Characterization and management of ERK inhibitor associated dermatologic adverse events: analysis from a nonrandomized trial of ulixertinib for advanced cancers.

Background Ulixertinib is the first-in-class ERK1/2 kinase inhibitor with encouraging clinical activity in BRAF- and NRAS-mutant cancers. Dermatologic adverse events (dAEs) are common with ulixertinib, so management guidelines like those established for epidermal growth factor receptor inhibitor (EGFRi)-associated dAEs are needed. Patients and Methods This was an open-label, multicenter, phase I dose escalation and expansion trial of ulixertinib evaluating data from 135 patients with advanced malignancies enrolled between March 2013 and July 2017. Histopathological features, management, and dAEs in 34 patients are also reported. Twice daily oral ulixertinib was administered at 10 to 900 mg in the dose escalation cohort (n = 27) and at 600 mg in 21-day cycles in the expansion cohort (n = 108). Results The incidence of ulixertinib-induced dAEs and combined rash were 79% (107/135) and 76% (102/135). The most common dAEs included acneiform rash (45/135, 33%), maculopapular rash (36/135, 27%), and pruritus (34/135, 25%). Grade 3 dAEs were observed in 19% (25/135) of patients; no grade 4 or 5 dAEs were seen. The presence of at least 1 dAE was associated with stable disease (SD) or partial response (PR) (OR = 3.64, 95% CI 1.52-8.72; P = .003). Acneiform rash was associated with a PR (OR = 10.19, 95% CI 2.67-38.91; P < .001). Conclusion The clinical spectrum of ulixertinib-induced dAEs was similar to EGFR and MEK inhibitors; dAEs may serve as a surrogate marker of tumor response. We propose treatment algorithms for common ERK inhibitor-induced dAEs to maintain patients' quality of life and dose intensity for maximal clinical benefit. Clinical Trial Registration: NCT01781429.

Obesity but not high-fat diet impairs lymphatic function.

BACKGROUND/OBJECTIVES: High-fat diet (HFD)-induced obesity has significant negative effects on lymphatic function, but it remains unclear whether this is a direct effect of HFD or secondary to adipose tissue deposition. METHODS: We compared the effects of HFD on obesity-prone and obesity-resistant mice and analyzed lymphatic function in vivo and in vitro. RESULTS: Only obesity-prone mice had impaired lymphatic function, increased perilymphatic inflammation and accumulation of lipid droplets surrounding their lymphatic endothelial cells (LECs). LECs isolated from obesity-prone mice, in contrast to obesity-resistant animals, had decreased expression of VEGFR-3 and Prox1. Exposure of LECs to a long-chain free fatty acid increased cellular apoptosis and decreased VEGFR-3 expression, while inhibition of intracellular inhibitors of VEGFR-3 signaling pathways increased cellular viability. CONCLUSIONS: Collectively, our studies suggest that HFD-induced obesity decreases lymphatic function by increasing perilymphatic inflammation and altering LEC gene expression. Reversal of diminished VEGFR-3 signaling may rescue this phenotype and improve lymphatic function.

Vertebral osteoid osteoma masquerading as a malignant bone or soft-tissue tumor on MRI.

PURPOSE: Four pediatric patients were sent to our institution with the diagnosis of soft-tissue/malignant bone tumor. In all cases an MRI was the initial study performed for neck or back pain. All were surgically proven to have an osteoid osteoma/osteoblastoma (OO) as a final diagnosis. The MRI findings are reviewed. METHODS: Four patients, three boys and one girl, ranging in age from 5 to 17 years, presented with symptoms of neck or back pain for 2 months to 2 years. Two had neurological findings. All patients underwent MRI. RESULTS: All MRIs demonstrated decreased T1 signal and increased T2 signal in the soft tissues and bone surrounding the lesions consistent with edema. Enhancement was observed in the adjacent soft tissues and in the lesion nidus retrospectively. CONCLUSION: Investigating neck or back pain with an initial MRI may lead to misleading diagnoses unless the radiologist is aware of the typical MRI appearance of vertebral osteoid osteoma.

Etoposide in combination with cyclophosphamide and total body irradiation or busulfan as conditioning for marrow transplantation in adults and children.

