Incidence and Risk Factors for Occult Level 3 Lymph Node Metastases in Papillary Thyroid Cancer.

BACKGROUND: Papillary thyroid cancer (PTC) frequently disseminates into cervical lymph nodes. Lateral node involvement is described in up to 50 % patients undergoing prophylactic lateral neck dissection. This study aimed to assess this finding and identify which factors predict for occult lateral node disease. METHODS: Patients with fine needle aspiration-confirmed PTC (Bethesda V or VI), without evidence of cervical lymph node metastases, underwent a total thyroidectomy with prophylactic ipsilateral central and level 3 dissection. Level 3 nodes were removed by compartmental dissection or by sampling the sentinel nodes overlying the jugular vein, according to surgeon preference. Data were collected prospectively from January 2011 to August 2014. Statistical analysis was performed by SPSS software. RESULTS: A total of 137 patients underwent total thyroidectomy with prophylactic ipsilateral central and level 3 dissection for PTC. The incidence of occult level 3 disease was 30 % (41/137 patients). A total of 48 % of patients (66/137) harbored occult central neck disease. A total of 80.5 % of patients with pN1b disease had macrometastases (≥2 mm), and 15 % exhibited skip metastases with central compartment sparing. In patients with pN1b disease, a median of 6 level 3 nodes were retrieved, with an average involved nodal ratio of 0.29. Multivariate regression demonstrated risk factors for occult lateral neck metastasis include tumor size (odds ratio 1.1), upper pole tumors (odds ratio 6.6), and vascular invasion (odds ratio 3.2) (p < 0.05). CONCLUSIONS: PTC is associated with a significant incidence of occult central and lateral nodal metastases. In patients undergoing prophylactic central neck dissection, inclusion of level 3 dissection should be considered in patients with large upper lobe cancers.

Cytotoxic and immune-mediated killing of human colorectal cancer by reovirus-loaded blood and liver mononuclear cells.

Reovirus is a promising oncolytic virus, acting by both direct and immune-mediated mechanisms, although its potential may be limited by inactivation after systemic delivery. Our study addressed whether systemically delivered reovirus might be shielded from neutralising antibodies by cell carriage and whether virus-loaded blood or hepatic innate immune effector cells become activated to kill colorectal cancer cells metastatic to the liver in human systems. We found that reovirus was directly cytotoxic against tumour cells but not against fresh hepatocytes. Although direct tumour cell killing by neat virus was significantly reduced in the presence of neutralising serum, reovirus was protected when loaded onto peripheral blood mononuclear cells, which may carry virus after intravenous administration in patients. As well as handing off virus for direct oncolytic killing, natural killer (NK) cells within reovirus-treated blood mononuclear cells were stimulated to kill tumour targets, but not normal hepatocytes, in a Type I interferon-dependent manner. Similarly, NK cells within liver mononuclear cells became selectively cytotoxic towards tumour cells when activated by reovirus. Hence, intravenous reovirus may evade neutralisation by serum via binding to circulating mononuclear cells, and this blood cell carriage has the potential to investigate both direct and innate immune-mediated therapy against human colorectal or other cancers metastatic to the liver.

Lumbar herniation following extended autologous latissimus dorsi breast reconstruction.

BACKGROUND: Reconstructive breast surgery is now recognized to be an important part of the treatment for breast cancer. Surgical reconstruction options consist of implants, autologous tissue transfer or a combination of the two. The latissimus dorsi flap is a pedicled musculocutaneous flap and is an established method of autologous breast reconstruction.Lumbar hernias are an unusual type of hernia, the majority occurring after surgery or trauma in this area. The reported incidence of a lumbar hernia subsequent to a latissimus dorsi reconstruction is very low. CASE PRESENTATION: We present the unusual case of lumbar herniation after an extended autologous latissimus dorsi flap for breast reconstruction following a mastectomy. The lumbar hernia was confirmed on CT scanning and the patient underwent an open mesh repair of the hernia through the previous latissimus dorsi scar. CONCLUSION: Lumbar hernias are a rare complication that can occur following latissimus dorsi breast reconstruction. It should be considered in all patients presenting with persistent pain or swelling in the lumbar region.

