bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of dexamethasone, ascorbic acid, thalidomide and arsenic trioxide (DATA) in high risk previously untreated (PU) and relapsed/refractory (RR) multiple myeloma (MM)
Authors: Baz R. C. , Kelly M. , Reed J. , Karam M. , Faiman B. , Andresen S. , Hussein M. A.
Published: March 2020

17535

Background: The combination of Thalidomide (T) and Dexamethasone (D) is often used first line in patients with MM. Arsenic trioxide (ATO) is active and well tolerated in patients with RR MM. ATO, D and T have non-overlapping toxicity. We therefore initiated a phase II study to assess the efficacy and toxicity of this combination in patients with high risk PU MM (serum B2 microglobulin>5.5, chromosome 13 or 14 abnormalities by FISH or the presence of peripheral plasma cells) and RR MM. Methods: On week 1, ATO was given at a dose of 0.25mg/kg IV on days 1–5. On weeks 2–12, ATO was given at the same dose twice weekly. On weeks 13–16, the patients did not receive treatment. Ascorbic acid 1000mg IV was given after each ATO infusion. D was given at a dose of 20mg orally on days 1–4 of a 28 days cycle, and T was started at a dose of 50mg daily and increased as tolerated to a dose of 100mg daily. A similar 16 weeks consolidation course was given. Maintenance included ATO 0.25mg/kg on days 1,8,15 and 22 every 12 weeks in addition to the above schedule for D, T and Ascorbic acid. Results: Sixteen patients were enrolled (3 with PU and 13 RR), 13 are evaluable for response. The median age was 57 years and 62% were males. The median number of prior chemotherapy regimen is 2 (range 0–6), 7 patients had received a prior T containing regimen, and 2 patients had received an ATO-containing regimen. Seven, seven and two patients had SWOG stages 2, 3 and 4 respectively. The mean serum B2 microglobulin was 7.1-mg/dL (s.d. 4.4). After a median follow up of 9.5 months (range 1–12), 9 patients progressed and 5 died. The median progression free survival was 9.4 months. The median progression free survival for responder has not been reached. Four patients had a PR (31%), 8 had stable disease (62%), and 1 had progressive disease. No patient had a QT>500 or a cardiac arrhythmia. Grade 3 leukopenia, anemia, neuropathy and renal failure occurred in 3, 2, 1 and 1 patients respectively. Three patients had a venous thromboembolic event (2 DVT and 1 PE). Conclusions: The addition of T to the combination of ATO, Ascorbic acid and D is safe, well tolerated and results in 30% PR and 61% stable disease in patients with poor risk MM.

[Table: see text]
Pitfalls in diagnosis of primary low-grade non-Hodgkin’s lymphomas of the spleen
Authors: Musteata V.
Published: March 2020

17559

Background: Primary low-grade (LG) non-Hodgkin’s lymphomas (NHL) of the spleen are indolent B-cell malignancies usually involving the liver, bone marrow (BM) and the blood while disseminating. The aim of the study was to outline diagnostic problems in primary LG NHL of the spleen, and to improve recommendations regarding the differential diagnosis between these lymphoproliferative disorders and benign abdominal organ pathology (BAOP). Methods: A series of 105 patients (pts) (age range of 15–82 years) with LG splenic NHL was enrolled in our study. In all pts the diagnosis was confirmed morphologically, with immunophenotyping in selected cases. The following histological types of splenic NHL had been identified: follicular (47.6%), small lymphocytic (37.1%), marginal-zone (11.4%), and mantle cell (3.9%) lymphoma. BM involvement and leukemic conversion (LC) were revealed at diagnosis in 102 (99.0%) and 85 (83.3%) pts, respectively. Results: Leading to diagnosis symptoms resulted from splenomegaly and hematological abnormalities. Of 41 (39.0%) pts with splenic NHL, that one had been initially interpreted and treated as chronic hepatitis with hypersplenism (17/16.2%), liver cirrhosis with portal hypertension and hypersplenism (11/10.5%), gastric ulcer/chronic gastroduodenitis (4/3.8%), chronic pancreatitis (3/2.9%), collagenosis (3/2.9%), or nephritis (1/0.9%). In 12 pts with a preliminary diagnosis of chronic hepatitis, or liver cirrhosis with portal hypertension and hypersplenism splenectomy was performed at the surgical departments of district hospitals as a treatment modality of choice. In these cases the initial histological examination of spleen specimens had failed to reveal the lymphomatous involvement, that led to delay in diagnosis. In 17 (16.2%) pts with stage IV disease LG splenic NHL was confirmed occasionally during prophylaxis follow up, or examinations axed on diagnosis of internal diseases. Conclusions: Primary LG NHL of the spleen exhibit the latent onset and nonspecific clinical picture, that usually lead to delay in diagnosis due to resemblance with BAOP. Progressive splenomegaly, LC, consequent liver, abdominal and peripheral lymph node enlargement may indicate the lymphoproliferative malignancy and require BM aspiration/biopsy for diagnosis.

No significant financial relationships to disclose.
Pirarubicin (THP) therapy for elderly aggressive non-Hodgkin’s lymphoma— T-COP vs reduced CHOP, and reduced T-COP in the patients with poor physical status
Authors: Mori M. , Oota M. , Taguchi H. , Ohno T. , Tanimoto M. , Miyata A. , Naoe T. , Murai Y. , Masuda M.
Published: March 2020

