1.78 and 1.07, respectively. The percent of peripheral blood mononuclear cells with tubulin bundle formation after administration of 20 mg/m2 Ixa with K was similar to that observed with single agent Ixa at a dose of 40 mg/ m2. The maximum tolerated dose of Ixa with K was 20 mg/m2. Dose limiting toxicities of Ixa with K were similar to those observed in previous Phase 1 studies of single agent Ixa and included prolonged neutropenia, febrile neutropenia, mucositis, elevated liver function enzymes, and fatigue. Conclusions: Oxidative metabolism by CYP3A4/5 appears to be a clinically important route of Ixa biotransformation. Inhibition of CYP3A4/5 by K affects the Ixa tolerable dose, increases the AUC and results in similar PD effects at half the recommended dose.

[Table: see text]
Extent of bronchioloalveolar pattern and expression of the epidermal growth factor receptor in surgically resected lung adenocarcinomas
Authors: Dahabreh I. J. , Janinis J. , Karagiani E. A. , Dountsis A. , Vasilikos K. , Spiliadi H. T. , Dahabreh I. J.
Published: March 2020

20065

Background: An increasing number of studies are exploring relations between the bronchioloalveolar differentiation of adenocarcinomas and clinical, radiological and molecular parameters. We investigated the potential relation between the extent of the bronchioloalveolar carcinoma (BAC) component of adenocarcinomas and the expression of the epidermal growth factor receptor (EGFR) protein. Methods: We retrospectively reviewed data from all patients who underwent surgery for lung cancer in our hospital between February 1, 2001 and May 31, 2005 (n = 366), and in whom pathologic analysis had revealed an adenocarcinoma histologic subtype. Paraffin embedded tissue samples were retrieved and re-examined. Samples exhibiting either a pure BAC histology or a mixed adenocarcinoma histology with a >50% BAC component (n = 46) were selected for EGFR expression analysis by immunohistochemical staining. Patient demographics, stage and tumor differentiation data were recorded. Histological analysis was carried out using the WHO 1999/2004 criteria for lung cancers. For EGFR expression evaluation, samples were assigned a score ranging from 0 to +3. Expression was considered positive when the score was +1 or higher. Statistical analysis was performed using the chi-square test. Results: Of the 46 tumor samples examined, 10 had a BAC component of 50–79% (group A), 18 had BAC component of 80–99% (group B) and 18 exhibited a pure BAC histology (group C). Male/female ratio was 61.3%/38.7%. Mean age at presentation was 61.6 years. Among group A, 4 patients were EGFR positive and 6 were EGFR negative. 16 group B patients were EGFR positive and 2 were EGFR negative. Similarly, 16 group C patients were EGFR positive and 2 were EGFR negative. This distribution suggests that EGFR is more often expressed with increasing BAC component (p = 0.0041). No correlation was observed between demographics and EGFR expression or the extent of BAC pattern. Conclusions: EGFR expression is related to the extent of the BAC component in adenocarcinomas, with statistical significance. Study of a larger number of patients and correlation of this finding with EGFR and Ras mutational status and responsiveness to therapy are warranted.

No significant financial relationships to disclose.
Ki-67/MIB-1 as prognostic factor for locoregional recurrence after adjuvant radiation therapy in early breast cancer: A population-based study
Authors: Mucciarini C. , Giovanardi F. , Masoni F. , Cirilli C. , Artioli F. , Cagossi K. , Sarti S. , Hakim R. , Iop A. , Federico M.
Published: March 2020

