Correction to: Merkel Cell Carcinoma Outcomes: Does AJCC8 Underestimate Survival?

C.R. Farley and M.C. Perez contributed equally to this publication and are co-first authors. J.S. Zager and M.C. Lowe contributed equally to this publication and are co-corresponding authors.

Merkel Cell Carcinoma Outcomes: Does AJCC8 Underestimate Survival?

INTRODUCTION: The eighth edition of the American Joint Committee on Cancer (AJCC8) Staging Manual provides important information for staging and prognostication; however, survival estimates for patients with Stage I-III Merkel cell carcinoma (MCC), a rare disease, may be as practical using data from large-volume centers as that collated for the AJCC analysis. As such, we compared our institutional outcomes to AJCC8. METHODS: Patients who presented from 2005 to 2017 with MCC to two high-volume centers were included. Demographics, clinicopathologic characteristics, survival and recurrence data were compiled, and outcomes compared to AJCC8. RESULTS: A total of 409 patients were included. Median age was 75 (range 29-98) years, and 68% were male. Median follow-up was 16 months (0-157). Five-year overall survival (OS) was 70%; 5-year disease-specific survival (DSS) was 84%. When stratified by extent of disease, 5-year OS was higher for patients with local disease compared to those with nodal disease (72.6% vs 62.7%, p=0.005). Similarly, patients with local disease had higher 5-year DSS than those with nodal disease (90.1% vs 76.8%, p=0.002). Five-year recurrence-free survival was 59.2% for all patients, 65.0% for local disease and 48.3% for nodal disease (p=0.033). CONCLUSIONS: Here, MCC patients with local or nodal disease have substantially higher OS rates than predicted in AJCC8 (5-year: 72.6% vs 50.6%; 62.7% vs 35.4%, respectively). Importantly, 5-year DSS was significantly better than the OS rates reported presently and in AJCC8. As clinicians and patients rely on AJCC to accurately prognosticate and guide treatment decisions, these estimates should be reassessed and updated to more accurately predict survival outcomes.

Treatment of cholangiocarcinoma with oncolytic herpes simplex virus combined with external beam radiation therapy.

Replication-competent oncolytic herpes simplex viruses (HSV), modified by deletion of certain viral growth genes, can selectively target malignant cells. The viral growth gene gamma(1)34.5 has significant homology to GADD34 (growth arrest and DNA damage protein 34), which promotes cell cycle arrest and DNA repair in response to stressors such as radiation (XRT). By upregulating GADD34, XRT may result in greater oncolytic activity of HSV strains deficient in the gamma(1)34.5 gene. The human cholangiocarcinoma cell lines KMBC, SK-ChA-1 and YoMi were treated with NV1023, an oncolytic HSV lacking one copy of gamma(1)34.5. Viral proliferation assays were performed at a multiplicity of infection (MOI, number of viral particles per tumor cell) equal to 1, either alone or after XRT at 250 or 500 cGy. Viral replication was assessed by plaque assay. In vitro cytotoxicity assays were performed using virus at MOIs of 0.01 and 0.1, with or without XRT at 250 cGy and cell survival determined with lactate dehydrogenase assay. Established flank tumors in athymic mice were treated with a single intratumoral injection of virus (10(3) or 10(4) plaque forming units), either alone or after a single dose of XRT at 500 cGy, and tumor volumes measured. RT-PCR was used to measure GADD34 mRNA levels in all cell lines after a single dose of XRT at 250 or 500 cGy. NV1023 was tumoricidal in all three cell lines, but sensitivity to the virus varied. XRT enhanced viral replication in vitro in all cell lines. Combination treatment with low-dose XRT and virus was highly tumoricidal, both in vitro and in vivo. The greatest tumor volume reduction with combination therapy was seen with YoMi cells, the only cell line with increased GADD34 expression after XRT and the only cell line in which a synergistic treatment effect was suggested. In KMBC and SK-ChA-1 cells, neither of which showed increased GADD34 expression after XRT, tumor volume reduction was less pronounced and there was no suggestion of a synergistic effect in either case. Oncolytic HSV are effective in treating human cholangiocarcinoma cell lines, although sensitivity to virus varies. XRT-enhanced viral replication occurs through a mechanism that is not necessarily dependent on GADD34 upregulation. However, XRT-induced upregulation of GADD34 further promotes tumoricidal activity in viral strains deficient in the gamma(1)34.5 gene, resulting in treatment synergy; this effect is cell type dependent. Combined XRT and oncolytic viral therapy is a potentially important treatment strategy that may enhance the therapeutic ratios of both individual therapies.

