bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypogonadism in male cancer patients treated with the tyrosine kinase inhibitors sunitinib (SUN) or sorafenib (SOR)
Authors: Wolter P. , Wildiers H. , Vanderschueren D. , Dumez H. , Clement P. , Schöffski P. 
Published: August 2020

3565 Background: SUN and SOR are multi-targeted tyrosine kinase inhibitors (TKIs) inhibiting several kinases (VEGFR- 1,2; c-kit; PDGFR-α,β; flt-3; RET). SUN is approved for treatment of imatinib-resistant gastrointestinal stromal tumors (GIST) and metastatic renal cell carcinoma (RCC), SOR is used for RCC and hepatocellular carcinoma. We observed in some pts with fatigue under TKI treatment low testosterone (T) levels and started assessing the incidence and severity of gonadal dysfunction prospectively in male pts receiving these TKIs. Methods: Gonadal status (serum total testosterone (TT), free testosterone (FT), sex-hormone binding globulin (SHBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were evaluated in pts with RCC or GIST under SUN or SOR. SUN was given at a daily dose of 50 mg p.o. 4 weeks on, 2 weeks off, SOR at a daily oral dose of 800 mg. Results: We identified 27 pts (median age 63, range: 27–77), for which data on gonadal function were available, 23 RCC (85 %), 4 GIST (15%), with 22 (85.5%) receiving SUN and 5 (18.5%) SOR. Median treatment duration was 48 (2–202) weeks, 13 (48%) underwent dose reductions, in 4 (15%) pts due to grade 3 fatigue. All pts had at least once during TKI treatment T levels lower than normal (TT < 300 ng/dL and/or FT < 5 ng/dL), 17 (63%) had a low T with normal LH/FSH, 4 (15%) a low T with an elevated LH/FSH and 6 (22%) a low T and elevated FSH, but normal LH. The median TT level in the whole group was 194 ng/dL (21–477, normal range: 300–1,000 ng/dL), the median FT level in the whole group was 4.01 (0.45–9.07, normal range: 5–20 ng/dL). In the SUN cohort the median levels for TT and FT were slightly lower on day 28 in comparison to day 1 (184.5 vs 206 ng/dL for TT and 3.935 vs 4.225 ng/dl for FT). Pts with information available on testosterone at baseline (n = 8) tended to have slightly diminished baseline T levels (median: 222.5 [61–319] ng/dL), but 50% of these pts had been treated with other TKIs before. Two pts with grade 3 fatigue under SUN had very low T levels shortly after starting SUN (21 and 28 ng/dL, respectively). Conclusions: We observed a high incidence of hypogonadism in male RCC and GIST pts under treatment with SUN or SOR. Hypogonadism may likely contribute to the fatigue associated with these agents. [Table: see text]
Pharmacokinetic and pharmacodynamic results of a 4-hr IV administration phase I study with EPC2407, a novel vascular disrupting agent
Authors: Read W. L. , Rosen P. , Lee P. , Anthony S. , Korn R. , Raghunand N. , Tseng B. , Whisnant J. , Von Hoff D. , Tibes R. 