20074

Background: Adjuvant radiotherapy (RT) has been shown to decrease the risk of locoregional recurrence (LRR) in women with infiltrating early breast cancer, with or without an associated systemic treatment. RT is more effective on high proliferating cells and we could evaluate the proliferative activity of any cancer through Ki-67/ MIB-1 antibodies. Adjuvant RT for breast cancer could show a greater efficacy to prevent LRR in the higher proliferating cancers. Methods: We conducted a retrospective analisys on all the 5004 cases of infiltrating early breast cancer diagnosed in the Province of Modena between 1989 and 2004 and registered in the Modena Cancer Registry. Beneath them we were able to find data about 1885 women who underwent adjuvant RT. We analyzed the data concerning this population on the basis of number of LRR and Ki-67 labeling index. Since the lack of a worldwide agreed Ki-67 cut off value representing an high proliferation rate of cell activity, we examinate our data in an univariate analisys establishing for the Ki-67 three different cut offs values ( 20%, 30% and 50%). Results: Between 1885 women who underwent RT, 91 ( 4.8%) had a LRR. Median follow-up was 6 years (range 1–15 years). Using a cut off for the Ki-67 of 20% to fix an high cell proliferation, 67 women had a Ki-67 < 20% and 24 ≥ 20%. The p-value was 0.176. Increasing the cut off to the 30%, 75 women had a Ki-67 < 30% and 16≥ 30%. The p-value was 0.048. Finally, considering the Ki-67 value to 50%, 87 women had a value < 50% and 4 ≥ 50%, with a p-value of 0.992. In our analisys, it doesn’t seem that an increasing Ki-67 value would be correlated with a higher LRR. We are considering in a further analisys the weight of the different sistemic therapies on our results. Conclusions: The Ki-67 expression doesn’t seem to be considered a statistically significant prognostic factor for LRR in early breast cancer after adjuvant RT.

No significant financial relationships to disclose.
Homocysteine (HC) level as possible predictor of pemetrexed efficacy
Authors: Symanowski J. , Simms L. , Melemed A.
Published: March 2020

20078

Background: Pemetrexed is a novel anticancer agent clinically active in several solid tumors, including malignant pleural mesothelioma (MPM), non-small cell lung cancer (NSCLC), and breast cancer. Pemetrexed’s anticancer activity is believed to be related to its inhibition of 3 enzymes involved with folate metabolism and DNA synthesis. Some side effects associated with its clinical activity are more pronounced if a patient (pt) has a folate deficiency and high HC levels (Niyikiza et al, Ann Oncol 1998). Given this connection, we hypothesized that high HC levels might predispose a pt to pemetrexed anticancer activity. In a related question, we examined if baseline HC levels varied among different cancers. Methods: To investigate these hypotheses, plasma HC levels were examined from pts in the pemetrexed-containing arm of a phase III MPM trial (N = 226; Vogelzang, JCO 2003); a phase III NSCLC trial (N = 265; Hanna, JCO 2004); and a phase II breast cancer trial (data pooled from 600 and 900 mg/m2 groups) (N = 92; Llombart, ASCO 2006). For each study, HC (high vs low) was used as a prognostic indicator variable for overall survival (OS) and progression-free survival (PFS). Different cut points distinguished pts with high vs low HC, and final analysis results were based on the optimal cut point that yielded the largest Wald chi-square value (smallest p-value). Results: Average baseline HC levels were similar for each trial: 11.0, 10.6, and 10.6 μmol/L for the MPM, NSCLC, and breast trial, respectively. The MPM data suggested that high HC pts had longer OS (all hazard ratios [HRs] <1). The NSCLC data showed comparable OS times regardless of HC level. MPM and NSCLC data for PFS was similar to OS results. PFS from the breast cancer study was also similar for both HC groups (HR ∼1). Conclusions: Average baseline HC level did not suggest differences in nutritional status of the 3 pt populations. Data examination from the 3 studies yielded contradictory results, suggesting that high HC level is not a predictor of a better efficacy response to pemetrexed.

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The analysis of NBS-1 gene mutation [657del(5)] in exon 6 in the population of 472 sporadic breast cancer patients in the Czech Republic
Authors: Melter J. , Pazdrova G. , Janku F. , Kleibl Z. , Novotny J. , Petruzelka L.
Published: March 2020

20087

Background: Nijmegen breakage syndrome (NBS) caused by mutation [657del(5)] in exon 6 of NBS-1 is an autosomal recessive disorder with microcephaly, immunodeficiency, radiosensitivity, and predisposition to lymphoid malignancies. Recently, high frequency of NBS-1 mutation was found in some Slavic populations. Because NBS-1 heterozygotes may have high incidence of neoplastic changes, there is an urgent need to clarify the role of NBS-1 mutation in breast cancer carcinogenesis. Methods: We analyzed the NBS-1 status in 472 sporadic breast cancer patients treated in the Department of Oncology, Charles University Prague. DNA was extracted from peripheral blood monocytes. Subsequently two PCRs for each sample were carried out. Reaction was visualized using electrophoresis on agarose gel. Agarose gel wells with both the NBS-1 gene-specific band and internal control band were interpreted as positive. Wells with internal control only were interpreted as negative. PCR from samples giving neither an internal control band nor specific band were repeated. DNA samples obtained from a previously typed NBS family were used as a positive control. Results: Based on previously published data we expect to find at least 5 mutation carriers. Surprisingly, in our population of 472 subjects there was no mutation identified. Conclusions: Based on results of this study there is no relationship between NBS-1 mutation and breast cancer incidence. Acknowledgment: The study was supported in part by the RASO grant from Czech Society of Oncology, and MSM0021620808.