17571

Background: We have previously reported that T-COP using pirarubicin (THP) is useful in treatment of NHL in elderly patients. In the present study on elderly aggressive NHL, the usefulness and safety were compared between THP and ADM using the optimum dose of THP (ML1). In patients with poor physical status, reduced dose T-COP was conducted (ML2). Methods: ML1 protocol: PS 0–3 and Alb ≥ 3.0 g/dl Patients in their 70s were assigned randomly to either T-COP (A group) or CHOP (B group) receiving THP (A) or ADM (B) 40 mg/m2,CPA 650 mg/m2, VCR 1 mg/m2dayl, P 40 mg/m2dayl -5. Patients in their 80s were assigned randomly to either T-COP (C) or CHOP (D) receiving THP (C) or ADM (D) 30, CPA 400, VCR 1, P 30. ML2 protocol: PS 4 or Alb < 3.0 g/dl. Patients in their 70s (E group) received THP 26, CPA 430, VCR 1, P 40. Patients in their 80s (F group) received THP 20, CPA 260, VCR 1, P 30. Each group underwent 3 courses every 3 weeks. CR (CR+CRu) patients underwent 6 courses or more. Results: Analyzed as competent cases were 173 out of 207 patients who were registered between Aug 99 and Dec 03. The CR rates were A: 83% (39/47), B: 74% (37/50), C: 67% (14/21), D: 74% (14/19), E: 58% (7/12), F: 33% 2/6, and 78% in T-COP (A + C) and 74% in CHOP (B + D). The 5-year survival rates were A: 50%, B: 35% (p < 0.05) and C: 26% D: 55% (p < 0.05.), demonstrating that T-COP in their 70s and CHOP in their 80s were significantly higher. The 5-year survival rate in ML1 was 41%. In multivariate analysis, factors influencing the survival (p < 0.01) in ML1 were age, the primary effect and treatment method. There were no significant differences in PS, CS, LDH and lesions outside nodes. Conclusions: Patients aged 70 years or older had the CR rate at 75.9% and a 5-year survival rate at 41%, demonstrating satisfactory outcomes. The results suggested that in 70s, THP 40 mg/m2 was more effective than ADM 40 mg/m2. In their 80s, ADM30 mg/m2 was more effective than THP30 mg/m2. ML2 was feasible in elderly patients with poor physical status.

No significant financial relationships to disclose.
Feasibility of pegfilgrastim as haematopoietic support for dose-dense every-2-week adjuvant chemotherapy in breast cancer
Authors: Gomez P. , Vilar E. , Saura C. , Cortes J. , Ocaña A. , Bellet M. , Carrera J. , Baselga J.
Published: March 2020

18606

Background: Dose-dense sequential chemotherapy has been safety supported with Filgrastim (F). Pegfilgrastim (PEGF) is a pegylated recombinant human granulocyte colony-stimulating factor (G-CSF) that has a long half-life, a fact that facilitates a less frequent dosing. Its safety and efficacy has been established in 21- and 28-days schedules. Methods: We have performed a retrospective analysis of medical records of 2 cohort of patients (n=38) treated at our institution between December 2003 and November 2005. All patients received Adriamicin 60 mg/m2 plus Ciclophosphamide 600 mg/m2 q2w for 4 cycles followed by Paclitaxel 175 mg/m2 q2w for 4 cycles. As G-CSF support, in Cohort A (n=29) PEGF was administered 6 mg on day 2 of each cycle and in Cohort B (n=9) F days 3 to 10 at 5 μg/kg. The primary end point was to explore the feasibility and safety in terms of febrile neutropenia (FN) events, number of treatment delays (TD), incidence of neutropenia grade 3 (NPG3) and 4 (NPG4) and mean absolute neutrophil count (ANC) on day 14 of cycle 1 to 7 for both groups. Indirect comparisons have been performed. Results: Patients characteristics in both cohorts were well balanced, except for age in cohort A compared with cohort B (44,89 versus 52,5, p = 0,02). FN events and TD were increased in cohort B compared with cohort A (22% versus 0%, p=0.051, both comparisons). No statistically significant difference in number of episodes of NPG3 and NPG4 was observed. Median ANC on day 14 for each treatment cycle was significantly greater for Cohort A than Cohort B, except for cycle 6. Conclusions: PEGF is very safe and efficacy in patients treated with dose-dense sequential adjuvant chemotherapy for breast cancer. It could be even more efficient than F in preventing febrile neutropenia events.

[Table: see text]
Co-administration of ondansetron and casopitant mesylate, a novel NK-1 receptor antagonist, results in augmented anti-emetic activity in the ferret
Authors: Gagnon R. C. , King A. G.
Published: March 2020

18608

Background: As monotherapies, ondansetron (a 5HT3 receptor antagonist) and casopitant mesylate ( GW679769 ) are effective anti-emetics in models of chemotherapy-induced nausea and vomiting in the ferret. To demonstrate the potential benefit of combination therapy, suboptimal doses of both ondansetron and casopitant mesylate were administered to ferrets receiving cisplatin. Methods: A 4x4 factorial design was utilized to test for therapeutically synergistic anti-emetic activity. Suboptimal doses (administered as monotherapy, which reduced vomiting and retching by >50% compared to control ferrets but did not result in complete protection) of each compound alone and in combination (0.3, 0.1, and 0.03 mg/kg) were administered 25 minutes prior to injection with cisplatin (10 mg/kg, IP). All emetic events/behaviors were recorded digitally via camera and DVR. Normal behaviors (eating, drinking, urination, defecation), emetic events (vomits, retches), and peri-emetic events (excessive mouth licking, burrowing, eye squinting, backward walking, and body scratching) were recorded temporally. All events were analyzed by finding the cumulative sum of events over time. Therapeutic synergy calculations were determined by analysis of variance. Results: Analysis of emetic events demonstrated the combination of ondansetron and casopitant mesylate resulted in significantly fewer events than either agent alone. Similar activity was demonstrated for vomits, retches, event latency, duration of emesis, water intake, food intake, and complete response. Conclusions: Co-administration of ondansetron and casopitant mesylate results in therapeutically synergistic anti-emetic and potential anti-nausea activity in this cisplatin-induced emesis model in ferrets. Pharmacokinetic analysis indicated no alteration of disposition of either agent. Therefore, we believe the synergy observed between ondansetron and casopitant mesylate is the result of their complementary mechanisms of pharmacologic action. Casopitant mesylate is currently in phase III trials for the prevention of PONV and CINV from moderately and highly emetogenic chemotherapy. It is also in clinical development for depression and anxiety.

