Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09).

BACKGROUND: Cutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision. METHODS: Participants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity. RESULTS: The trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009-2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03-2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study. CONCLUSION: Due to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

Hypofractionated or Conventionally Fractionated Adjuvant Radiotherapy After Regional Lymph Node Dissection for High-Risk Stage III Melanoma.

AIMS: Adjuvant radiotherapy can be beneficial after regional lymph node dissection for high-risk stage III melanoma, as it has been shown to reduce the risk of recurrence in the node field. However, the optimal fractionation schedule is unknown and both hypofractionated and conventionally fractionated adjuvant radiotherapy are used. The present study examined the oncological outcomes of these two approaches in patients treated in an era before effective systemic immunotherapy became available. MATERIALS AND METHODS: This retrospective cohort study involved 335 patients with stage III melanoma who received adjuvant radiotherapy after therapeutic regional lymph node dissection for metastatic melanoma between 1990 and 2011. Information on tumour characteristics, radiotherapy doses and fractionation schedules and patient outcomes was retrieved from the institution's database and patients' medical records. RESULTS: Hypofractionated radiotherapy (median dose 33 Gy in six fractions over 3 weeks) was given to 95 patients (28%) and conventionally fractionated radiotherapy (median dose 48 Gy in 20 fractions over 4 weeks) to 240 patients (72%). Five-year lymph node field control rates were 86.0% (95% confidence interval 78.4-94.4%) for the hypofractionated group and 85.5% (95% confidence interval 80.5-90.7%) for the conventional fractionation group (P = 0.87). There were no significant differences in recurrence-free survival (RFS) (41.7%, 95% confidence interval 32.5-53.5 versus 31.9%, 95% confidence interval 26.1-38.9; P = 0.18) or overall survival (41.2%, 95% confidence interval 32.1-52.8 versus 45.0%, 95% confidence interval 38.7-52.4; P = 0.77). On multivariate analysis, extranodal spread was associated with decreased RFS (P = 0.04) and the number of resected lymph nodes containing metastatic melanoma was associated with decreased RFS (P = 0.0006) and overall survival (P = 0.01). CONCLUSION: Lymph node field control rates, RFS and overall survival were similar after hypofractionated and conventionally fractionated adjuvant radiotherapy. The presence of extranodal spread and an increasing number of positive lymph nodes were predictive of an unfavourable outcome.

[Determination of the block range of ultrasound-guided lumbar erector spinal plane and its application in lumbar spine surgery].

Objective: To determinate the block range of lumbar erector spinal plane (ESPB), and investigate the efficacy of ESPB in lumbar spine surgery. Methods: Forty patients who underwent posterior lumbar fusion in the Second Affiliated Hospital of Wenzhou Medical University from November 2019 to August 2020 were randomly divided into two groups (with n=20 in each group) using the random number table: the experimental group (group E) and control group (group C). All the patients received ultrasound-guided bilateral ESPB with 20 ml of 0.375% ropivacaine (group E) or equal volume of normal saline (group C) on each side before induction of general anesthesia. The range of weakened temperature sense in each patient was measured at 10 min, 20 min and 30 min after ESPB, respectively. Dosage of analgesic drug, visual analog scale (VAS), and incidence of adverse events were recorded and compared between the two groups. Results: In group E, the dermatomal distribution and area of weakened temperature sense at 10 min, 20 min, 30 min after ESPB were T9-S1 (222±16) cm2, T8-S2 (352±22) cm2, T8-S3 (481±24) cm2, respectively. The intraoperative dosage of remifentanil in group E was (0.76±0.02) mg, which was significantly lower than that of group C (0.97±0.06) mg (P<0.05). Oxycodone consumption in group E at 0-12 h and 12-24 h after surgery was (4.9±0.4) mg and (8.4±1.2) mg, respectively, which were lower than those in group C [(14.5±2.4) mg and (19.3±2.4) mg, respectively] (both P<0.05). The VAS during rest and movement within 24 h after operation in group E were significantly lower than those in group C (both P<0.05). The passive exercise in bed in group E started at (3.3±0.3) h postoperatively, which was earlier than that in group C (4.6±0.3) h (P<0.05). Conclusion: The blocking effects of T12-S1 segment after ultrasound-guided lumbar ESPB is definite, which can effectively decrease the amounts of analgesics during and after the lumbar fusion surgery, reduce postoperative rest and exercise VAS score, and contribute to a rapid recovery of the patients.