Homozygosity for the pathogenic RET hotspot variant p.Cys634Trp: A consanguineous family with MEN2A.

Multiple endocrine neoplasia type 2 (MEN2) is a dominantly inherited condition with defined correlations between the genetic variant and clinical presentations. The location of pathogenic variants in the RET gene is a significant determinant of disease presentation and is associated with variable gene activation. Heterozygous pathogenic variants in codon 634 result in earlier onset of medullary thyroid carcinoma and higher incidence of phaeochromocytoma. Here we describe a consanguineous family with MEN2A that includes two children homozygous for the established pathogenic variant p. Cys634Trp. Both parents and a sibling were confirmed to being heterozygotes. Previous reports of biallelic or multiple RET variants have been limited to weakly activating variants. We present the first report of individuals homozygous for the highly activating RET p. Cys634Trp pathogenic variant and discuss disease severity and onset in this rare occurrence.

Adrenal Incidentaloma.

An adrenal incidentaloma is now established as a common endocrine diagnosis that requires a multidisciplinary approach for effective management. The majority of patients can be reassured and discharged, but a personalized approach based upon image analysis, endocrine workup, and clinical symptoms and signs are required in every case. Adrenocortical carcinoma remains a real concern but is restricted to <2% of all cases. Functional adrenal incidentaloma lesions are commoner (but still probably <10% of total) and the greatest challenge remains the diagnosis and optimum management of autonomous cortisol secretion. Modern-day surgery has improved outcomes and novel radiological and urinary biomarkers will improve early detection and patient stratification in future years to come.

Randomized trial of low versus high carbon dioxide insufflation pressures in posterior retroperitoneoscopic adrenalectomy.

BACKGROUND: Posterior retroperitoneoscopic adrenalectomy has gained widespread acceptance for the removal of benign adrenal tumors. Higher insufflation pressures using carbon dioxide (CO2) are required, although the ideal starting pressure is unclear. This prospective, randomized, single-blinded, study aims to compare physiologic differences with 2 different CO2 insufflation pressures during posterior retroperitoneoscopic adrenalectomy. METHODS: Participants were randomly assigned to a starting insufflation pressure of 20 mm Hg (low pressure) or 25 mm Hg (high pressure). The primary outcome measure was partial pressure of arterial CO2 at 60 minutes. Secondary outcomes included end-tidal CO2, arterial pH, blood pressure, and peak airway pressure. Breaches of protocol to change insufflation pressure were permitted if required and were recorded. RESULTS: A prospective randomized trial including 31 patients (low pressure: n = 16; high pressure: n = 15) was undertaken. At 60 minutes, the high pressure group had greater mean partial pressure of arterial CO2 (64 vs 50 mm Hg, P = .003) and end-tidal CO2 (54 vs 45 mm Hg, P = .008) and a lesser pH (7.21 vs 7.29, P = .0005). There were no significant differences in base excess, peak airway pressure, operative time, or duration of hospital stay. Clinically indicated protocol breaches were more common in the low pressure than the high pressure group (8 vs 3, P = .03). CONCLUSION: In posterior retroperitoneoscopic adrenalectomy, greater insufflation pressures are associated with greater partial pressure of arterial CO2 and end-tidal CO2 and lesser pH at 60 minutes, be significant. Commencing with lesser CO2 insufflation pressures decreases intraoperative acidosis.

Prospective evaluation of the utility of routine neuromonitoring for an established thyroid surgical practice.