No significant financial relationships to disclose.
Deletion polymorphism of the GSTM1 gene in lung cancer patients from the Lake District in Turkey
Authors: Coskun Ari F. , Bosgelmez G. , Coskun H. S. , Polat M. , Kisioglu N. , Ergurhan Ilhan I.
Published: March 2020

20089

Background: Association of glutathione-S-transferase M1 (GSTM1) polymorphisms and cancer has been demonstrated. Especially the deletion polymorphism of GSTM1 has been related to risk for lung cancer in some studies. We thus investigated the frequency of GSTM1-null genotype in lung cancer patients and healthy individuals from the Lake District in Turkey. Methods: Cases were recruited among patients with clinically and histologically confirmed diagnosis of lung cancer patients from the Lake District. Controls were selected among the nonsmoking healthy blood donors applied to hospital in same region. DNA samples were extracted from whole blood using proteinaz K (20 mg/mL) digestion in lysis buffer (10 mM Tris-HCl, 400 mM NaCl, 2 mM EDTA, % 10 SDS). Homozygous deletion of the GSTM1 gene was determined by PCR using the primers E4F: 5′-CTGCCCTACTTGATTGATGGG-3′, E5R: 5′-CTGGATTGTAGCAGATCATGC-3′, corresponding to exons 4 and 5 of the GSTM1 gene. PCR products were analyzed by 1% agarose gel electrophoresis and UV transilluminator was then used to evaluate the product content. Individuals carrying the GSTM1 gene were identified by the presence of a 273 bp DNA fragment. Results: The study comprised 30 patients and 30 controls. The frequency of GSTM1-null genotype was found to be (n = 14) 46.7% in lung cancer patients and (n = 5) 16.6% in controls. The difference was statistically significant (Fisher’s chi square test: 4.80, P: 0.0251). Conclusion: We found an increased incidence of GSTM1-null genotype among lung cancer patients, indicating that the GSTM1 absence is associated with a slightly increased lung cancer risk in people from the Lake District in Turkey.

No significant financial relationships to disclose.
Identification of potential cancer targets from diagnostic and prognostic gene signatures
Authors: Vansant G. , Oades K. , Pickering M. , Monforte J.
Published: March 2020

20096

Background: The purpose of this study was to determine the potential of gene signature development to also identify leads among different tumor types compared to normal cells. The theory is that cancer cells will express unique markers that are related to their growth and metastatic potential and therefore be potential targets for therapeutics. Methods: Multiplex PCR Approximately 100 genes were chosen to produce 3 multiplexes for RT-PCR analysis. These genes were identified from gene signatures found in peer reviewed manuscripts. RT and PCR primer pairs designed for each gene to be monitored are chimeric, with a gene specific sequence and a universal sequence common to all forward and reverse primers, respectively. A pair of universal primers that recognize the universal sequences in the chimeric primers are included in the reaction in great excess, with one fluorescently labeled. After reverse transcription and a few rounds of PCR, these universal primers drive the reactions, so all the PCR products are essentially amplified by the universal primer set. The chimeric primers are designed to produce PCR products that all have a difference in length of approximately 5 base pairs, resulting in a stratified set of labeled PCR products. 25ng of total RNA from each tumor derived cell line was used as template for the reverse transcription reactions. Half of these reactions were carried over as templates for the PCR reactions. The PCR products were fluorescently labeled during the PCR reaction and analyzed on a capillary electrophoresis system. Results: Many genes were expressed at high levels across all cancer cell types compared to control cells including an A kinase anchoring protein, cyclin-E2, JPO1, mucin 1, and the transferrin receptor CD 71. Conclusions: Analysis of the expression of genes that are part of diagnostic and prognostic gene signatures in tumor related cell lines revealed many genes whose expression were altered in tumor derived cells that are potentially related to the ability of the carcinogenic cells to proliferate and metastasize. Subsequently, a secondary benefit of the development of prognostic or diagnostic gene signatures with statistical analysis, may be the elucidation of potential therapeutic targets for the treatment of cancer.