[Table: see text]
Reversal of anorexia with megestrol acetate (MA): Impact on quality of life (QoL) in non-metastasic lung cancer patients (pts) undergoing radiation therapy
Authors: Pardo J. , Mena A. , Monleon A. , Macias V. , Sole J. , Hernández M. , Macia M.
Published: March 2020

18613

Background: Anorexia is a common and major problem in cancer patients. Its ethiology is multifactorial and has negative effects on pts QoL. Up to 30% of non-metastasic lung cancer pts receiving radiotherapy will develop anorexia during treatment. We conducted a randomized trial comparing the efficacy of two different doses of MA. The results of the first 130 pts included, presented at ASCO 2003, indicated that MA at doses of 600 mg/day is significantly more effective in the treatment of anorexia in these pts than low doses (320 mg/day) of MA. Here we present the results of the quality of life sub-study which purpose is to evaluate the effect of reversing anorexia in pts health related quality of life (HRQOL). Methods: From February 1999 to April 2003, 160 non-mestastatic lung cancer pts who developed anorexia during radiotherapy were randomized to receive either 320 mg/day or 600 mg/day of MA. All pts who developed anorexia filled up the EuroQuol (EQ-5D) quality of life questionnaire before treated with MA and the responders did it again when appetite was regained. The endpoint was improvement in pts HRQOL (defined as an increase > 5 mm in the EQVAS score between the second and first questionnaires). Results: The analysis of the EuroQuol (EQ-5D) questionnaires of the 131 pts who responded to treatment with MA shows that 106 pts (81%) had an improvement > 5 mm in the EQVAS score while 19 % did not. The difference is statistically significant (Binomial test: p < 0.0001). Regarding differences between the two series, 42 pts improved in the 320 mg arm versus 64 in the 600 mg arm which is not statistically significant (Fisher test: p = 0.501). Conclusions: Our results indicate that reversal of anorexia with MA has a clinically significant improvement in HRQOL in non-metastatic lung cancer pts undergoing radiation therapy. The absence of statistically significant differences between the two series may be due to the sample size.

[Table: see text]

No significant financial relationships to disclose.
Primary adrenocortical carcinoma: A retrospective review of The Cleveland Clinic Foundation experience between 1995 to 2002
Authors: Tirgan N. J. , Hamrahian A. H.
Published: March 2020

18614

Background: Primary adrenocortical carcinoma (PAC) is a rare disease with a incidence of 1 per million. PAC’s are highly malignant tumors with guarded prognosis. Radical surgery is the treatment of choice. Methods: The pathology database and medical charts of these patients were retrospectively reviewed. Results: There were 14 females, 8 males, and 95% were caucasion. The mean age was 49.2 ± 11.8 years (females 51.6 years, males 45 years). The mean size of the tumor was 12.6 ± 5.1 cm (range of 3.6 to 25 cm). Thirteen patients (59.1%) presented with left and nine (40.9%) with right sided PAC. Seventy- two percent of the patients had abdominal, back, and/or flank pain. Forty five percent of patients had symptoms related to hypercortisolism and/or hyperandrogenism. Twelve patients (55%) had functional tumors (hypercortisolism 67%, hyperandrogenism 42%, and DHEA-S hypersecretion 42%) and ten were non-functional. Five percent of the tumors were classified as stage I, 33% were stage II, 38% were stage III, and 24% were stage IV. Twelve patients (55%) had distant metastases (liver 75%, lung 67%, retroperitoneum 33%, kidney 17%, contra-lateral adrenal gland 17%). All 22 patients had adrenalectomies (open 91%; laparoscopic 9%). The microscopic margin of resection were negative in 14 and positive in 6 patients. The information for 18 patients were evaluable for treatment. Eight patients received post-op therapy. Four patients received Mitotane (o,p’-DDD) alone (three died at 2, 29, and 213 months; and one is alive at 38 months after diagnosis). Three patients received both Mitotane and chemotherapy (two died at 3 and 43 months, one is alive at 140 months). One patient received only chemotherapy and died at 8 months. Ten patients received no post-op therapy. The estimated 5-year survival for the entire group was 48% (Kaplan-Meier survival estimate, 95% confidence interval). The estimated 5-year survival for stage III was 33%, and for stage IV was 30%. There were no deaths in patients with stage II group. The estimated 5-year survival for the treated group (8 patients) was 33% and 58% for the untreated group (10 patients). Conclusions: In PACs, surgery remains the main method of therapy. In our experience, Mitotane with or without chemotherapy did not improve survival.

No significant financial relationships to disclose.
Healing by design: The influence of an artistic design on the well being of cancer patients—A 10 years follow up
Authors: Samonigg H. , Andritsch E. , Dietmaier G. , Bauernhofer T. , Andritsch H. , Zloklikovits S. , Kasparek A. K. , Stoeger H. , Schaberl-Moser R. , Ploner F.
Published: March 2020

18615

Background: The style of the surrounding in which cancer patients, who experience physical as well as high psychological distress are treated, can help them to acquire a sense of security, to reduce their anxiety and depression. Inspired by this model the famous artist F. Hundertwasser created the redesign of the oncological ward with the aim to generate an atmosphere of security by utilizing bright, warm and vivid colours, light and plants. The aim of this study was to investigate in a prospective manner whether the artistic redesign have an influence on the welfare of cancer patients using standardized questionnaires pre and immediately post reconstruction and in a follow up 10 years later. Methods: A total of 261 patients were interviewed (93 before the redesign, 81 immediately and 87 ten years after redesign) to assess the influence of depression (Zerssen Depression Scale, PD-S) quality of life (Spitzer Index)and perceptions of the ward design (semi-structured interview) on wellbeing (Zerrsen Mood Scale, Bf-S). Results: A factor analysis of the semi-structured interview yielded four factors assessed with a MANOVA showing that patients interviewed after redesign reported more positive effects of the ward design (F2;227 = 484.274; p < 0.001). In addition, they were more content with treatment and medical care (F2;227 = 20.103; p < 0.001), more positive in their emotions and thoughts regarding illness (F2;227 = 8.600; p = 0.003) and placed greater importance on the fixtures (F2;227 = 6.067; p = 0.003) than the patients interviewed before the redesign. In a regression analysis depression, the “impact of ward design”, quality of life, gender, “emotions and thoughts regarding illness”, age and education predicted wellbeing with an “R” of 0.0469 (p < 0.05). Conclusions: The results provide important aspects for the discussion if the physical surroundings in which cancer patients are treated serve as a potentially positive factor in the “healing process”.