Desmoplastic melanoma: a review of its pathology and clinical behaviour, and of management recommendations in published guidelines.

Desmoplastic melanomas are uncommon. Their behaviour differs from that of other melanoma subtypes; therefore, management guidelines for non-desmoplastic melanomas may not be applicable. This review sought to examine all available evidence relating to the behaviour and management of desmoplastic melanomas, based on review of all relevant English-language publications, and to critically assess the recommendations for their management in current published melanoma management guidelines. Compared with other melanoma subtypes, patients with 'pure' desmoplastic melanomas (where ≥90% of the invasive melanoma is of desmoplastic melanoma subtype) have much lower rates of sentinel node positivity and distant metastasis. Local recurrence rates are higher for desmoplastic melanomas, but resection margins wider than those recommended for non-desmoplastic melanomas have not been shown to be of benefit. Adjuvant radiotherapy reduces the risk of local recurrence when a satisfactory histological clearance (≥8 mm) cannot be achieved. Of 29 published melanoma management guidelines identified, only 11 specified management for desmoplastic melanomas, while seven simply stated that the feature should be reported. Desmoplastic melanoma is a unique melanoma subtype with biology that differs from that of other melanoma subtypes. It requires specific management strategies but few current guidelines address these.

Radiation Therapy as an Alternative Treatment for Desmoid Fibromatosis.

AIM: To determine the outcome after radiation therapy for desmoid fibromatosis. MATERIALS AND METHODS: A retrospective review of 50 patients treated between 1988 and 2016 in a specialised bone and soft tissue tumour clinic. RESULTS: The median age at the time of radiation therapy was 36.8 years (range 15.1-69.0) and the median follow-up time was 51 months. Forty-three patients underwent radiation therapy as the definitive treatment with a median dose of 56 Gy (range 30-58.8 Gy). The median dose for the seven patients treated with postoperative radiation therapy was 50.4 Gy (range 48-56 Gy). Eleven patients (22%) developed progressive disease after radiation therapy at a median time of 41 months (range 12-113 months). The recurrences were within the radiation therapy field in four patients and outside the field in seven patients. One patient developed a radiation-induced malignancy 20 years after treatment. CONCLUSIONS: Radiation therapy is an alternative treatment in the management of desmoid fibromatosis. It should be considered in patients for whom surgical resection is not feasible, or as adjuvant therapy after surgery with involved margins where any further recurrences would cause significant morbidity.

Limb preservation surgery with extracorporeal irradiation in the management of malignant bone tumor: the oncological outcomes of 101 patients.

BACKGROUND: En bloc resection, extracorporeal irradiation (ECI) and reimplantation have been used selectively at our centers as part of limb preservation surgery of malignant bone tumors since 1996. We report the long-term oncological outcomes. PATIENTS AND METHODS: One hundred one patients were treated with ECI at two Australian centers between 1996 and 2011. A single dose of 50 Gy was delivered to the resected bone segments. The irradiated bones were reimplanted immediately as a biological graft. Patients were treated with chemotherapy as per standard protocol. The three main histological diagnoses were Ewing's sarcoma (35), osteosarcoma (37) and chondrosarcoma (20). There were nine patients with a range of different histologies. RESULTS: There was one local recurrence (2.86%) in Ewing's sarcoma and the 5-year cumulative overall survival was 81.9%. There was no local recurrence in osteosarcoma and five distant recurrences. The 5-year cumulative overall survival was 85.7%. The local recurrence rate was 20% (4 of 20) in chondrosarcoma, and the 5-year cumulative overall survival was 80.8%. Limb preservation was achieved in 97 patients. For the 64 patients with disease in the pelvis or lower limb, 53 (82.3%) could walk without aids at the time of last follow-up. CONCLUSIONS: This large series of ECI shows an excellent long-term local control. It is a good alternative reconstruction method in selected patients. The overall survival is comparable to other published series.

Human papillomavirus modifies the prognostic significance of T stage and possibly N stage in tonsillar cancer.

