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Oncolytic viruses (OVs) are an emerging class of cancer therapeutics that offer the benefits of selective replication in tumour cells, delivery of multiple eukaryotic transgene payloads, induction of immunogenic cell death and promotion of antitumour immunity, and a tolerable safety profile that largely does not overlap with that of other cancer therapeutics. To date, four OVs and one non-oncolytic virus have been approved for the treatment of cancer globally although talimogene laherparepvec (T-VEC) remains the only widely approved therapy. T-VEC is indicated for the treatment of patients with recurrent melanoma after initial surgery and was initially approved in 2015. An expanding body of data on the clinical experience of patients receiving T-VEC is now becoming available as are data from clinical trials of various other OVs in a range of other cancers. Despite increasing research interest, a better understanding of the underlying biology and pharmacology of OVs is needed to enable the full therapeutic potential of these agents in patients with cancer. In this Review, we summarize the available data and provide guidance on optimizing the use of OVs in clinical practice, with a focus on the clinical experience with T-VEC. We describe data on selected novel OVs that are currently in clinical development, either as monotherapies or as part of combination regimens. We also discuss some of the preclinical, clinical and regulatory hurdles that have thus far limited the development of OVs.Oncolytic viruses (OVs) provide a novel cancer treatment strategy, with a mechanism of action and toxicity profiles that are distinctly different to those of more traditional therapies. Thus far, four OVs have entered clinical use globally, yet only talimogene laherparepvec (T-VEC) has entered widespread clinical use. In this Review, the authors describe the clinical and regulatory experience with T-VEC thus far, and how this can guide the development of novel OVs. Discussions of a range of novel OVs with the potential for clinical implementation in the near future are also provided.

Purpose of ReviewThe therapeutic landscape for non-melanoma skin cancer (NMSC) has recently expanded with the development of effective and targeted immunotherapy. Here, we provide an overview of the role of immunotherapy in the management of advanced cutaneous carcinomas.Recent FindingsSeveral agents were recently U.S. Food and Drug Administration (FDA)-approved for the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma, Merkel cell carcinoma, and basal cell carcinoma. However, recent approvals in tissue-agnostic indications may also benefit other NMSCs including cutaneous adnexal solid tumors with high tumor mutation burdens or microsatellite instability. Furthermore, while FDA-approved indications will likely continue to expand, continued studies are needed to support the role of immunotherapy in the neoadjuvant, adjuvant, and refractory settings.SummaryImmunotherapy is emerging as the standard of care for several advanced NMSCs not amenable to surgery and radiation. Ongoing evaluation of the clinical trial landscape is needed to optimize enrollment and ensure continued innovation.

Keratinocyte carcinomas include squamous-cell carcinoma of the skin and basal-cell carcinoma and are the predominant forms of nonmelanoma skin cancer. Keratinocyte carcinomas are the most common cancer in humans, with an annual incidence greater than all other cancers combined. 1,2 Whereas the vast majority of basal-cell and squamous-cell carcinomas are cured with local destruction or surgical excision, treatment of keratinocyte carcinomas can lead to considerable morbidity and health care–related economic burden. Furthermore, a subgroup of patients with nonmelanoma skin cancers have poor outcomes, including recurrence, metastases, and death. Owing to the sheer number of keratinocyte carcinomas that are diagnosed each year, . . .

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a low-grade, indolent tumor found almost exclusively on the eyelids that may histologically mimic metastatic breast carcinoma. To our knowledge, we present the first case of EMPSGC located on the external ear, and the first case with histologic evidence of vascular and perineural invasion. Due to the aggressive potential of this lesion, wide local excision and adjuvant radiation therapy were performed to help reduce the risk of recurrence.

Objectives To describe a 10‐year single center experience with parotid gland malignancies and to determine factors affecting outcomes. Study Design Retrospective review. Methods The institutional cancer registry was used to identify patients treated surgically for malignancies of the parotid gland between January 2005 and December 2014. Clinical and pathologic data were collected retrospectively from patient charts and analyzed for their association with overall survival (OS) and disease‐free survival (DFS). Results Two hundred patients were identified. Mean age at surgery was 57.8 years, and mean follow‐up time was 52 months. One hundred two patients underwent total parotidectomy, while 77 underwent superficial parotidectomy, and 21 underwent deep lobe resection. Seventy patients (35%) required facial nerve (FN) sacrifice. Acinic cell carcinoma was the most common histologic type (22%), followed by mucoepidermoid carcinoma (21.5%) and adenoid cystic carcinoma (12.5%). Twenty‐nine patients (14.5%) experienced recurrences, with mean time to recurrence of 23.6 months (range: 1‐82 months). Five‐ and 10‐year OS were 81% and 73%, respectively. Five‐ and 10‐year DFS were 80% and 73%, respectively. In univariate analyses, age > 60, histologic type, positive margins, high grade, T‐stage, node positivity, perineural invasion, and FN involvement were predictors of OS and DFS. In the multivariate analysis, histology, positive margins, node positivity, and FN involvement were independent predictors of OS and DFS. Conclusions Our single‐center experience of 200 patients suggests that histology, positive margins, node positivity, and FN involvement are independently associated with outcomes in parotid malignancies. Level of Evidence 4