No significant financial relationships to disclose.
Darbepoetin Alfa assessment in chemotherapy induced anemia
Authors: Samantas E. , Rigatos S. K. , Konstantinopoulou A. , Vourli G. , Siganaki M. , Pectasides D. , Pectasides M. , Papakostas E. , Karagianidis G. , Aravantinos G.
Published: March 2020

18617

Background: Anemia is a very common complication of cancer and its treatment. Epoetins have been proven effective in correcting anemia in cancer patients resulting to the reduction of the need for blood transfusions and having a positive impact to the quality of life (QoL). Darbepoetin alfa, is a novel erythropoiesis stimulating protein (NESP) with longer half life. Methods: This is a prospective, single-centre, clinical trial. Patients with haemoglobin < 12 g/dl, suffering from cancer (solid tumor or lymphoma), for whom chemotherapy is scheduled for at least 12 weeks and have life expectancy >6 months and performance status ECOG 0–2,are treated with Darbepoetin alfa 150 mg per week subcutaneously for at least 12 weeks. Full blood count should be tested at least every 2 weeks and biochemistry every 4 weeks. QoL was assessed before and after treatment using the FACT-An (Functional Assessment of Cancer Therapy-Anemia) scale. Primary endpoint is the correction of anemia (Hb value above 12 g/dl). Frequency of the demographic and clinical characteristics were reported for the categorical variables, while mean and standard deviation were reported for continuous variables, such as age and Hb levels. Results: Fifty-six (56) patients entered the study, 66% of them female. Median age was 64 years. The more common cancers were colorectal (26.8%) ovarian (17.9%), breast (16.1%), lung (12.5%), and bladder (8.9%). Two thirds of the patients had not received previous chemotherapy. A statistically significant increase for Hb was found between week 0 and 12 [1.48; 95% CI 1.07–1.88; p < 0.001]. The increase was significant from 3rd week onwards. There was no evidence of significant difference in any of the QoL components or for significant change in mean fatigue sub-scale (fatigue, non-fatigue), between the two assessments. Conclusions: Darbepoetin alfa given at 150 mg per week subcutaneously to cancer patients under chemotherapy appears to correct anaemia, but has not positive impact on QoL, within the limits of the sample size of this study.

No significant financial relationships to disclose.
Capecitabine and irinotecan in elderly patients with advanced or metastatic gastro-intestinal tumors
Authors: Kattan J. , Abou Yared J. , Farhat F. , Chahine G. , Nasr F. , Moukadem W. , Younes F. , Ghosn M.
Published: March 2020

18619

Background: Capecitabine and Irinotecan exhibit single-agent activity in gastro-intestinal tumors. Their combination seems safe and effective. Adult patients with advanced or metastatic gastric or colorectal cancers were enrolled separately in 2 phase II trials dealing with the combination of both drugs. The aim of this study was to evaluate retrospectively the toxicities and the safety profile of this combination in elderly patients (≥ 65 years) as first line therapy for advanced or metastatic gastro-intestinal cancers. Methods: Patients with advanced or metastatic adenocarcinomas of the colon or the stomach aged 65 years or more were treated with the combination of: Irinotecan 80 mg/m2 IV d1,8,15, and Capecitabine 1250 mg/m2 orally d 1–14, Q 4w. Toxicities were graded according to the NCI common toxicities criteria version 3. Results: 24 naïve-chemotherapy patients were included. Median age was 68 years (extremes 65 to 88). Primary tumor was stomach, colon, and rectum in 13, 9, and 2 cases respectively. Frequent sites of metastases were liver (18), lymph nodes (8), peritoneum (7), and lung (5). They received 113 cycles with median number 4.7/patient, and extremes 1 to 14. Serious toxicities graded as IV were universally absent. Grade III anemia, diarrhea, and vomiting were encountered in 1, 1, and 2 patients respectively. Grade II anemia, leucopenia, diarrhea, alopecia, fatigue, and vomiting were recorded in 5, 2, 4, 2, 2, and 6 patients respectively. Hand-foot syndrome was observed as only grade I in 2 patients. There was no febrile neutropenia. In the other hand, objective response was encountered in 9 patients (37.5%), with median response duration of 6 months (extremes 1 to 15). After a median follow-up of 36 months, 19 patients died from progression of their disease with mean overall survival of 5.5 months (extremes 1 to 28). Conclusion: The combination of Irinotecan and Capecitabine according to our schedule revealed an excellent safety profile with easily manageable toxicities. This schedule is highly suitable for elderly patients.

No significant financial relationships to disclose.
Lymphopenia and monocytopenia versus MASCC score system in patients with febrile neutropenia
Authors: Baykara M. , Demirkazik A. , Elhan A. , Yalcin B. , Buyukcelik A. , Dogan M. , Utkan G. , Tek I. , Doruk H. , Akan H. , Icli F.
Published: March 2020