Effects of preexisting immunity on the response to herpes simplex-based oncolytic viral therapy.

Herpes simplex viruses (HSV) type 1 are the basis of a number of anticancer strategies that have proven efficacious in animal models. They are natural human pathogens and the majority of adults have anti-HSV immunity. The current study examined the effect of preexisting immunity on the response to herpes-based oncolytic viral treatment of hepatic metastatic cancer in a murine model designed to simulate a clinical approach likely to be utilized for nonneurological tumors. Specifically, the anticancer effects of NV1020 or G207, two multimutated HSV-1 oncolytic viruses, were tested in immunocompetent mice previously immunized with a wild-type herpes simplex type 1 virus. Mice were documented to have humoral as well as cell-mediated immunity to HSV-1. Tumor response to oncolytic therapy was not measurably abrogated by immunity to HSV at the doses tested. The influence of route of viral administration was also tested in models of regional hepatic arterial and intravenous therapy. Route of viral administration influenced efficacy, as virus delivered intravenously produced some detectable attenuation while hepatic arterial therapy remained unaffected. These results demonstrate that when given at appropriate doses and in reasonable proximity to tumor targets, HSV-based oncolytic therapy can still be expected to be effective treatment for patients with hepatic malignancies.

Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection.

The objective of the study was to evaluate the utility of NV1042, a replication competent, oncolytic herpes simplex virus (HSV) containing the interleukin-12 (IL-12) gene, as primary treatment for hepatic tumors and to further assess its ability to reduce tumor recurrence following resection. Resection is the most effective therapy for hepatic malignancies, but is not possible in the majority of the patients. Furthermore, recurrence is common after resection, most often in the remnant liver and likely because of microscopic residual disease in the setting of postoperative host cellular immune dysfunction. We hypothesize that, unlike other gene transfer approaches, direct injection of liver tumors with replication competent, oncolytic HSV expressing IL-12 will not only provide effective control of the parent tumor, but will also elicit an immune response directed at residual tumor cells, thus decreasing the risk of cancer recurrence after resection. Solitary Morris hepatomas, established in Buffalo rat livers, were injected directly with 10(7) particles of NV1042, NV1023, an oncolytic HSV identical to NV1042 but without the IL-12 gene, or with saline. Following tumor injection, the parent tumors were resected and measured and the animals were challenged with an intraportal injection of 10(5) tumor cells, recreating the clinical scenario of residual microscopic cancer. In vitro cytotoxicity against Morris hepatoma cells was similar for both viruses at a multiplicity of infection of 1 (MOI, ratio of viral particles to target cells), with >90% tumor cell kill by day 6. NV1042 induced high-level expression of IL-12 in vitro, peaking after 4 days in culture. Furthermore, a single intratumoral injection of NV1042, but not NV1023, induced marked IL-12 and interferon-gamma (IFN-gamma) expression. Both viruses induced a significant local immune response as evidenced by an increase in the number of intratumoral CD4(+) and CD8(+) lymphocytes, although the peak of CD8(+) infiltration was later with NV1042 compared with NV1023. NV1042 and NV1023 reduced parent tumor volume by 74% (P<.003) and 52% (P<.03), respectively, compared to control animals. Treatment of established tumors with NV1042, but not with NV1023, significantly reduced the number of hepatic tumors after resection of the parent tumor and rechallenge (16.8+/-11 (median=4) vs. 65.9+/-15 (median=66) in control animals, P<.025). In conclusion, oncolytic HSV therapy combined with local immune stimulation with IL-12 offers effective control of parent hepatic tumors and also protects against microscopic residual disease after resection. The ease of use of this combined modality approach, which appears to be superior to either approach alone, suggests that it may have clinical relevance, both as primary treatment for patients with unresectable tumors and also as a neoadjuvant strategy for reducing recurrence after resection.