BACKGROUND: Despite the association with more advanced nodal stage, patients with human papillomavirus (HPV) positive oropharyngeal cancers have better outcomes. We examined whether the HPV can modify the effect of known prognostic factors in tonsillar cancer. PATIENTS AND METHODS: A total of 489 patients from 10 centres were followed up for recurrence or death for a median of 3.2 years. Determinants of the rate of locoregional recurrence, death from tonsillar cancer and overall survival were modelled using Cox regression. RESULTS: The prognostic value of T and N stages were modified by HPV as indicated by statistically significant interaction terms. After adjusting for age, gender and treatment, T stage appeared relevant only for HPV-positive cancers (where a higher T stage was associated with worse outcomes). There was some evidence that N stage was a more relevant prognostic factor for HPV-negative than -positive cancers. There was no evidence that the HPV modifies the effect of age, gender or grade on outcomes. CONCLUSIONS: This study suggests that the prognostic significance of the conventional staging system in tonsillar cancer is modified by HPV.

Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy.

OBJECTIVE: This study examines the prognostic significance of human papillomavirus (HPV) in patients with locally advanced oropharyngeal squamous cell carcinoma (SCC) treated primarily with surgery or definitive radiotherapy. METHODS: One hundred and ninety-eight patients with Stage 3/4 SCC were followed up for recurrence in any form or death from any cause for between 1 and 235 months after diagnosis. HPV status was determined using HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. Determinants of recurrence and mortality hazards were modelled using Cox's regression with censoring at follow-up dates. RESULTS: Forty-two per cent of cancers were HPV-positive (87% type 16). HPV predicted loco-regional control, event-free survival and overall survival in multivariable analysis. Within the surgery with adjuvant radiotherapy (n=110), definitive radiotherapy-alone (n=24) and definitive radiotherapy with chemotherapy (n=47) groups, patients with HPV-positive cancers were one-third or less as likely to have loco-regional recurrence, an event or to die of any cause as those with HPV-negative cancers after adjusting for age, gender, tumour grade, AJCC stage and primary site. The 14 patients treated with surgery alone were considered too few for multivariable analysis. CONCLUSION: HPV status predicts better outcome in oropharyngeal cancer treated with surgery plus adjuvant radiotherapy as well as with definitive radiation therapy±chemotherapy.

Detection of unsuspected spinal cord compression in melanoma patients by 18F-fluorodeoxyglucose-positron emission tomography.

AIM: Positron emission tomography (PET) using (18)F-fluorodeoxyglucose can detect early or small metastatic deposits of melanoma and guide subsequent correlative anatomical imaging and treatment. The aim of this study was to assess the value of PET in demonstrating spinal cord compression by otherwise unsuspected metastatic disease. METHODS: Reports of 1365 PET studies performed on patients with melanoma were reviewed. Fifty patients considered to be at risk of spinal cord compression on the basis of PET were identified and 35 patients were analysed. Magnetic resonance imaging and computed tomography were used to confirm or refute the diagnosis. The symptoms and signs at the time of PET and follow-up status were compared between patients with and without confirmed spinal cord compression. RESULTS: In nine patients (26%) compression of the spinal cord or adjacent neurological structures was confirmed and eight of these patients had immediate treatment. Survival was poor in both patient groups, but three patients with confirmed compression maintained good neurological functional status following treatment. CONCLUSION: PET can detect imminent, unsuspected spinal cord compression in patients with metastatic melanoma. Immediate anatomical imaging of the spine is recommended in patients who have evidence of spinal cord compression on PET.

Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction.