Published: August 2020

3569 Background: EPC2407 is a 4-aryl-chromene single isomer microtubulin inhibitor with vascular disrupting and apoptotic activity at nanomolar concentrations. In an earlier phase I study dosing by 1 hr infusions daily x3 on a 21 day cycle, DLT at 21 mg/m2 was pain at tumor sites and vasoconstriction with increases of BP and QTc. MTD was 13 mg/m2 over 1 hr (ASCO 2008, Abst 2531). All drug-related toxicities resolved within an hour of stopping the infusion. Prolonged infusion of EPC2407 to extend exposure of tumor vasculature was designed with administration of EPC2407 over 4 hrs for 3 consecutive days of a 21 day cycle. Eleven patients have received this schedule and their cancers included leiomyosarcoma, colo-rectal, ovary, hepatocellular (2), NSCLC, pancreas, carcinoid, hemangiopericytoma, larynx and small bowel. Results: Doses escalated from 13 to 30 mg/m2 over 4 hours, with MTD determined to be 24 mg/m2. DLTs at 30 mg/m2 were similar to those seen in the 1 hr infusion, with pain at tumor sites in 1 participant and asymptomatic ST depression in a second. Other toxicities were also similar and included transient hypertension. QTc increases were not significant and no new toxicities were encountered. T1/2 with 4 hr infusion was ∼2hr, also seen with 1 hr infusion. AUC and Cmax values were similar to that predicted from the 1 hr data except AUC at 13 mg/m2 was lower than expected. DCE-MRI was done at baseline and after infusion on day 3, cycle 1. Analysis to date of DCE-MRI data of 4 patients showed a median decrease of 40% in both tumor permeability (Ktrans) and tumor perfusion volume (Vp). The two patients with hepatocellular carcinoma had notable stable disease and clear clinical benefit. Both patients received 18 mg/m2 dose, with one receiving 7 cycles over 5 months, and the other still on study (cycle 6) with stable disease for at least 4 cycles. Conclusions: EPC2407 shows clinical promise, with infusion-associated toxicities characteristic of the VDA drug class but without sustained or cumulative toxicity. Studies combining EPC2407 with conventional cytotoxic/cytostatic regimens are being designed. [Table: see text]
Phase Ib study of NGR-hTNF, a selective vascular targeting agent (VTA), in combination with cisplatin in patients with refractory solid tumors
Authors: Citterio G. , De Braud F. G. , Gregorc V. , De Pas T. M. , Scalamogna R. , Boselli S. , Giovannini M. , Caligaris-Cappio F. , Lambiase A. , Bordignon C. 
Published: August 2020

3570 Background: NGR-hTNF is a VTA exploiting a tumor-homing-peptide (NGR) that selectively binds to an aminopeptidase N/CD13 overexpressed on tumor blood vessels. In preclinical models, significant synergy between low-dose NGR-hTNF and cisplatin was shown. Methods: Patients with resistant/refractory solid tumors were treated with NGR-hTNF given with a low-dose, doubling-dose scheme (0.2–0.4–0.8–1.6 μg/m2) as 1-hour intravenous infusion, in combination with cisplatin 80 mg/m2, both given every 3 weeks. A 3+3 escalation/de-escalation design was followed. PK sampling was performed after the first 3 cycles. DLT definition: any G3–4 toxicity related to NGR-hTNF. Results: 22 patients (median age: 60 years, range, 47–75; 14M/8F; ECOG PS 0/1 12/10) with different tumor types were evaluated over 77 cycles (range, 1–10). Median number of prior regimens was 3 (range, 1–6) and 12 patients (55%) were previously treated with platinum-based regimens. Both NGR-hTNF Cmax and AUC increased proportionally with dose. The combination was safe without PK interaction or exacerbation of platinum-associated toxicity profile. No shedding of soluble TNF receptors was observed up to 0.8 μg/m2. As expected for the low-dose range explored, MTD was not reached and no DLTs were registered at 0.2 μg/m2 (n = 4), 0.4 μg/m2 (n = 3) and 1.6 μg/m2 (n = 3). At 0.8 μg/m2, a patient had a G3 transient acute infusion reaction. This cohort was expanded up to 6 patients for safety reasons, with no DLTs registered, and up to 12 patients, for preliminary activity evaluation. At this dose level of 0.8 μg/m2, two lung cancer patients, both pre-treated with platinum, achieved a partial response (-79%) and a significant tumor shrinkage (-28%) lasting 7.2 and 6.7 months, respectively, and an additional 4 patients experienced stable disease for a median duration of 6.4 months. The median progression-free survival for all patients (n = 22), for patients enrolled at 0.8 μg/m2 (n = 12), and for patients pre-treated with platinum (n = 9) was 2.7, 4.7, and 4.3 months, respectively. Conclusions: The combination of NGR-hTNF 0.8 μg/m2 with cisplatin 80 mg/m2 shows a favourable toxicity profile and promising antitumor activity. [Table: see text]
Effects of vascular endothelial growth factor (VEGF) signaling inhibition on human erythropoiesis
Authors: Maitland M. L. , Kasza K. E. , Snider K. L. , Sit L. , Cohen E. E. , Seiwert T. Y. , Karrison T. , Ratain M. J. , Vokes E. E. 