Laparoscopic appendectomy for Crohn's disease of the appendix presenting as acute appendicitis.

BACKGROUND: Crohn's disease confined to the appendix is rare but has been well described in the literature. It can mimic acute appendicitis clinically. After surgical treatment, recurrences of Crohn's disease are rare. We report the first case of treatment by laparoscopic appendectomy of Crohn's disease confined to the appendix. METHODS: A healthy 32-year old man presented with a week-long history of vague lower abdominal pain. Diagnostic work-up, which included CT, enteroclysis, and routine blood work, revealed a patent appendiceal lumen with an inflammatory mass in the right lower quadrant. RESULTS: Diagnostic laparoscopy revealed an inflamed appendix, and a laparoscopic appendectomy was performed, with frozen-section examination revealing Crohn's disease of the appendix. Two years after surgery, the patient has not had a recurrence of symptoms. CONCLUSIONS: Crohn's disease of the appendix can mimic acute appendicitis, although often with a more indolent course. The disease may be treated successfully by laparoscopic appendectomy, with good long-term results.

Clinical challenges presented by three simultaneous solid tumors.

BACKGROUND: Simultaneous tumors are rare, and their management can be challenging. The simultaneous presentation of cervical carcinoma, renal cell carcinoma, and appendiceal carcinoma has not been previously described. CASE: A 57-year-old woman presented with cervical cancer. During her workup, she was diagnosed with mucinous appendiceal carcinoma and clear cell carcinoma of the kidney. One year following surgery, she remains without evidence of disease and with continually improving nutritional status. CONCLUSION: When simultaneous tumors are diagnosed, optimal care requires the creative expertise of a multidisciplinary team. Standard sequential therapies may be problematic in patients undergoing major surgery to treat another primary tumor, and sequential treatment delays rather than combining therapies can jeopardize cure. Treatment planning should utilize a coordinated multidisciplinary approach.

Granular cell tumor--a unique neoplasm of the internal anal sphincter: report of a case.

Granular cell tumors are rare, invariably benign, and often solitary tumors, which infrequently involve the gastrointestinal tract. We report the unique presentation of a granular cell tumor of the internal anal sphincter in a 75 year-old female. The tumor was detected during investigation of new rectal bleeding and was excised using a transanal approach and sphincter repair. At five-year follow-up the patient reported normal continence to stool and flatus and demonstrated no evidence of tumor recurrence. Immunohistochemical studies cite the Schwann neural cell as the origin of the granular cell tumor. Cytoplasmic features include acidophilic, p-aminosalicylic acid-positive, diastaseresistant granules. Granular cell tumors may be located anywhere in the body, but anorectal involvement is rare. In our own search of the world literature, no other cases were reported specifically to involve the anal sphincter. Granular cell tumors are usually detected incidentally but may be symptomatic, especially when the anorectal region is involved. Symptoms include perianal discomfort and bleeding. Adequate local excision is effective for both diagnosis and treatment of anorectal granular cell tumors. Careful follow-up should be performed after excision because of the risk of recurrence.

Three cases of small bowel intussusception in relation to a rare lesion: inflammatory fibrous polyps.

BACKGROUND/AIMS: Inflammatory fibrous polyps (IFPs), also known as inflammatory pseudotumors, occur rarely in the gastrointestinal tract. IFPs have variable presentations, often presenting as small bowel obstruction due to intussusception or, less commonly, as an incidental finding on radiological examinations or screening colonoscopies. The diagnosis and management of IFPs will be discussed through a review of the literature and a series of cases from our own institution. METHODS: A retrospective analysis of the diagnosis, management and complications of IFPs was performed by a literature review. This was accompanied by a series of 3 cases of IFPs, 2 of which causing intussusception, diagnosed and treated in our own institution. CONCLUSIONS: IFP is a rare disease and has a variable presentation, from asymptomatic to small bowel obstruction due to intussusception. IFPs cannot be differentiated from malignancy without histological examination. Therefore, whether diagnosed incidentally or in the setting of intussusception, the treatment of IFPs is surgical resection of the involved bowel.

