High GILT Expression Is Associated with Improved Survival in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition.

Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II restricted presentation of multiple melanoma antigens. There is variable GILT protein expression in malignant melanocytes in melanoma specimens. High GILT mRNA expression in melanoma specimens is associated with improved overall survival, before the advent of immune checkpoint inhibitors (ICI). However, the association of GILT in metastatic melanoma with survival in patients treated with ICI and the cell type expressing GILT associated with survival have not been determined. Using RNA sequencing datasets, high GILT mRNA expression in metastatic melanoma specimens was associated with improved progression-free and overall survival in patients treated with ICI. A clinical dataset of metastatic melanoma specimens was generated and annotated with clinical information. Positive GILT immunohistochemical staining in antigen presenting cells and melanoma cells was observed in 100% and 65% of metastatic melanoma specimens, respectively. In the subset of patients treated with ICI in the clinical dataset, high GILT protein expression within melanoma cells was associated with improved overall survival. The association of GILT mRNA and protein expression with survival was independent of cancer stage. These studies support that high GILT mRNA expression in bulk tumor samples and high GILT protein expression in melanoma cells is associated with improved survival in ICI-treated patients. These findings support further investigation of GILT as a biomarker to predict the response to ICI.

Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients.

INTRODUCTION: Colorectal cancer (CRC) diagnosed before age 30 years is a fatal disease whose biology remains poorly understood. To understand its pathogenesis, we compared molecular and clinical data in surgically treated early-age onset and adult onset patients. MATERIALS AND METHODS: Clinical data and tumor tissue were collected retrospectively for 94 patients with early-age onset CRC (age ≤30 years) and compared to 275 adult CRC patients (age ≥50 years). Tumor morphology, microsatellite instability (MSI) and stability (MSS), KRAS and BRAF mutations, and mismatch repair (MMR) expression (MSH2, MLH1, MSH6, PMS2) were assessed. RESULTS: Early-age CRC was distinguished from adult CRC by advanced stage presentation (P<0.001), frequent high grade cancers (P<0.001), and poor prognosis (P<0.001). MSI was associated with favorable survival and MMR loss in both groups. Compared to adults, MSI in early-onset CRC was more prevalent (P<0.01), not tightly linked to MLH1/PMS2 loss, and never associated with BRAFV600E mutations (P<0.01). MSS/BRAFV600E genotype had poor prognosis and was more prevalent in early-age CRC (9% vs. 3%). DISCUSSION: Specific genetic subtypes are found at different frequencies in early-age onset and adult onset CRC. Complete absence of the indolent MSI/BRAFV600E genotype and enrichment in the unfavorable MSS/BRAFV600E genotype help explain the poor prognosis of early onset CRC.

Routine biopsy of Cloquet's node is of limited value in sentinel node positive melanoma patients.

BACKGROUND AND OBJECTIVES: Biopsy of Cloquet's node (CN) during groin dissection has been used to indicate need for pelvic dissection. With earlier detection of microscopic regional disease in the era of sentinel node biopsy (SNB), frequency of positive CN may be so low that routine biopsy is unwarranted. METHODS: Patients with positive groin SNB from 2000 to 2008 were identified from two centers. Cases where CN was identified at completion node dissection were selected. Lymphoscintigraphic, surgical, pathologic, and recurrence data were reviewed. RESULTS: CN was identified in 53 cases. Median age was 44.5 years (range 7-77); median Breslow depth, 1.98 mm (range 0.5-25.0); % Clark's level IV/V, 90%; and % ulceration, 41.5%. Fifty (94.3%) underwent groin dissection alone; three others underwent concomitant pelvic dissection. Two (3.8%) patients had positive CN; both had additional indications for pelvic dissection. Delayed pelvic recurrence rate was 2/53 (3.8%); both patients had negative CN. In the three patients treated with concurrent groin and pelvic dissection, CN reflected pelvic nodal status in two cases; the third had pelvic metastases despite negative CN. CONCLUSIONS: After positive SNB, disease involvement of CN is rare. Patients with positive biopsies of CN in the SNB era appear likely to have additional indications for pelvic dissection, minimizing utility of CN biopsy. Routine intraoperative sampling of CN may not be warranted during groin dissection for positive SNB.