Published: August 2020

3575 Background: In rodents, inhibition of VEGF signaling increases production of red blood cells. Major clinical trials of VEGF signaling inhibitors have not reported on these effects in human patients (pts). Methods: To determine whether disruption of VEGF signaling in humans is associated with increased erythropoiesis, we analyzed red blood cell (RBC) and hemoglobin (Hgb) measurements in pts at a single institution enrolled in a phase II trial of axitinib in advanced thyroid cancers (16 pts), a study of sorafenib in advanced solid tumors (57 pts), and a randomized phase II trial of concomitant fluorouracil, hydroxyurea, and radiation with (14 pts) or without bevacizumab (8 pts) for locally advanced cancers of the head and neck. In the axitinib and sorafenib trials, no pt received red cell transfusions (Tf) or erythropoiesis stimulating agents (ESAs). Three pts in the chemoradiotherapy study received Tf or ESAs and were excluded from further analysis. Erythropoietin (EPO) plasma concentrations were measured only on pts in the sorafenib study at baseline, and days 8 and 35. Mixed models with random intercept were used to determine the effect of VEGF signaling inhibitors on RBC and Hgb. Repeated measures analysis of variance was used to examine whether EPO levels changed over time. Results: Over the first 84 day interval of treatment RBC increased for each day on axitinib (4 K/mcl [95% CI 2, 7], p < 0.001) or sorafenib (3K/mcl [2, 4], p < 0.001). Similar results were detected for Hgb. For the first 68 day interval of chemoradiotherapy alone, the RBC declined over time (-13K/mcl/day [-16, -10]) but less so (-7K/mcl [-10, -5]) with added bevacizumab (interaction p = 0.003). EPO levels changed with sorafenib exposure, most notably, increasing by 38% between days 8 and 35 (p < 0.001 by Wilcoxon signed rank test). Conclusions: VEGF signaling inhibition is associated with increased RBC and EPO production. This effect might contribute to positive and negative clinical consequences of exposure to VEGF signaling inhibitors. [Table: see text]
A safety and schedule seeking trial of Bcl-2 inhibitor obatoclax in previously untreated older patients with acute myeloid leukemia (AML)
Authors: Raza A. , Galili N. , Borthakur G. , Carter T. H. , Claxton D. F. , Erba H. P. , DeAngelo D. J. , Berger M. S. , Schimmer A. 
Published: August 2020

3579 Background: Obatoclax (Ob) is a small-molecule inhibitor of all Bcl-2 prosurvival proteins. In a previous study a 70 year old patient with untreated AML had a cytogenetic CR 8 days after receiving 20 mg/m2 of Ob over 24 hrs. This study evaluated the single-agent response rate in older patients with previously untreated AML. Methods: A Safety phase to evaluate escalating doses of Ob given by 3-hr infusion was performed. Based on previous results, the dose of 60 mg over 24 hrs was used for the 24-hr infusion arm of the Schedule Seeking phase, in which Ob was administered as either a 3-hr or 24-hr infusion for 3 consecutive days every 2 wks. The endpoint of the Schedule Seeking phase was CR after C2 in 16 randomized patients. Eligibility criteria included age ≥ 70, untreated AML (1 prior Rx allowed in Safety phase), ECOG PS ≤2, adequate renal and hepatic function. PK samples were collected during C1. Results: 18 patients (8 male; median age 82) were enrolled. 2/3 patients enrolled into the 1st cohort (30 mg x 3 days) of the Safety phase had DLT events (ataxia and somnolence). 3 patients enrolled into a 20 mg x 3 days cohort had no DLTs; this dose was used for Schedule Seeking patients receiving 3-hr infusions. In the Schedule Seeking phase, 7 patients were randomized to receive 20 mg by 3-hr infusion and 5 were randomized to receive 60 mg by 24-hr infusion. The most common (>25%) AEs were euphoric mood (50%), ataxia (38%), & somnolence (38%). Efficacy data after C2 show that 3 patients in the 20 mg 3-hr infusion cohort in the Safety phase and 1 at the same dose & schedule in the Schedule Seeking phase had ≥50% decrease in BM blasts after C2, which was not seen in the 60 mg 24-hr infusion cohort. There were no CRs. There was a single death by D28 (24-hr infusion). There were significant differences in PK by infusion schedule. Conclusions: MTD for Ob as a 3-hr infusion administered in older patients with AML on 3 consecutive days is 20 mg/day, and both this regimen and 60 mg as a 24-hr infusion x 3 days were well tolerated. Evidence of biological activity was seen with the 3-hr infusion schedule but not with the 24-hr infusion schedule, suggesting that efficacy may be improved with the 3-hr infusion schedule and may be related to PK differences. [Table: see text]
A phase I trial of GMX1777, an inhibitor of nicotinamide phosphoribosyl transferase (NAMPRT), given as a 24-hour infusion
Authors: Pishvaian M. J. , Marshall J. L. , Hwang J. J. , Malik S. , He A. R. , Deeken J. F. , Kelso C. B. , Cotarla I. , Berger M. S. 