18622

Background: The purpose of this study was determine the clinical significance of lymphopenia and monocytopenia in terms of its duration and depth in patients with febrile neutropenia (FEN) and MASCC scores parametres. Methods: Sixty-six patients with FEN were prospectively analysed. Recurrent FEN episodes were excluded in this trial. Twenty-four patients had solid tumors, 42 patients had lymphoma-leukemia. Patients with MASCC-scores ≥21 evaluated as low-risk (LR) and the ones with their scores <21 were high-risk (HR). Results: Thirty-six patients had HR and the rest had LR. Lymphocyte count <700/mm3 and monocyte count <100/mm3 were found as 91.6% and 86.6% in HR and in LR groups, respectively.The rate of refractory fever(RF) in HR patients was clearly high.Patients with protracted neutropenia (PN) had higher rate of RF (p = 0.007). Patients with longer duration of neutropenia and monocytopenia tended to have RF (p = 0.052, p = 0.018). The rate of administered AFT was significantly high in HR patients (p = 0.005). AFT was administered to one third of HR patients, but no patient received AFT in LR-group (p < 0.001). In group with neutropenia duration (ND) <10 days, one patient received AFP (p < 0.001). AFT was given to most of the patients who had longer duration of lymphopenia or monocytopenia (respectively; p = 0.002, p = 0.001), and who had leukemia (p = 0.001). The most important parameters effecting the duration of antibiotic therapy (DAT) was found to be ND. DAT >14 days was found more than fourfold in patients PN (p = 0.007). Fifty-five percent out of patients with solid tumor or lymphoma were given <14 days antibiotic therapy. But, most of patients with leukemia had antibiotics >14 days (p = 0.002).The rate of antibiotic therapy >14 days was higher in patients with longer duration of lymphopenia and monocytopenia (respectively; p = 0.073, p = 0.062). The most important parameter that influences on antibiotic modification (AM) was severity of monocytopenia on the first day of FEN. The rate of AM was found in aproximately nine-fold in patients that had monocyte counts ≤100/ mm3 as compared to monocyte ≥100/ mm3 (p = 0.01). Conclusions: The depth of monocytopenia and durations of lymphopenia and monocytopenia were the important parameter influencing antibiotic modification in FEN.

No significant financial relationships to disclose.
Arterial blood carboxyhemoglobin as a predictor for response after chemotherapy in patients with lung cancer
Authors: Nakayama K. , Yasuda H. , Sasaki T. , Suzuki T. , Asada M. , Okinaga S. , Yamaya M.
Published: March 2020

20029

Background: It is desirable to predict the response to chemotherapy in patients with lung cancer using a simple and reliable method. Arterial blood carboxyhemoglobin concentration (Hb-CO) is a useful biomarker for severity in inflammatory pulmonary diseases and is associated with cancer tissue volume in operable NSCLC. However, arterial Hb-CO as a predictor for response to chemotherapy in advanced lung cancer has not been reported. Methods: We enrolled 35 patients with SCLC and 66 ones with NSCLC in stage III or stage IV, treated with chemotherapy between October 2000 and December 2002. All patients with SCLC were treated with PE (cisplatin 80 mg/m2, day 1 and etoposide 100 mg/m2, day 1-day 3) every 3 weeks. The patients with NSCLC were treated with either VC (vinorelbine 25 mg/m2, day 1 and 8 plus cisplatin 80 mg/m2, day 1) or DG (gemcitabine 1100 mg/m2, day 1 and day 8 plus docetaxel 60 mg/m2, day 1) every 3 weeks. Arterial Hb-CO were examined before and at during chemotherapy and the response rate were studied. The patients with either a partial response (PR) or a complete response (CR) were categorized as responder, whereas patients with no change (NC) or progressive disease (PD) were as non-responders. According to the analysis in aterial Hb-CO, the patients were divided into two subgroups, patients with high (≥0.3%) or low (<0.3%) maximum changes in the Hb-CO (ΔHb-CO) during chemotherapy. Results: The response rate was 80% in SCLC and 38% in NSCLC. In responder patients with SCLC or NSCLC, the arterial Hb-CO significantly increased and reached maximum at day 4 of the 1st cycle of chemotherapy. In contrast, in non-responder patients, the Hb-CO did not increase during the chemotherapy. The response rate in patients with high ΔHb-CO was significantly higher than that with low ΔHb-CO in SCLC (26/26 vs 2/9, P < .001) and NSCLC (24/24 vs 1/42, P < .001). The high ΔHb-CO at day 4 of the 1st chemotherapy cycle was significantly associated with the response to the chemotherapy in SCLC (Odd ratio, OR = 12.5 [95% CI: 3.13–50, P < .001]) and in NSCLC (OR = 25 [95% CI: 3.23–100, P < .01]) (logistic regression analysis). Conclusions: Increases in arterial Hb-CO at day 4 of the 1st chemotherapy cycle in SCLC and SCLC may be a predictor of response to chemotherapy.

No significant financial relationships to disclose.
Effects of PKC beta inhibitor enzastaurin on parental and chemoresistant ovarian cancer cell lines
Authors: Meinhold-Heerlein I. , Bauerschlag D. O. , Bräutigam K. , Maass N. , Mundhenke C. , Hilpert F. , Kaisenberg von C. , Jonat W. , Bauknecht T. , Arnold N.
Published: March 2020

20037

Background: Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase C beta (PKCβ), inhibits induction of angiogenesis and apoptosis. Activation of PKCβ has been correlated with tumor cell proliferation and invasiveness. The impact of Enzastaurin was investigated in an ovarian cancer tissue culture model utilizing the parental cell line HEY and resistant subclones against different cytostatic drugs. Methods: The ovarian cancer cell line HEY was used to develop subclones with selective resistance against Cisplatin, Etoposide, Docetaxel and Paclitaxel, respectively. The ovarian cell line IGROV-1 with high expression of PKC beta served as control. All cell lines were stimulated with 5 μM Enzastaurin for up to four hours. Immunoblotting analyses determined the expression of GSK3β, a target of PKCβ. Proliferation and apoptosis induction after Enzastaurin treatment was analysed by a proliferation assay and DAPI staining. Results: All cell lines showed phosphorylation of GSK3β, the highest expression level was found in parental and Cisplatin-resistant HEY cells as well as in IGROV-1 cells. Phosphorylation decreased after stimulation with 5 μM Enzastaurin for 30 minutes, most obvious detectable in parental and Cisplatin-resistent HEY cells and also IGROV-1 cells. Proliferation and apoptosis assays demonstrated the Paclitaxel- and Docetaxel-resistant HEY cells as the most sensitive cell lines for Enzastaurin treatment. In contrast, Cisplatin-resistant HEY cells and IGROV-1 cells exhibited the highest resistance against Enzastaurin. Conclusion: The results indicate that ovarian cell lines with a high expression level of active PKCβ like Cisplatin-resistant HEY cells and IGROV-1 cells display also strong phosphorylation of GSK3β. Though in these cell lines the inhibitory effect of Enzastaurin is most prominent, the cell proliferation is hardly affected, nor apoptosis is accelerated when Enzastaurin concentrations up to 10–15 μM were used. Compared to the Cisplatin-resistant variants the normal HEY cells are more sensitive to the inhibitor. Taxane-resistant cells seem to respond to low concentrations of Enzastaurin. Therefore, Enzastaurin may become an effectful drug to treat ovarian carcinomas with resistance to Taxane-based chemotherapies.