Improved testing for microsatellite instability in colorectal cancer using a simplified 3-marker assay.

BACKGROUND: In colorectal cancer (CRC), microsatellite instability (MSI) is a valuable marker of defective DNA mismatch repair that identifies cancers with distinct phenotypic properties, including favorable survival. However, the optimal assay for MSI status is unknown. We have evaluated a simplified 3-marker assay for MSI and compared it with the 5-marker (NCI) assay to see if technical variations in MSI testing are important. MATERIALS AND METHODS: DNA samples from 357 CRCs were evaluated for MSI using the 5 microsatellite markers recommended for the NCI assay (BAT 25, BAT26, D2S123, D5S346, and D17S250). Results were compared with a simplified 3-marker assay (BAT25, BAT26, and D2S123). CRCs identified as MSI were evaluated for their clinical, pathological, and genetic characteristics. RESULTS: The 5-marker assay identified 96 cancers as MSI. Only 56 of these were MSI by the 3-marker assay (3-marker+ group), leaving 40 cases identified as MSI only by NCI criteria (3-marker- group). The remaining 261 cancers were microsatellite stable (MSS). The 3-marker+ MSI tumors had features characteristic of MSI tumors: more proximal, poorly differentiated, associated with hereditary nonpolyposis colorectal cancer (HNPCC), more BRAF mutations, fewer KRAS mutations, better 5-year disease-specific survival, more frequent mismatch repair (MMR) protein loss, and less likely to be metastatic on presentation (P < .05). Chromosomal arm loss was observed only in 3-marker- MSI and MSS cancers (P < .05). CONCLUSION: The 3-marker MSI assay outperforms the traditional 5-marker assay for identifying patients with favorable prognosis and homogeneous clinical and genetic features. More accurate MSI testing should improve prognostic and predictive scoring systems for colorectal cancer.

Therapy for unresectable recurrent and in-transit extremity melanoma.

BACKGROUND: Unresectable recurrent and in-transit extremity melanoma presents a dilemma for the treating physician. While the disease is confined to the involved limb, the survival mimics that of multiple nodal metastases, with a 10-year survival rate of approximately 40%. This represents late-stage disease for which curative treatment options are limited. METHODS: To review the current treatment strategies for stage IIIB (N2c) in-transit and recurrent melanoma focusing on the options for unresectable disease, MEDLINE was searched for studies of known and experimental treatments for in-transit and recurrent extremity melanoma. Further results were obtained after review of the initial citations. RESULTS: For unresectable recurrences and in-transit metastases, therapies are limited to palliative (radiation), local (intratumoral injection, laser ablation and electroporation), regional (isolated limb perfusion/infusion), and systemic (chemotherapy) when local or regional techniques are not feasible. CONCLUSIONS: In this patient population, intratumoral techniques have a limited role with current treatment regimens, but with the development of new drugs, these techniques may have more utility. If not contraindicated, regional techniques provide the greatest control and have minimal operative morbidity. Until new regimens are available, systemic therapy continues to be associated with considerable toxicity and only marginal response rates.

A current perspective on local excision of rectal cancer.

Local excision of rectal cancer is appealing because of its technical ease and excellent functional results, but concern over inadequate pathologic staging and inferior treatment outcomes when compared with radical surgery remain a major hurdle for its widespread use. Local failure rates in modern series for local excision are 4%-18% for T1 rectal cancers and 22%-67% for T2 cancers, and cancer cure rates are only 70%-80%. In addition, data from the past decade suggest that preoperative staging with endorectal ultrasound, use of postoperative adjuvant chemotherapy/radiation therapy, and aggressive salvage surgery have not been reliable methods of limiting local tumor recurrence or improving long-term cure rates. At present, highly stringent criteria for patient selection are recommended, yet such stringency decreases the utility of the procedure. What are needed are new approaches to an old problem. Novel strategies under evaluation include enhanced imaging modalities for lymph node metastases, neoadjuvant chemotherapy/radiation therapy, and more liberal use of immediate salvage resection for high-risk pathologic features. Molecular profiling of tumors with genetic markers and better integration of traditional and gene-targeted systemic therapy are promising approaches for the future. This review of the literature evaluates the recent successes and failures of local excision of rectal cancer and provides a current perspective on the expanded use of local excision without compromising care.