Published: August 2020

3581 Background: GMX1777 is a pro-drug which converts to GMX1778, a potent and specific small molecule inhibitor of NAMPRT, the rate-limiting enzyme in NAD+ synthesis. NAMPRT activity is increased in tumor cells dependent on the glycolytic pathway. The aims of this first-in-man study were to define a dose of GMX1777 administered by 24-hr infusion with acceptable safety for phase II studies, and to determine the pharmacokinetic (PK) parameters of both GMX1777 and GMX1778. Methods: GMX1777 was administered at ascending doses as a 24 hour IV infusion q21 days to successive cohorts of patients with advanced malignancies. Single patient cohorts were utilized until a toxicity >Grade (Gr) 1 was observed during cycle (C) 1; then a standard 3+3 dose escalation schema was used. PK samples were drawn during C1. Results: 19 patients (11 males; median age 57) received doses of 60, 120, 160, 200 or 140 mg/m2 over 24 hours. 49 doses were administered. There were no toxicities >Gr 1 during C1 at 60 mg/m2; however Gr 2 toxicities were observed at 120 mg/m2 and the cohort was expanded to 3 patients. Gr 4 GI hemorrhage and Gr 4 thrombocytopenia occurred at 200 mg/m2, leading to expansion of the 160 mg/m2 cohort. 3/6 patients at 160 mg/m2 had erythematous symmetrical Gr 3 rash occur during C2–5. Six patients enrolled at 140 mg/m2 had no Gr 3 rash and 140 mg/m2 was determined to be the MTD. Preliminary data indicate that the most common (>30%) adverse events of all grades were nausea (89%), diarrhea (79%), fatigue (68%), vomiting (58%), anorexia (42%), pruritis (42%), thrombocytopenia (42%), rash (37%), anemia (32%), constipation (32%), dyspnea (32%), and insomnia (32%). Lab findings include lymphopenia. Two patients had stable disease for > 4 cycles (6 & 4 mos), and 3 additional patients had SD for ≥ 3 mos. Preliminary PK data document rapid conversion of GMX1777 to GMX1778 at all dose levels. Conclusions: The MTD for GMX1777 administered as a 24 hour infusion q21 days is 140 mg/m2. Thrombocytopenia, GI hemorrhage, and skin rash (the last occurring after multiple cycles) were encountered at higher doses. Single-agent GMX1777 exhibited moderate clinical activity, suggesting that inhibition of NAMPRT should be explored in other schedules or in combination with other agents. [Table: see text]
Pharmacogenetic analysis in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line irinotecan (IR)+/− cetuximab (CB): The EPIC experience
Authors: Yang D. , Pohl A. , Zhang W. , Lurje G. , Ning Y. , El-Khoueiry A. , Khambata-Ford S. , Langer C. , Iqbal S. , Lenz H. 