PURPOSE: In an attempt to intensify conditioning therapy for bone marrow transplantation of hematologic malignancies, a retrospective three center evaluation of escalating doses of etoposide added to cyclophosphamide and either total body irradiation or busulfan was undertaken. METHODS AND MATERIALS: Seventy-six patients who received etoposide (25-65 mg/kg) added to cyclophosphamide (60-120 mg/kg) and either total body irradiation (12.0-13.2 Gy) or busulfan (12-16 mg/kg) were evaluable for toxicity. Fifty-one of the evaluable patients received allogeneic transplants, while twenty-six received autologous transplants. A comparative analysis of toxicities according to conditioning regimen, donor source and etoposide dose was made. RESULTS: Similar toxicities were observed among the treatment groups with the exception of more frequent skin (p = 0.003) and life threatening hepatic toxicities (p = 0.01) in the busulfan treated patients. Life threatening or fatal toxicities were not influenced by donor source, either when analyzed by treatment group or etoposide dose. Etoposide at a dose of 60-65 mg/kg in combination with TBI and cyclophosphamide was associated with a significantly increased incidence of life threatening or fatal toxicities compared with a combination using a dose of 25-50 mg/kg (15 of 24 vs. 5 of 20; p = 0.013). The maximally tolerated dose of etoposide in combination with busulfan and cyclophosphamide cannot be definitively established in this analysis in part due to the heterogeneity of the patient population and treatment schemes. CONCLUSION: Although toxicities with bone marrow transplant preparative regimens containing etoposide in combination with cyclophosphamide and total body irradiation or busulfan were frequently severe, treatment related mortality risk was believed to be acceptably low.

Treatment of malignant fibrous histiocytoma of the heart.

Primary soft tissue sarcoma of the heart is encountered infrequently in clinical practice. Treatment is reported of an intracardiac malignant fibrous histiocytoma, consisting of maximal surgical resection followed by 5600 cGy of conventionally fractionated radiation therapy. Transesophageal echocardiograms done during follow-up were useful in assessing tumor control. Aspects of patient care are discussed in conjunction with a review of the available literature.

Radiotherapy of malignant subdiaphragmatic implants in advanced ovarian carcinoma: a new technique.

We report the development of a new technique using remote afterloading intraoperative radiation therapy to deliver a tumoricidal dose to diaphragmatic tumor implants. A multi-positional lucite applicator was designed based on anatomic studies of the diaphragmatic surface to accommodate a high dose rate iridium source in a series of needles placed 1.5 cm apart. The applicator curvature can vary from planar to full accommodation of the diaphragmatic surface with a constant source to surface distance of 0.5 cm. The applicator has been piloted in three patients with ovarian carcinoma with residual subdiaphragmatic disease found at second look laparotomy, to deliver a dose of 1,500 to 2,000 cGy at 0.5 cm. Tolerance of the diaphragm and hepatic surface has been excellent. There were no postoperative complications and no deterioration in liver function studies. The additional postoperative external beam irradiation directed with the aid of surgically placed clips and gated to respiratory movements permits achievement of a tumoricidal dose while limiting the treated volume and related toxicities.

Lack of protective effect of thromboxane synthetase inhibitor (CGS-13080) on single dose radiated canine intestine.

The effect of a thromboxane A2 synthetase inhibitor (CGS-13080) on canine intestine was studied using a single dose of radiation, and radioactive microspheres were used to determine resultant blood flow. Thromboxane A2 causes vasospasm and platelet aggregation and may play a dominant role in radiation injury. However, there was no effect on the intestinal blood flow diminution occurring after radiation in this laboratory model using this thromboxane A2 synthetase inhibitor.

Choledochal cyst and biliary atresia in the neonate: imaging findings in five cases.

The radiologic findings in five neonates with choledochal cyst associated with extra-hepatic biliary atresia are described. All five patients (age range, 13-72 days) presented with jaundice and acholic stools. In all four patients who underwent sonographic examination, a cystic structure separate from the gallbladder representing the choledochal cyst was shown. The diagnosis of atresia of the distal common bile duct was made preoperatively in all cases by hepatobiliary scintigraphy. Diagnosis was confirmed by surgical findings and was demonstrated by intraoperative cholangiography in four cases. All patients were successfully treated with surgical intervention within 1 month from the time of diagnosis. Early detection of this rare disorder, which may be distinct from choledochal cyst found in children and adults, is important to prevent fatal complications of biliary obstruction. The combined use of sonography and hepatobiliary scintigraphy can correctly identify this subset of patients with persistent neonatal jaundice and provide valuable information for prompt surgical management.

A randomized study of the efficacy of adjuvant local graft irradiation following renal transplantation.