[Table: see text]
Never-smoking history predicts long-term survival in patients with non-small cell lung cancer with postoperative recurrence
Authors: Fujiwara Y. , Kiura K. , Toyooka S. , Hotta K. , Tabata M. , Takigawa N. , Kozuki T. , Ohashi K. , Matsuo K. , Tanimoto M.
Published: March 2020

20047

Background: Factors affecting long-term survival after postoperative recurrence in non-small cell lung cancer (NSCLC) patients have not been fully understood. Furthermore, molecular features of them also have remained undetermined. The aim of this study was to identify these possible factors and to investigate their association with epidermal growth factor receptor (EGFR) mutation. Methods: Fifty-eight patients with postoperative recurrent NSCLC treated at Okayama University Hospital between January 1999 and December 2003 were retrospectively analyzed. We defined those surviving for 2 years or longer after postoperative recurrence as long-term survivors. Tumor samples for EGFR mutation analysis were available in 32 (55%) patients and were examined in exons 18 to 21 of EGFR using direct sequence method. Results: Demographics of 58 patients were as follows: median age 65 years (range, 33–85 years), male/female, 69%/31%; adenocarcinoma/others, 69%/31%; ever/never-smokers, 66%/34% and local/local and distant/distant recurrence; 29%/10%/61%. Median survival time and 1-year survival rate for 58 patients were 22.7 months and 79%, respectively, with a minimum follow-up time of 2 years. Half of 28 long-term survivors did not have any smoking history, whereas only 6 never-smokers were included in the remaining 30 patients who died within 2 years, indicating that never-smoking history is significantly associated with long-term survival (p=0.016). In multivariate analysis, never-smoking history was a significant predictive factor for long-term survival (Odds ratio 4.90, 95% confidence interval: 1.26–19.00, p=0.022). Among 32 patients analyzed for EGFR mutation, patients harboring EGFR mutation in ever-smokers and in never-smokers were 10% and 82%, respectively. Seven (47%) of 15 long-term survivors analyzed had EGFR mutation; however, only 4 (24%) of 17 patients who died within 2 years did (p = 0.169). Conclusions: Our data suggest that never-smoking history might have a favorable effect on long-term survival in postoperative recurrent NSCLC patients, and long-term survivors tend to have EGFR mutation.

No significant financial relationships to disclose.
Polymorphisms of the thiopurine S-methyl transferase gene (TMPT) in a Mexican population
Authors: Candelaria M. , Taja-Chayeb L. , Vidal S. , Gutiérrez O. , Ostrosky P. , Duenas-Gonzalez A.
Published: March 2020

20049

Background: Polymorphisms at the thiopurine S-methyltransferase coding gene (TPMT) determine enzyme activity and as a consequence the development of toxicity of thiopurine drugs. Methods: To test the frequency of polymorphisms of TPMT gene in Mexican population. 36 DNA samples from volunteer donors were analyzed. Genomic DNA from peripheral leukocytes was isolated by standard methods. Known (wild type and polymorphic) sequenced PCR fragments of the TPMT gene were used used as controls. PCR amplification: Fragments of the TPMT gene were amplified using the following oligonucleotides primers: Exon 5: 5′-CTGCATGTTCTTTGAAACCCTATGAA-3′ and 5′-CTTGAGGACAGAGAGGCTTTGACCTC-3′; exon 7: 5′-CTCCACACCCAGGTCC-ACACATT-3′ and 5′-GTATAGTACTAAAAAATTAAGACAGCTAAAC-3′; exon 10: 5′-AATCCTGATGTCATTCTTCATAGTATTT-3′ and 5′-CATCCATTACATTTTCAGG-CTTTAGCATAAT-3′. PCR products were then analyzed by denaturating high performance liquid chromatography (DHPLC) for the most frequent mutant TPMT alleles, according to the method developed by Schaeffeler et al (Clin Chem 2001; 47: 548) on an analysis system from Transgenomics Results: A high frequency of gene polymorphisms was identified, particularly in the exon 7 (14/36 = 38%), followed by exon 10 (3/36 = 8.3%) and 5 (2/36 = 5.5%). After analysing the three exons, the presence of mutations discriminating for TPMT alleles showed that 7/36 (19.4 %) were silent and located at T474C, in exon 7 (*1S) and 7/36 (19.4 %) were functional, and located in TPMT alleles *2 (2/36 = 5.5%), *3B (2/36 = 5.5%), *4 (2/36 = 5.5%) and *3B/4 (1/36= 2.7%). Conclusions: This is the first analysis of the polymorphisms at this gene in a Mexican population. The frequency of known silent polymorphisms was higher than those reported in other world regions but the frequency of functional polymorphism is within the range found in other reports. DHPLC is a highly sensitive, rapid and efficient method to identify relevant TPMT gene mutations which allows the screening for genetic variability in the TPMT gene . This trial was supported by a grant of CONACYT.