BACKGROUND: Patients with hepatic or renal dysfunction are often treated with 5-fluorouracil (5-FU), but there are few data to confirm the safety of this practice. PATIENTS AND METHODS: Patients with solid tumors were eligible if they were able to fit into one of three organ dysfunction cohorts: I, creatinine >1.5 but < or =3.0 mg/dl and normal bilirubin; II, bilirubin >1.5 but <5.0 mg/dl with normal creatinine; or III, bilirubin > or =5.0 mg/dl with normal creatinine. 5-FU doses were escalated separately within each of the three cohorts. Leucovorin (LV) dosage was fixed at 500 mg/m(2). 5-FU was given as a 24-h infusion at 1000, 1800 or 2600 mg/m(2), and plasma concentrations were measured every 3 h during the first two infusions for each patient. RESULTS: Sixty-four patients were treated. Toxicities did not appear to be related to organ dysfunction cohort. A weekly dose of of 5-FU 2600 mg/m(2) produced dose-limiting toxicity (DLT) in six of 20 evaluable patients. These DLTs included grade 3 fatigue (n = 3), grade 2 neutropenia precluding weekly dosing (n = 1), grade 3 thrombocytopenia (n = 1) and grade 3 mental status changes (n = 1). There was no relationship between serum bilirubin or serum creatinine and 5-FU clearance. CONCLUSIONS: Patients with elevated bilirubin may be safely started on a weekly regimen of 5-FU 2600 mg/m(2) with leucovorin 500 mg/m(2) as a 24-h continuous infusion.

Carotid sinus syndrome secondary to head and neck malignancy: case report and literature review.

We report two cases of carotid sinus syndrome secondary to head and neck malignancy. The underlying mechanisms unique to head and neck malignancy and treatments of the syndrome are discussed.

Genomic cloning and promoter analysis of aortic preferentially expressed gene-1. Identification of a vascular smooth muscle-specific promoter mediated by an E box motif.

Aortic preferentially expressed gene-1 (APEG-1) was originally identified as a 1.4-kilobase (kb) transcript preferentially expressed in differentiated vascular smooth muscle cells (VSMC). Its expression is markedly down-regulated in de-differentiated VSMC, suggesting a role for APEG-1 in VSMC differentiation. We have now determined that APEG-1 is a single-copy gene in the human, rat, and mouse genomes and have mapped human APEG-1 to chromosome 2q34. To study the molecular mechanisms regulating its expression, we characterized the genomic organization and promoter of mouse APEG-1. APEG-1 spans 4.5 kb in the mouse genome and is composed of five exons. Using reporter gene transfection analysis, we found that a 2. 7-kb APEG-1 5'-flanking sequence directed a high level of promoter activity only in VSMC. Its activity was minimal in five other cell types. A repressor region located within an upstream 685-base pair sequence suppressed the activity of this 2.7-kb promoter. Further deletion and mutation analyses identified an E box motif as a positive regulatory element, which was bound by nuclear protein prepared from VSMC. In conjunction with its flanking sequence, this E box motif confers VSMC-specific enhancer activity to a heterologous SV40 promoter. To our knowledge, this is the first demonstration of an E box motif that mediates gene expression restricted to VSMC.

Preclinical evaluation of chimeric L6 antibody for the treatment of Kaposi's sarcoma with radioimmunotherapy.

L6 is a murine IgG2a monoclonal antibody with panadenocarcinoma reactivity. Chimeric L6 (ChL6), the variable region of murine L6 combined with a human IgG1 constant region, has been used in clinical trials for the delivery of radioimmunotherapy to patients with breast cancer. AIDS-associated Kaposi's sarcoma (KS), a malignancy of vascular endothelium, may be an excellent candidate for systemic radioimmunotherapy because KS is well vascularized and radioresponsive. Because ChL6 has been noted to bind vascular endothelium, our hypothesis was that ChL6 will recognize and bind KS tumors making this a potentially useful antibody for the treatment of KS with radioimmunotherapy. To test this hypothesis, 4 human KS spindle cell cultures established from cutaneous punch biopsy specimens (KS-MR, KS-NO, KS-JD and KS 6-3E) and one well-characterized human KS cell line (KS Y-1) were assessed for L6 immunoreactivity. All 5 cell cultures were L6 positive by immunohistochemistry. KS Y-1 cells grown as nude mouse xenografts were also L6 positive by immunohistochemistry. Competitive binding assays performed on the KS Y-1 and KS 6-3E cell cultures showed high density and high affinity cell binding. Biodistribution experiments performed on nude mice with KS Y-1 xenografts demonstrate tumor targeting by ChL6. These findings indicate that ChL6 may be a useful antibody for the radioimmunotherapy of KS. Future experiments will assess the therapeutic efficacy of radiolabeled ChL6 with and without concurrent systemic radiosensitizing chemotherapy.