John Spillane

Parathyroid hormone-related protein localization in breast cancers predict improved prognosis

In a prospective study of 526 consecutive patients with operable breast cancer, the significance of positive parathyroid hormone-related protein (PTHrP) staining by immunohistology has been evaluated for a median of 10-year follow-up. Improved survival was observed for the 79% of tumors which stained positively for PTHrP [estimated univariate hazard ratio, 0.43; 95% confidence interval (95% CI), 0.30-0.62; P < 0.001]. Adjustments for N stage, progesterone receptor status, and log tumor size changed this estimate only slightly to 0.47 (95% CI, 0.63-0.69; P = 0.001). Patients with PTHrP-positive primary tumors were less likely to develop bone metastases (hazard ratio, 0.63; 95% CI, 0.41-0.98; P = 0.04). PTHrP status was associated with estrogen receptor (P = 0.01), progesterone receptor (P = 0.03), and menopausal status (P = 0.006) but was not significantly associated with tumor size, vascular invasion, tumor grade, or patient age. Of 19 patients requiring surgery for bone metastases, the primary cancers were PTHrP negative in seven, all but one of whom had PTHrP-positive bone metastases. All 12 patients with PTHrP-positive primary cancers also had positive bone metastases. We conclude that increased production of PTHrP by breast cancers confers on them a less invasive phenotype, an effect distinct from the bone resorption-stimulating action that favors bone metastasis. It is likely that the latter property is influenced by factors in the bone microenvironment.

CANCER STEM CELLS: A REVIEW

Research has been increasing in recent years into the application of stem cell biology to clinical medicine, particularly its role in the evolution and metastasis of tumours. Stem cells may be the target cell for malignant transformation, and tumour formation could be considered a disorder of stem cell self‐renewal pathways. Cancer stem cells have been identified in acute myeloid leukaemia and in breast and central nervous system tumours. Cancer stem cells may have a specific role in tumour metastasis, and their understanding may provide insights into the development of predictive and prognostic markers and specific therapeutic interventions.

CD271 Expression on Patient Melanoma Cells Is Unstable and Unlinked to Tumorigenicity.

The stability of markers that identify cancer cells that propagate disease is important to the outcomes of targeted therapy strategies. In human melanoma, conflicting data exist as to whether hierarchical expression of CD271/p75/NGFR (nerve growth factor receptor) marks cells with enriched tumorigenicity, which would compel their specific targeting in therapy. To test whether these discrepancies relate to differences among groups in assay approaches, we undertook side-by-side testing of published methods of patient-derived melanoma xenografting (PDX), including comparisons of tissue digestion procedures or coinjected Matrigel formulations. We found that CD271(-) and CD271(+) melanoma cells from each of seven patients were similarly tumorigenic, regardless of assay variations. Surprisingly variable CD271 expression patterns were observed in the analyses of sibling PDX tumors (n = 68) grown in the same experiments from either CD271(-) or CD271(+) cells obtained from patients. This indicates unstable intratumoral lineage relationships between CD271(-) and CD271(+) melanoma cells that are inconsistent with classical, epigenetically based theories of disease progression, such as the cancer stem cell and plasticity models. SNP genotyping of pairs of sibling PDX tumors grown from phenotypically identical CD271(-) or CD271(+) cells showed large pairwise differences in copy number (28%-48%). Differences were also apparent in the copy number profiles of CD271(-) and CD271(+) cells purified directly from each of the four melanomas (1.4%-23%). Thus, CD271 expression in patient melanomas is unstable, not consistently linked to increased tumorigenicity and associated with genetic heterogeneity, undermining its use as a marker in clinical studies. Cancer Res; 76(13); 3965-77. ©2016 AACR.

Bidirectional esophageal dilatation in pharyngoesophageal stenosis postradiotherapy

Severely stenosed radiation‐induced benign strictures around the level of cricopharyngeus post–radical chemoradiation for head and neck or upper esophageal cancers pose significant management problems. We report our technique of bidirectional assessment and dilatation of pharyngoesophageal strictures in patients with an in situ percutaneous endoscopic gastrostomy (PEG) tube. The upper gastrointestinal surgeon approached the area of stenosis in a retrograde manner through the PEG tube to guide the otolaryngeal surgeon who performed anterograde dilatation via a rigid laryngoscope. Between 2005 and 2009, bidirectional esophageal dilatation was performed on 5 patients at our institution. Video fluoroscopy confirmed improved patency of stenosed esophagus in all cases and good improvement in swallowing ability in 4 patients. The ability to accurately assess pharyngoesophageal strictures using bidirectional visualization and transillumination is the key modification of our technique. We suggest using bidirectional esophageal dilatation on difficult cases with severe pharyngoesophageal stenoses although extreme care is required.

Intralesional PV‐10 for in‐transit melanoma—A single‐center experience

Patients with in‐transit melanoma metastasis have longer median survival than patients with distant metastatic disease. Furthermore, local disease control is an important endpoint for symptom management. The treatment of unresectable loco‐regional recurrence or in‐transit disease has been historically managed with a combination of treatments including surgery, radiotherapy, isolated limb infusion or perfusion as well as systemic therapies. Intralesional PV‐10 has been used at Peter MacCallum Cancer Centre since 2010, and the current report presents a retrospective analysis of patient outcomes, reporting the response rates, durability of responses, and observed toxicities.