A prospective randomized study investigating the effectiveness of adjuvant local graft irradiation (LGI) following renal transplantation was performed at Georgetown University Hospital from 1983 until 1988. One hundred and thirty-eight patients were enrolled in the study with 117 patients receiving cadaver kidney transplantations and 21 patients receiving living related kidney transplantations. Seventy-one patients were randomized to receive adjuvant local graft irradiation consisting of 600 cGy in four fractions with chemical immunosuppression whereas the remaining 67 patients received chemical immunosuppression only (control group). The two groups were comparable at entry with respect to potentially important prognostic variables. Median follow-up for all patients was 30 months. The 3-year actuarial allograft success rate was 75% and 68% for the local graft irradiation and control groups, respectively. A nonsignificant trend favoring the irradiated group was noted. Subgroup analysis of the 21 recipients of kidneys from living related donors suggested an improvement in allograft survival for the local graft irradiation arm. Cadaver allograft survival was not significantly different between the two treatment arms. There was no apparent benefit in kidney function or time to the first rejection episode in the group receiving local graft irradiation.

Hysterectomy with extended surgical staging and radiotherapy versus hysterectomy alone and radiotherapy in stage I endometrial cancer: a comparison of complication rates.

Extended surgical staging (ESS) has been added to total hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) in patients with clinical Stage I endometrial cancer in order to better define patterns of metastatic spread and the response to treatment. Adjuvant radiotherapy has a demonstrated efficacy in decreasing central recurrence in Stage I disease. The combined use of radical surgery and pelvic radiotherapy for cervical cancer patients results in an increased incidence of complications. This study compares major complication rates in Stage I endometrial cancer patients who underwent either TAHBSO with ESS or TAHBSO alone followed by adjuvant external beam radiotherapy (RT). Records of 52 patients with clinical stage I endometrial cancer were reviewed. Thirty-two patients underwent TAHBSO plus ESS and 20 patients had TAHBSO alone. All patients received postoperative, whole pelvis external radiotherapy. Four patients suffered complications potentially related to treatment which required rehospitalization, and all 4 were in the group which had undergone ESS. A comparison of complication rates between the ESS + RT group (4/37 or 10.8%) and TAHBSO + RT group (0/20) suggested a trend toward significance (P less than 0.10). Treatment protocols using extended surgical staging prior to adjuvant radiotherapy in Stage I endometrial cancer should examine complications potentially related to this combination, to further define treatment risks and benefits.

Postoperative adjuvant external-beam radiotherapy in surgical stage I endometrial carcinoma.

A combined surgical and radiotherapeutic approach is widely in Stage I endometrial adenocarcinoma. The technique and timing of the radiotherapy varies from center to center. Postoperative external-beam (EB) radiotherapy has the advantage of patient selection based upon surgical findings, comprehensive treatment of the pelvic nodal and vaginal cuff areas, and elimination of the need for an intracavitary procedure. Although frequently utilized, this technique is surprisingly poorly described in the medical literature. From 1979 to 1986, 46 surgical Stage I patients received adjuvant postoperative EB therapy at Georgetown University Hospital (GUH) (Washington, DC). Indications for treatment were Grade greater than or equal to 2 and/or depth of myometrial invasion of greater than 33%. The 5-year actuarial survival was 90% with a disease-free survival of 82%. The failure rate within the irradiated field was 6.5% with a distant failure rate of 8.7%. The rate of significant long-term complications was acceptable at 6.5%. The authors conclude that postoperative EB radiotherapy is an effective adjuvant therapy with results comparable to other available radiotherapeutic techniques.

Escalating doses of etoposide with cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation.

In a phase I study 28 patients with lymphohematopoietic malignancies were treated with escalating doses of etoposide combined with cyclophosphamide 120 mg/kg and either fractionated total body irradiation (TBI) 1320 cGy in 11 fractions (n = 17) or busulfan 16 mg/kg (n = 11). Twenty transplants were allogeneic, seven autologous and one syngeneic. The maximally tolerated dose of etoposide in combination with TBI and cyclophosphamide was 60 mg/kg; at etoposide doses of 65 mg/kg three patients developed life-threatening or fatal mucosal toxicity. In combination with busulfan, the maximally tolerated dose of etoposide was 30 mg/kg. At an etoposide dose of 40 mg/kg two patients developed life-threatening or fatal toxicity (one mucosal, one hepatic). Mucositis requiring narcotic analgesics, hepatotoxicity, hematologic toxicity and interstitial pneumonitis were otherwise similar in TBI and busulfan-treated patients. Skin toxicity was observed significantly more often in the busulfan group. Five deaths occurred before day +30, two in the TBI group and three in the busulfan group. Eleven patients are surviving, ten in continuous complete remission, at a median of 9 (range 3-23) months following transplantation. Etoposide in combination with TBI and cyclophosphamide or busulfan and cyclophosphamide is associated with significant but acceptable toxicities. The maximally tolerated dose of etoposide is higher when combined with TBI than with busulfan. Promising response rates in this high risk group of hematologic malignancies warrant further evaluation of these etoposide containing conditioning regimens.