Objective To describe outcomes after cartilage-sparing wide local excision for primary melanoma of the external ear. Study Design Retrospective analysis of patients undergoing external ear melanoma excision using a cartilage-sparing approach at a university-based tertiary care center between 2010 and 2018. Setting University-based tertiary care center. Subject and Methods Chart review was performed for all patients over age 18 who were treated for melanoma of the external ear at Massachusetts Eye and Ear between 2010 and 2018. Patients with melanoma in situ or with melanomas in noncartilaginous areas of the ear (eg, lobule) were excluded. Results A total of 8 patients underwent cartilage-sparing excision. Sentinel lymph node biopsy was performed in 7 patients, with positive lymph nodes in 1 of 7 cases. Positive margins and local recurrence occurred in 1 of 8 (12.5%) patients during a mean (SD) follow-up time of 22.5 (15.1) months (SE, 5.3 months). No distant metastasis or death was observed. Conclusion Cartilage-sparing wide local excision for melanoma of the external ear is a surgical approach that enables surgeons to follow guideline-recommended oncologic excision margins but has the added benefit of improved postoperative aesthetic outcomes as well as reconstructive options through preservation of the auricular cartilage framework.

Merkel cell carcinoma is a rare cutaneous neuroendocrine carcinoma with a high rate of regional and distant metastasis and mortality. Here, we report a novel case of Merkel cell carcinoma which presented as a primary lesion to the left cheek with regional lymph node involvement and was treated with pembrolizumab and radiation. Widely metastatic disease eventually revealed on autopsy clinically mimicked immune-related organ insult leading to management with immunosuppressants. The patient also had a biopsy-confirmed immune-related cutaneous adverse event during admission. The case highlights a rare circumstance in which disease progression masqueraded as multiple immune-related end-organ adverse events. Contribution of on-target anti-PD-1 toxicity remains a possibility.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer with a high risk of recurrence and metastasis. MCC is generally associated with advanced age, fair skin, sun exposure, immunosuppression, and in the majority of cases, the Merkel cell polyomavirus. Neuroendocrine malignancies are associated with a variety of paraneoplastic neurological syndromes (PNS), characterized as autoimmune responses to malignancy-associated expression of neural antigens. Our literature review underscores previous case reports of MCC-associated PNS with voltage-gated calcium channel (VGCC) and anti-Hu (or ANNA-1) autoantibodies. We present the case of a 59-year-old male with regionally metastatic Merkel cell carcinoma complicated by the paraneoplastic manifestation of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. His primary lower neck subcutaneous MCC and metastasis were initially treated with surgery. Additional recurrent lymph node metastases were successfully treated with definitive intensity-modulated radiation therapy. His PNS improved with rituximab therapy. Although rare, this case highlights that in the setting of seizures and prominent psychiatric symptoms accompanying an MCC diagnosis, evaluation for autoimmune paraneoplastic encephalitis is warranted. Awareness and detection of preexisting PNS are crucial in the era of immune checkpoint inhibitors (ICI) for advanced MCC, where treatment with ICI has the potential to exacerbate preexisting autoimmune PNS and lead to worsened or even lethal neurologic immune-related adverse events (nirAEs).

The surgical resection of solid tumours can be enhanced by fluorescence-guided imaging. However, variable tumour uptake and incomplete clearance of fluorescent dyes reduces the accuracy of distinguishing tumour from normal tissue via conventional fluorescence intensity-based imaging. Here we show that, after systemic injection of the near-infrared dye indocyanine green in patients with various types of solid tumour, the fluorescence lifetime (FLT) of tumour tissue is longer than the FLT of non-cancerous tissue. This tumour-specific shift in FLT can be used to distinguish tumours from normal tissue with an accuracy of over 97% across tumour types, and can be visualized at the cellular level using microscopy and in larger specimens through wide-field imaging. Unlike fluorescence intensity, which depends on imaging-system parameters, tissue depth and the amount of dye taken up by tumours, FLT is a photophysical property that is largely independent of these factors. FLT imaging with indocyanine green may improve the accuracy of cancer surgeries. The shift in fluorescence lifetime of tumour tissue with respect to normal tissue after systemic injection of the near-infrared dye indocyanine green can be used to distinguish tumour tissue from normal tissue with high accuracy.

Objective Total parotidectomy yields a large surgical defect that leads to both cosmetic and functional deficits which can be addressed with reconstruction. We evaluated the role of a pedicled submental flap for this reconstruction. Methods We reviewed all submental flap reconstructions that were performed for total parotidectomy defects between 2014 and 2016. Data regarding harvest technique, postoperative complications, flap survival, and adjuvant treatment details were recorded. Subjective information regarding retained volume after reconstruction was also obtained. Results During the time period, eight patients were identified and in all cases the patients underwent total parotidectomy with facial nerve sacrifice. All patients were discharged within 2 days of hospitalization with no complications or concerns regarding the viability of the flap. All but one patient had radiation therapy. Results with 9.9‐ to 37.5‐month follow‐up (mean 22.0 months) show limited volume loss without major contour defect or ear deformity in the follow‐up period. Conclusions Submental flap reconstruction is a feasible and reliable method for total parotidectomy defect. The inclusion of the mylohyoid muscle aids flap reliability and adds bulk. Inclusion of the dermis helps contour the overlying skin. The flap does not add morbidity or increased complexity intraoperatively or postoperatively. Level of Evidence 4