Published: August 2020

4022 Background: EPIC, a multinational phase III clinical trial with IR + CB vs IR alone in mCRC pts in the second-line setting after failure of FOLFOX demonstrated a benefit for IR+CB in progression-free survival (PFS) and response rate (RR). We evaluated functional germline polymorphisms involved in the EGFR- (EGF, EGFR), angiogenesis- (VEGF, IL-8, CXCR-2) - and drug- metabolism related genes (UGT1A1, MTHFR) for their potential role as molecular predictors for clinical outcome in pts treated with CB/IR vs. IR alone. Methods: DNA was extracted from all available formalin-fixed paraffin-embedded tumor samples from the phase III EPIC trial (US sites only). Genotyping was performed using PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols. Results: 186 pts were treated either with IR/CB (arm A, 84 pts) or IR (arm B, 102 pts) only. In arm A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts (94%) had SD or PD. Median PFS in arm A was 3.0 months (95%CI: 2.4- 4.1 months) vs 2.7 months (95%CI: 2.2–2.9 months) in arm B; median overall survival (OS) was 9.3 months (95%CI: 7.1–12.1 months) in arm A vs. 12.3 months (95%CI: 10.4- 17.9 months) in arm B. K-ras mutation status was not significantly associated with PFS or response to CB/IR in the subgroup of 186 patients. We found an EGFR-CA- repeat in intron 1 in arm A to be associated with PFS (p=0.031, log-rank test). In arm B, we found a significant association with RR (p=0.0103, Fisher's exact test) for MTHFR1298. Furthermore, MTHFR 677 (p =0.0048, log-rank test) and MTHFR 1298 (p=0.038, log-rank test) were also found to be associated with OS in arm B. In multivariate analysis, EGFR-CA-repeat was significantly associated with PFS (adjusted p= 0.023). Furthermore, MTHFR 677 and MTHFR 1298 was associated with OS (adjusted p=0.028 and 0.026, respectively, Cox-proportional hazards models), independent from K-ras mutation status, race and number of disease sites. Conclusions: Our study demonstrates the potential predictive value of polymorphisms in the EGFR- and MTHFR- gene in mCRC pts treated with IR+ CB. Further validation in additional clinical trials is necessary. [Table: see text]
TYMS genotype-directed neoadjuvant chemoradiation for rectal cancer
Authors: McLeod H. L. , Myerson R. J. , Zehnbauer B. , Trinkaus K. , Malyapa R. S. , Mutch M. G. , Abbey E. E. , Alyasiry A. , Fleshman J. W. , Tan B. R. 
Published: August 2020

4028 Background: Downstaging (DS) of rectal cancers is achieved in 45% of pts with neoadjuvant 5FU and radiation (XRT). A 28bp repeats in the thymidine synthase gene (TYMS) appears to define disparate DS rates (60% vs 22%). We conducted a prospective single-institution Phase II study using TYMS genotyping to direct neoadjuvant chemoRT for pts with rectal cancer. Methods: Pts with T3/ T4, N0–2, M0–1 rectal adenocarcinoma staged with transrectal ultrasound (TRUS) or CT/MRI are eligible. After informed consent is obtained, pts with TYMS *2/*2, *2/*3, or *2/*4 (Good-risk) are treated with 50.4 Gy 3-D XRT and 5FU continuous infusion at 225 mg/m2/d throughout XRT. Patients with TYMS *3/*3 or *3/*4 (Bad-risk) are treated with 5FU and XRT plus irinotecan at 50 mg/m2 IV weekly x 5. Pts underwent restaging and resection 6–10 weeks after therapy. The 1o endpoints are DS and pathologic complete response (pCR) rates. 2o endpoints include toxicity, recurrence rates and OS. Adjuvant therapy was directed by the pt's physician. The study was powered to ascertain whether DS was significantly >45% in ‘good risk‘ patients and >22% in ‘bad risk‘ patients. Results: Overall, 135 pts (median age 56, range 26–85; M:F 2:1; black-18, white-119) are enrolled, of which 27.4% (37/135) are ‘bad risk‘. DS, pCR and toxicity rates were evaluable in 121 patients and are shown below. The rate of DS met the a priori criteria for significance for both the ‘good risk‘ and ‘bad risk‘ groups. 1 death/1 perforation was observed in each group. Conclusions: This is the first study to prospectively use TYMS genotyping to direct neoadjuvant chemoXRT in pts with rectal cancer. The high efficacy of 5FU/XRT in ‘good risk‘ pts was prospectively confirmed. High rates of DS and pCR were also achieved among ‘bad risk‘ pts with the addition of irinotecan to neoadjuvant 5FU/XRT. These results are encouraging for the conduct of a randomized study of genotype-guided neoadjuvant therapy for locally advanced rectal cancer. [Table: see text] [Table: see text]
Outcome of colon cancer patients with synchronous metastases
Authors: Sobhani I. , Roudot-Thoraval F. , Mesli F. , Landi B. , Aparicio T. , Louvet C. , DesGuetz G. , Mitry E. 