Pulmonary fibrosis after bone marrow transplantation responsive to treatment with prednisone and cyclosporine.

Interstitial pneumonitis and biopsy-proven pulmonary fibrosis developed in a 35-year-old man with acute myeloblastic leukemia 4 months after conditioning with total body irradiation, etoposide and cyclophosphamide and allogeneic marrow transplantation from an HLA-identical sister. The patient had no evidence of graft-versus-host disease. Under treatment with cyclosporine and prednisone the patient became asymptomatic and radiographic changes of the chest normalized. Following discontinuation of immunosuppressive treatment the patient again became dyspneic, and chest radiographs showed bilateral diffuse interstitial infiltrates. Concurrently there was a rise in serum transaminases. Treatment with prednisone again resulted in resolution of all symptoms and normalization of radiographic and hepatic function abnormalities. This case indicates that late onset interstitial pneumonitis may respond to immunosuppressive therapy. Conceivably, such pulmonary disease may represent the first or only manifestation of chronic graft-versus-host disease.

Radiotherapy in the management of pancreatic islet cell tumors.

Malignant islet cell tumors are commonly treated with surgical resection. Chemotherapy is reserved for residual, unresectable, or metastatic disease. The role for radiotherapy has not been clearly defined. This article describes three cases of advanced islet cell tumors treated effectively with radiotherapy. This experience, in addition to that from other published reports, suggests that radiotherapy is a useful mode for treating advanced islet cell carcinoma.

The combined use of interferon and radiotherapy in cancer management.

Preclinical studies have suggested combination therapy with interferon and radiation results in an enhanced cytotoxic effect. Both additive and synergistic effects have been reported in mammalian cells in tissue culture. A phase I trial was designed to determine patient tolerance to concomitant Schering interferon alfa-2b (Intron A) and radiation therapy (RT). RT was delivered in standard fashion (five times a week in 180 rad fractions). Interferon was injected subcutaneously 2 hours prior to irradiation. Sixteen patients, divided into groups of three, received interferon at dose levels of 2 X 10(6) to 30 X 10(6) IU/m2 given five or three times a week. Planned dose escalations were stopped at 5 X 10(6) IU/m2 by patient tolerance. We observed a significant difference in tolerance to treatment between the patients receiving interferon three times a week and those receiving interferon five times a week. Eight of nine patients treated five times a week developed grade III-IV toxicity resulting in hospitalization and discontinuation of interferon; radiation was not discontinued. Only two of seven patients treated three times a week were hospitalized, with grade II toxicity (anorexia), but both were subsequently able to continue treatment with both interferon and radiation. We have identified a maximum tolerated dose and schedule of interferon (5 X 10(6) IU/m2 three times a week) for use in future combined modality trials to assess the potential clinical effectiveness of interferon in combination with RT.

Phase I combined modality clinical trial of alpha-2-interferon and radiotherapy.

Sixteen patients were enrolled in a Phase I study of the combined use of recombinant DNA alpha-2-interferon (IFN) and radiation therapy, conducted at the Georgetown University Hospital (GUH) from February 1, 1984 to September 20, 1985. Escalating IFN doses ranging from 2.0 X 10(6) IU/m2 to 5 X 10(6) IU/m2 were administered to groups of six patients per IFN dose level. Three patients at each dose level were treated on a 5-day-a-week schedule and three patients were treated on a 3-day-a-week schedule. Significant toxicity including dehydration, infection, deep vein thrombosis, and myocardial infarction was noted throughout in patients receiving IFN five times per week, with eight of nine requiring hospitalization during the treatment course. There was one treatment-related death. In the five-times-per-week group, only 22% of patients tolerated the full initially planned IFN dosage and 44% tolerated the full initially planned radiation dosage, compared to 100 and 86%, respectively, in the three-times-per-week group. A tolerance dose and schedule of 5.0 X 10(6) IU/m2 of alpha-2-interferon administered subcutaneously three-times-per-week in conjunction with standard radiotherapy has been identified for use in future combined modality trials.