Post‐operative survival following metastasectomy for patients receiving BRAF inhibitor therapy is associated with duration of pre‐operative treatment and elective indication

Introduction Metastasectomy can provide durable disease control for selected patients with metastatic melanoma. Vemurafenib is a BRAF kinase inhibitor which has demonstrated significant improvement in disease-specific survival in patients with metastatic melanoma with a BRAF gene mutation. This study examined the efficacy and safety of metastasectomy during treatment with vemurafenib. Methods A retrospective review was performed of all patients receiving vemurafenib at Peter MacCallum Cancer Centre. Patient records were reviewed to identify patients undergoing surgery within 30 days of vemurafenib therapy. Descriptive statistics and survival analysis were performed. Results Nineteen patients underwent 21 metastasectomies including craniotomy (57%), spinal decompression (14%), small bowel resection (14%), lung resection (9.5%) and neck dissection (4.5%). Indications for surgery were: an isolated residual focus of disease (n = 2); isolated progressive disease in the setting of stability elsewhere (n = 9); and symptomatic disease (n = 8). Grade 2 or higher surgical complications occurred in 19% of cases and there was one peri-operative death. Median post-operative survival was seven months. There was a trend toward improved post-operative survival for patients with longer duration of vemurafenib therapy (P = 0.04) and for those undergoing elective surgery (P = 0.07). Conclusion Resection of oligometastatic disease during BRAF-targeted therapy is safe. Selected patients have durable post-operative disease control. J. Surg. Oncol. 2015 111:980–984.

Prospective evaluation of prognostic indicators for early recurrence of cutaneous melanoma.

The majority of melanomas are thin lesions with an excellent prognosis; however, significant tumor heterogeneity exists, and a small percentage of patients with early-stage disease may progress to metastatic recurrence. This study aimed to assess whether prognostic factors previously shown to be significant in predicting stage I and stage II melanoma recurrence were consistent in a large prospectively collected patient cohort, and to identify novel prognostic factors associated with early recurrence to inform follow-up protocols. There were 1029 patients with stage I and stage II melanoma included in the analysis, of whom 123 developed a recurrence during follow-up (median 2.13 years). Multivariable analysis identified ulceration, presence of mitoses, Clark level, presence of lymphovascular invasion, and a history of autoimmune disease as factors independently associated with recurrence. These data identified patients with stage I–II melanoma with very low-risk for recurrence: no ulceration, zero mitoses, a low Clark level, no lymphovascular invasion, and possibly no history of autoimmune disease. These patients do not require intensive follow-up: 12 monthly reviews and full skin checks may be appropriate. Ongoing research into prognostic factors for recurrence in early-stage melanoma is important.

Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma

Background As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance. Patients and methods From 2009, patients with stage 3 melanoma routinely underwent PET +/- MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were carried out of imaging outcomes. Results One hundred and seventy patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56%-83%. Negative scans had predictive values of 89%-96% for true non-recurrence [negative predictive values (NPV)] until the next scan. A negative PET at 18 months had NPVs of 80%-84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median). Conclusions Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.

Outcomes following management of squamous cell carcinoma of the scalp: A retrospective series of 235 patients treated at the Peter MacCallum Cancer Centre

Squamous cell carcinoma of the scalp is a common clinical problem in an aging population. Despite its high incidence, little has been documented regarding treatment or outcomes.

Melanoma in the very elderly, management in patients 85 years of age and over

OBJECTIVES Melanoma treatment in the elderly can entail complex decision making. This study characterizes the presentation, management, and outcome of melanoma in the very elderly. METHOD Retrospective review of all patients in their 85th year or older presenting to a tertiary referral cancer centre between 2000 and 2012 with American Joint Committee on Cancer stages 0-II cutaneous melanoma. RESULTS 127 patients, 26 with in-situ disease and 101 with stages I-II disease, were included. For invasive primary disease, the median age was 87years (IRQ=86-89). Most patients had melanomas with poor prognoses at diagnosis: 49.5% were ulcerated, 68.3% mitotically active (mitotic rate≥1), and the median tumor thickness was 3.7mm (IQR=1.7-5.8). Nodular melanomas were the most frequent subtype (31.7%, 32/101). Only 66.3% received an excision margin≥10mm. Suboptimal excision margins were associated with increased risk of local recurrence (HR=6.87, 95% CI=5.53-8.20, p=0.0045) but not poorer disease specific survival (DSS, p=0.37) or overall survival (OS, p=0.19). Sentinel node biopsy (SNB) did not influence survival (DSS, p=0.39, OS, p=0.78). Median OS was 33months. Overall, one-third (34.7%) of patients died from causes other than melanoma during the follow up period. In patients aged ≥90 only 1 patient (4.3%) died from melanoma, while 10 patients (43.5%) died of other causes. CONCLUSIONS Older patients have thick, mitotically active and frequently ulcerated melanomas. An excision margin≥10mm should be considered to reduce risk of local recurrence. SNB did not impact on survival. With increasing age, patients will more commonly die of causes other than melanoma regardless of the extent of surgical care.