Published: August 2020

4029 Background: Metastatic colon cancer patients may undergo chemotherapy without colon surgery. However, the outcome of patients has not been evaluated and antiagiogenic agents can not be given. The aim of the present cohort study was to analyse factors influencing patients’ survival. Methods: Consecutive patients [N=228, mean age (sd) 64 (12) yrs, median follow-up 20 mths;84 females] treated in 6 teaching hospitals received chemotherapy for metastatic colonic cancer, either as the first step, or after surgery. Progressive free survival (PFS) was estimated using Kaplan-Meïer method. Factors associated with PFS were tested by means of Log rank test and results are presented in terms of medians of survival (95% CI). Factors independently related to PFS were tested using a Cox model and results are presented as hazard ratio. Results: 105 patients with colon cancer and synchronous metastatsis underwent colon surgery prior to chemotherapy (68 males, mean age 64 yrs) when 123 patients were treated first by chemotherapy ± biotherapy (76 males, mean age 63 yrs). By univariate analysis, following factors were significantly associated with PFS: surgery first 25.5 (18.6 - 32.5) vs chemotherapy first 18.3 (14.7 - 21.9) mths p = 0.006; curative surgery: yes 35.7 (29.6 - 41.8) vs no 18.4 (15.6 - 21.2) mths p < 0.001; tumour histological differentiation : no : 13.4 (6.2 - 20.6) vs well : 24.7 (20.4 - 29.1) mths p<0.001; synchronous metastases: liver only 25.5 (20.5 - 30.6) vs peritonea&nodes : 18.4 (10.6 - 26.1) vs pulmonary & other sites : 16.5 (14.7 - 18.3) mths p < 0.0001; need for colonic stent: yes 16.4 (9.3 - 23.5) vs no 23.9 (21.1 - 26.7) months p < 0.0001; antiangiogenic drug: yes 36.6 (28.7 - 44.5) vs no : 20.7 (18.3 - 23.1) p = 0.033. After Cox multivariate analysis five independent factors were found to be associated with PFS. Conclusions: Colon surgery before chemotherapy plus bevacizumab appears to be the more appropriate choice, and associated with longer PFS, especially for those patients with well differentiated tumours and synchronous liver metastases. [Table: see text] No significant financial relationships to disclose.
Polypectomy or surgery for malignant colonic polyps: Do we need to change the NCCN guidelines?
Authors: Wasif N. , Tomlinson J. S. , Maggard M. A. , Giuliano A. E. , Ko C. Y. 
Published: August 2020

4031 Background: Colonoscopic screening and appreciation of the adenoma-carcinoma sequence have led to increased detection and removal of colonic polyps. The National Comprehensive Cancer Network (NCCN) considers polypectomy alone to be adequate therapy for low-grade invasive T1 polyps that are limited to the head/stalk region and can be excised with negative margins. We examined the implications of this guideline for the general population. Methods: The National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database (1988–2003) was queried to identify patients with invasive T1 colonic polyps. Patients treated with a polypectomy (PP) were compared with those who received a surgical resection (SR). Results: Of 9,162 patients with invasive T1 colonic polyps, 61.6% (11,812) underwent SR and 38.4% (7,350) underwent PP. The percentage of polyps removed increased from 4.2% (812) in 1988 to 9% (1739) in 2003. Patients undergoing SR vs. PP had larger polyps (median size 1.3 vs. 1.0 cm, p <0.001) and higher grade tumors (8.6% vs. 4.7%, p <0.001). The percentage of node positivity was 7% after SR, or 8.9% if at least 12 nodes were resected. The percentage of node positivity reached a surprising 6% in 1,478 patients who underwent SR for low-grade polyps limited to the head/stalk, and nodal status significantly affected the 3-year disease-specific survival of this subgroup: 83% with nodal metastases vs. 96% without nodal metastases (p < 0.003). Conclusions: Malignant colonic polyps with favorable histological features have a 6% risk of lymph node metastases even when removed with negative margins, bringing into question the NCCN recommendation that PP alone is adequate therapy. No significant financial relationships to disclose.