Jejunal diverticulosis: a rare entity with multiple presentations, a series of cases.

BACKGROUND/AIMS: Jejunal diverticulosis (JD) is a rare disease that has a variable presentation. The signs, symptoms, diagnosis, complications and treatment of JD will be discussed through a review of the literature and a series of cases from our own institution. METHODS: A retrospective analysis of the diagnosis, treatment and complications of JD was performed by a literature review. This was accompanied by a series of four cases of JD diagnosed and treated in our own institution. CONCLUSIONS: JD is a rare disease in which most patients are asymptomatic. However, JD's different complications are serious and can be fatal. The treatment is mainly surgical; however, there have been cases where nonsurgical management was successful.

Use of radiolabelled iododeoxyuridine as adjuvant treatment for experimental tumours of the liver.

BACKGROUND: The aim of the study was to determine whether hepatic regeneration stimulates growth of tumour residing within the liver, and whether a difference in the rate of DNA synthesis in liver and tumour may be used to target cancer using the radiolabelled thymidine analogue 5-iodo-2'-deoxyuridine (IUdR). METHODS: Partial hepatectomy was performed on Buffalo rats bearing solitary nodules of syngeneic Morris hepatoma. Liver and tumour DNA synthesis was measured by incorporation of radioactive IUdR. [(125)I]IUdR was tested as an adjuvant therapy after hepatectomy in Buffalo rats bearing diffuse microscopic Morris hepatomas to simulate the clinical situation. RESULTS: Liver regeneration enhanced liver and tumour DNA synthesis as measured by incorporation of radioactive IUdR. Liver DNA synthesis returned to baseline by 7 days, whereas tumour DNA synthesis remained above baseline level. Hepatectomy enhanced the growth of microscopic liver tumours. [(125)I]IUdR (250 micro Ci or 1 mCi/kg) administered 4 days after hepatectomy significantly reduced tumour growth without signs of systemic toxicity or liver dysfunction. CONCLUSION: The local environment of the regenerating liver stimulates tumour growth. The thymidine analogue [(125)I]IUdR may be used preferentially to target tumour DNA synthesis in the regenerating liver, and may prove useful as an adjuvant therapy for hepatic tumours after surgical resection.

Combination vascular delivery of herpes simplex oncolytic viruses and amplicon mediated cytokine gene transfer is effective therapy for experimental liver cancer.

BACKGROUND: Herpes simplex type I (HSV)-based vectors have been used experimentally for suicide gene therapy, immunomodulatory gene delivery, and direct oncolytic therapy. The current study utilizes the novel concept of regional delivery of an oncolytic virus in combination with or serving as the helper virus for packaging herpes-based amplicon vectors carrying a cytokine transgene, with the goal of identifying if this combination is more efficacious than either modality alone. MATERIALS AND METHODS: A replication competent oncolytic HSV (G207) and a replication incompetent HSV amplicon carrying the gene for the immunomodulatory cytokine IL-2 (HSV-IL2) were tested in murine syngeneic colorectal carcinoma and in rat hepatocellular carcinoma models. Liver tumors were treated with vascular delivery of (1) phosphate-buffered saline (PBS), (2) G207, (3) HSV-IL2, (4) G207 and HSV-IL2 mixed in combination (mG207/HSV- IL2), and (5) G207 as the helper virus for packaging the construct HSV-IL2 (pG207/HSV-IL2). RESULTS: Tumor burden was significantly reduced in all treatment groups in both rats and mice treated with high-dose G207, HSV-IL2, or both (p < 0.02). When a low dose of virus was used in mice, anti-tumor efficacy was improved by use of G207 and HSV-IL2 in combination or with HSV-IL2 packaged by G207 (p < 0.001). This improvement was abolished when CD4(+) and CD8(+) lymphocytes were depleted, implying that the enhanced anti-tumor response to low-dose combined therapy is immune mediated. CONCLUSIONS: Vascular regional delivery of oncolytic and amplicon HSV vectors can be used to induce improved anti-tumor efficacy by combining oncolytic and immunostimulatory strategies.