No significant financial relationships to disclose.
Expression of metastasis suppressor gene maspin in breast cancer brain metastases
Authors: Schem C. , Stark A. M. , Mehdorn H. M. , Jonat W. , Maass N.
Published: March 2020

20057

Background: Recently our demonstrated that the expression of several Metastasis Suppressor Genes (MSG) is reduced in breast cancer brain metastases. Current data suggest that MSG Maspin (serpin B5) is a promising candidate for further treatment options. So, we examined the mRNA and protein expression of Maspin in normal breast tissue, breast cancer primaries, -brain metastases and breast cancer cell lines. Methods: Maspin mRNA expression was examined by real time reverse transcription polymerase chain reaction (RT-PCR) in fresh frozen samples from normal breast tissue, breast cancer primaries and -brain metastases. Furthermore maspin was examined in poorly invasive and non-metastatic breast cancer cell lines MCF-7, T47-D, in highly invasive and metastatic MDA-MB-231 breast cancer cells (231-parental) and in brain- and bone-selective metastatic clones (231-brain, 231-bone). Maspin protein was detected by immunohistochemistry in paraffin-embedded sections from 16 patients with breast cancer primaries and brain metastases using a specific monoclonal mouse antibody. Results: In relation to normal breast tissue, maspin mRNA expression was decreased in primary tumors and again decreased in brain metastases. Normalized ΔCT values were 1 (normal tissue), 0.3 (primary tumors) and 0.13 (brain metastases). Immunohistochemistry revealed the same tendency. 3 of 16 (19%) breast cancer primaries were positive whereas none of the brain metastases showed positive maspin staining. In comparison to poorly invasive breast cancer cell lines, maspin mRNA expression was decreased in 231-parental, increased in 231-brain and not detectable in 231-bone. Conclusions: Maspin expression is reduced in breast cancer brain metastases. It is differentially expressed in brain- and bone-selective metastatic cell lines. These results suggest an important role for maspin in breast cancer brain metastasis.

No significant financial relationships to disclose.
O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and relation to 1p/19q loss in low grade gliomas: A GICNO study
Authors: Nicolardi L. , Bertorelle R. , Bonaldi L. , Compostella A. , Roma A. , Tebaldi E. , Pession A. , Reni M. , Franceschi E. , Ghimenton C.
Published: March 2020

20064

Background: 1p and 19q deletions have been associated with a favorable response to chemotherapy and a good prognosis in patients (pts) with oligodendroglioma. MGMT promoter methylation has been associated with a longer survival in pts with glioblastoma who receive alkylating agents. As yet, there are no data on the expression of MGMT, and on the relationship between 1p/19q deletions and MGMT promoter methylation in low grade glioma (LGG). Methods: Pts that received a first line chemotherapy regimen with temozolomide for progressive LGG were enrolled in the study, designed to investigate the correlation between MGMT methylation status and 1p/19q deletions in this setting. 1p/19q deletions were analysed by FISH, and MGMT promoter methylation by methylation specific PCR (MSP). Results: Seventy-five pts (26 females, 49 males; median age 42 years: range 22–68 years) were accrued. Of these, 48 (64%) had oligodendrogliomas (O), 19 (25.3%) astrocytomas (A), and 8 (10.6%) oligoastrocytomas (OA); 44 (58.7%) had a history of epilepsy, 41 (54.7%) had a frontal tumor localization, 27 (36%) had MRI contrast enhancing lesions, and 35 (46.7%) had been pre-treated with radiotherapy. 1p/19q deletions, evaluable in 58 pts (77.3%), were both present in 36 pts (62%), (3 being A and 2 OA); 18 pts (31%) had no loss; 1 pt (1.7%) had 1p loss; 3 pts (5.2%) 19q loss. Combined 1p and 19q loss was not correlated with a frontal localization (p = 0.12), median age (0.47) and/or gender (0.62). MGMT promoter methylation, present in 17 (56.6%) of 30 assessable cases, was significantly associated with combined 1p/19q deletions (p = 0.03). MGMT promoter methylation was not significantly associated with age (p = 0.46), gender (p = 0.2), tumor localization (p = 0.12) and/or histology (0.37). Conclusions: 1p/19q deletions are strictly correlated to histology and to MGMT promoter methylation; further prospective trials are required to clarify the impact of these molecular signatures on clinical outcome.

No significant financial relationships to disclose.
Analysis of serum HER-2/neu levels (S-HER2) in breast cancer (BC) patients (pts)
Authors: Palmeri S. , Mangiameli A. , Vaglica M. , Allegro R. , Macaluso M. C. , Bongiovanni A. , Di Noto L. , Vasta D. , Raciti L. , Lio D.
Published: March 2020

20092

Background: Circulating serum levels of the extracellular domain of the HER-2/neu receptor have been described in up to 15–30% of pre-surgical BC pts and 45% of metastatic BC (MBC) pts. S-HER2 has been reported to have a potential prognostic and predictive role in BC pts. Methods: We conducted a prospective evaluation of the S-HER2 levels in BC pts with the aim of studying its prognostic role and correlation with the clinical situation.The S-HER-2 levels were measured by an ELISA immunometric test (cut-off 13 ng/ml) at the first visit and then every 3 months.All pts gave a written informed consent. Results: From Jan ‘05 97 consecutive BC pts [68 st I-III; 29 (1 male) st.IV; median age at entry: 60y (28–83)] have been accrued and a total of 196 serum samples have been tested for S-HER2 (mean = 2/pt).Preliminary results are reported.Elevated S-HER2 levels at the first dosage (bS-HER2) were present in 25% of primary and 52% of MBC pts.In 68 primary BC pts the tumor HER2 status was 0/1+ in 54% (bS-HER2 >13 ng/ml = 22%) and 2+/3+ in 22% (bS-HER2 >13 ng/ml = 27%); there was no correlation between bS-HER2 with tumor HER2 status, size,axillary nodes, ER status, grading according to the Fisher’s exact test. In 29 MBC pts the tumor HER2 status was 0/1+ in 24% (bS-HER2 >13 ng/ml = 24%) and 2+/3+ in 48% (bS-HER2 >13 ng/ml = 21%); there was no correlation between S-HER2 and sites of metastases/n.of sites even if the S-HER2 median value was 18 and 12.5 ng/ml in visceral vs no visceral metastases.We also observed in 35% of MBC pts experiencing progression of disease that S-HER2 sequential values increased from baseline;in 21% of MBC pts that experienced complete remission the S-HER2 values decreased <13 from baseline. Conclusions: This analysis showed no definite association between bS-HER-2 and clinical parameters.Further evaluations in a larger group of pts and association with response,survival and changes of S-HER2 status will be conducted.