No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) mutations in breast and cervical cancer
Authors: Park M. S. , Puttaswamy K. , Gombos Z. , Geza A. , Brose M. S.
Published: March 2020

20101

Background: EGFR is a tyrosine kinase receptor in the HER family which is widely expressed in a number of epithelial tumors and is believed to play a key role in cell proliferation. Molecular analysis of the EGFR gene in patients with non-small-cell lung cancer have identified a distinct subset of tumors that possess specific point mutations in the tyrosine kinase region of the EGFR gene, which correlate to response to tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Clinical trials involving TKIs are currently under way for patients with breast and cervical cancer. While responses thus far may have been modest it is unclear whether specific EGFR mutations are present in breast and cervical cancers which identify patients with improved prognosis and better response to therapy in these cancers. Using clinical samples with 5 years of follow-up clinical data, we have set out to determine whether EGFR mutations exist in breast and cervical cancers, and how these mutations, if any, correlate with the clinical data. Methods: We plan to perform sequence analysis of the tyrosine kinase domain of the EGFR gene (exons 18–24) in 50 archival breast and 44 cervical cancer specimens using PCR amplification and sequencing of genomic DNA. Clinical information has been extracted from patient charts on samples and will be correlated with the presence of any EGFR mutations identified. Results: To date we have collected 50 breast and 44 cervical tumor blocks and have isolated genomic DNA from the specimens. Sequencing for point mutations in exons 18–24 is underway. Clinical data on the cervical cancer specimens revealed a mean age at diagnosis of 48.2 years, tumor grades that were mostly intermediate (50%) and high (45%), and all FICO stages at diagnosis (43% stage I, 30% stage II, 5% stage III, 5% stage IV). In addition the rate of recurrence was 32%, and survival rate was 82% with an average time of follow-up for the set of 4.9 years. Conclusions: Our data will further elucidate the role of point mutations in EGFR gene in breast and cervical cancer prognosis and response to therapy, and will complement data currently being collected in clinical trials using TKIs.

No significant financial relationships to disclose.
Prognostic implications of YKL-40 overexpression in breast cancer
Authors: Kim S. H. , Das K. , Noreen S. , Coffman F. , Hameed M.
Published: March 2020

20115

Background: YKL-40 has been implicated as a connective tissue growth factor and a migratory factor for endothelial cells. Elevated serum levels of YKL-40 have been found to correlate with worse survival in a variety of malignancies including breast cancer. We wished to determine if tumor overexpression of this protein also had prognostic implications in breast cancer. Methods: A prospectively collected database of breast cancer patients treated at the University Hospital of Newark was used for analysis. Immunohistochemical analysis was performed on 115 patients for whom full clinical information and follow up was available. Specimens were categorized as lacking immunoreactivity (0), having focal sparse immunoreactivity (1), or strong more diffuse immunoreactivity (2). Results: YKL-40 expression was noted in 38 patients (33%). Of these, 24 demonstrated strong (2) immunoreactivity (21%). Strong (2) YKL-40 immunoreactivity significantly correlated with larger tumor size (p < .05). Tumors expressing any level of YKL-40 were also significantly more likely to be estrogen and/or progesterone receptor negative (p < .01). No significant correlation was demonstrated between YKL-40 status and nodal stage. At a mean follow up of 2.3 years, disease-free survival was significantly worse in the subset of patients whose tumors overexpressed any level of YKL-40 compared to the non-expressors (p < .01). In multivariate analysis, YKL-40 status was independent of T-stage and N-stage in predicting disease recurrence. Conclusions: Immunoreactivity for YKL-40 was a significant predictor of breast cancer relapse in this subset of patients. This was independent of T or N-stage and suggests that tumor immunohistochemistry for this protein may be a valuable prognostic marker in breast cancer.

No significant financial relationships to disclose.