No significant financial relationships to disclose.
Phase 1 study of CPX-1, a fixed ratio formulation of irinotecan (IRI) and floxuridine (FLOX), in patients with advanced solid tumors
Authors: Batist G. , Chi K. , Miller W. , Chia S. , Hasanbasic F. , Fisic A. , Mayer L. , Swenson C. , Janoff A. , Gelmon K.
Published: March 2020

2014

Background: In vitro studies have shown that varying the ratio of individual agents in drug combinations can result in synergistic, additive or antagonistic activity against tumor cells. CPX-1 is a liposomal formulation of IRI and FLOX in a fixed 1:1 molar ratio which was selected as optimal in vitro and confirmed to be synergistic in vivo in preclinical tumor models. CPX-1 overcomes the dissimilar pharmacokinetics (PK) of the individual drugs, enables sustained maintenance of this ratio after IV administration, and was evaluated in a Phase I open-label, dose-escalation study. Methods: Starting dose was 30 U/m2 (1 Unit of CPX-1 contains 1 mg IRI + 0.36 mg FLOX) given on day 1 and 15 of each 28-day cycle. Dose escalation was by modified Fibonacci with 4 subjects/cohort. Eligibility included: ≥ 18 yo; advanced solid tumor; ECOG PS ≤ 2; adequate bone marrow/liver/renal function. PK analysis was done on day 1 and 15 of the first cycle. Results: 26 subjects (16M:10F), median age 54.5 y (21–72), all with prior therapy, enrolled in 6 cohorts with the 5th cohort expanded to 6 subjects. Diagnoses: 8 colorectal, 3 pancreatic, 3 ovarian, 2 breast, 2 gastric, 2 esophageal, 2 sarcomas, 1 renal cell, 1 prostate, 1 NSCLC and 1 sphenoid sinus. Response: 20 subjects evaluable: 2 confirmed PRs (NSCLC 8+ wks; Colon 13+ wks, in a patient with prior IRI exposure) and 13 with SD (8–24+wks). Safety: DLTs were observed at the 6th dose level: 4 subjects with DLTs: 3 diarrhea (one resulting in death due to dehydration/ARF) and one neutropenia. Other possibly related grade 3 and 4 events included one each of: grade 3 diarrhea, grade 3 vomiting, grade 3 neutropenia, grade 3 fatigue, grade 3 compression fracture and arthralgia and pulmonary embolism grade 4. PK: In all 14 subjects analyzed to date the 1:1 molar ratio of IRI to FLOX was maintained for 24 hours and metabolites 5-FU and SN-38 were present in the plasma. Conclusions: CPX-1 represents a new approach to developing drug combinations in which drug ratios are pre-selected in vitro based on optimal antitumor activity and maintained systemically through pharmacokinetic control. Phase 2 studies are planned with a recommended dose of 210U/m2 of CPX-1.

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Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2’-deoxycyticine (FdCyd) & its metabolites 5-fluoro-2’-deoxyuridine (FdUrd), 5-fluorouracil (FU), 5-fluorouridine (FUrd), & 5-fluorocytosine (FC) in plasma of patients treated with FdCyd
Authors: Beumer J. H. , Parise R. A. , Newman E. M. , Doroshow J. H. , Synold T. W. , Lenz H. , Egorin M. J.
Published: March 2020

2023

Background: The DNA methyltransferase inhibitor, FdCyd, is in phase I clinical trials. It is combined with tetrahydrouridine (THU), a cytidine deaminase inhibitor, to prevent rapid metabolism of FdCyd to the pharmacologically active metabolites FdUrd, FU, FUrd, & FC. We assessed the plasma levels of these active, yet undesired, metabolites in patients receiving FdCyd+THU. Methods: We developed a hydrophilic interaction chromatography LC-MS/MS assay capable of simultaneously quantitating FdCyd & metabolites. Patients were treated with 5 daily, 3-h infusions of FdCyd at doses of 5–80 mg/m2. Plasma was obtained before & at the end of infusions (EOI) on days 1 & 5. Results: The lower limits of quantitation for FU, FdUrd, FUrd, FC & FdCyd were 1, 1.5, 10, 3, & 10 ng/ml, respectively, & the assay for each analyte was linear over a 300–1000 fold range of concentrations. Plasma FdCyd increased with dose from 19–96 ng/ml at 5 mg/m2 to 1600–1728 ng/ml at 80 mg/m2, as previously described. FdUrd was not detectable in plasma of patients treated with FdCyd doses <20 mg/m2, & then increased from 2.31 ng/ml at 20 mg/m2 to 3.5–5.7 ng/ml at 80 mg/m2. FU was present in plasma of patients treated at all doses studied, & FU concentrations increased with dose. Inter-patient variability in concentrations was 1.5–3 fold (FdUrd) and 2–4 fold (FU). FUrd & FC were only present in the day 1 plasma sample of one patient, who was treated at 40 mg/m2, & were not present in the day 5 sample of that patient. No FdCyd or metabolite was detected in day 5 pretreatment plasma of the 2 patients treated with 80 mg/m2 of FdCyd. Conclusions: FdCyd administered with THU undergoes little catabolism. The EOI FU and FdUrd concentrations in plasma of patients treated with FdC+THU are <10% those observed after therapeutic continuous infusions of FU or FdUrd. Thus, selective inhibition of DNA methylation with FdCyd+THU is feasible. The LC-MS/MS assay developed will be a valuable tool to pharmacologically support continuing clinical development of FdCyd. Support: NO1-CM52202, P30CA47904, U01CA62505, & P30CA33572.

No significant financial relationships to disclose.