BACKGROUND: The use of routine intraoperative neuromonitoring (IONM) is controversial in thyroid surgery. Guidelines have been published to standardize IONM. This study examines the impact of routine IONM on a high-volume thyroid surgeon. METHODS: A prospective study was conducted using IONM between May 2013 and December 2014. Demographics, type of operation, pathology, recurrent laryngeal nerve (RLN) and external branch of the superior laryngeal nerve (EBSLN) visualization and sub-type classification, cricothyroid or cricopharyngeal twitch/electrode depolarization were obtained, and complications were recorded. Outcomes were compared with 500 thyroidectomies performed by the same surgeon without neuromonitoring. RESULTS: Two hundred and ninety-nine total thyroidectomies and 191 hemithyroidectomies were performed with IONM resulting in 789 RLN and 789 EBSLN at risk of injury. Demographics, indication, pathology and complications were similar between the two groups. IONM provided additional information for 58 RLN dissections (7.4%) stratifying surgical decision-making. Loss of signal was detected in 1.8% of nerves at risk. IONM assisted in identification of 109 (13.8%, P < 0.0001) EBSLN, including a 15.8% improvement in identifying type 2b EBSLN. Utility of IONM was not predicted by surgery indication; however, multinodular goitre was a significant predictor of IONM assisted identification of type 2b EBSLN (OR = 2.24, P = 0.01). CONCLUSION: Routine IONM provides intraoperative information to a high-volume thyroid surgeon regarding the recurrent and external nerves over and above direct visualization alone, and its utility could not be predicted by operative indication.

A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma.

Pathogenic ALK translocations have been reported in papillary thyroid carcinoma (PTC). We developed and validated a screening algorithm based on immunohistochemistry (IHC), followed by fluorescence in situ hybridization (FISH) in IHC-positive cases to identify ALK-rearranged PTC. IHC and FISH were performed in a cohort of 259 thyroid carcinomas enriched for aggressive variants. IHC was positive in 8 cases, 6 confirmed translocated by FISH (specificity 75%). All 251 IHC-negative cases were FISH negative (sensitivity 100%). Having validated this approach, we performed screening IHC, followed by FISH in IHC-positive cases in an expanded cohort. ALK translocations were identified in 11 of 498 (2.2%) of all consecutive unselected PTCs and 3 of 23 (13%) patients with diffuse sclerosing variant PTCs. No ALK translocations were identified in 36 PTCs with distant metastases, 28 poorly differentiated (insular) carcinomas, and 20 anaplastic carcinomas. All 14 patients with ALK translocations were female (P=0.0425), and translocations occurred at a younger age (mean 38 vs. 48 y, P=0.0289 in unselected patients). ALK translocation was an early clonal event present in all neoplastic cells and mutually exclusive with BRAF mutation. ALK translocation was not associated with aggressive clinicopathologic features (size, stage, metastasis, vascular invasion, extrathyroidal extension, multifocality, risk for recurrence, radioiodine resistance). We conclude that 2.2% of PTCs are ALK-translocated and can be identified by screening IHC followed by FISH. ALK translocations may be more common in young females and diffuse sclerosing variant PTC but do not connote more aggressive disease.

Atypical Presentation of Riedel's Thyroiditis: Multifocal Nodular Fibrosis and Resolution with Levothyroxine.

BACKGROUND: Riedel's thyroiditis is characterised by chronic inflammatory invasive fibrosclerosis of the thyroid gland, surrounding structures, and extrathyroidal fibrosis. We present a case of Riedel's thyroiditis associated with nodular fibrosis of the lungs and liver. CASE: A 40-year-old woman presented with a 3-month history of neck swelling, difficulty swallowing and breathlessness on exertion. Core biopsy of the goitre revealed dense fibrous tissue with mixed chronic inflammatory cells. A staging computed tomography scan revealed a large thyroid mass encasing the oesophagus and compressing the trachea, multiple bilateral pulmonary nodules with no evidence of lymphadenopathy, and multiple suspicious nodular lesions in the liver. A thorascopic biopsy of a lung lesion in its entirety revealed a hyalinising lung lesion with no evidence of malignancy. Following the introduction of levothyroxine replacement, symptomatic improvement occurred in parallel with improvements in imaging. CONCLUSION: To our knowledge, this is the first description of Riedel's thyroiditis presenting with nodular extrathyroidal fibrosis, and which showed resolution following institution of levothyroxine.

Surgical specialization and training - its relation to clinical outcome for colorectal cancer surgery.

RATIONALE, AIMS AND OBJECTIVES: Surgical sub-specialization has been considered to be a major factor in improving cancer surgery-related outcomes in terms of 5-year survival and disease-free intervals. In this article we have looked at the evidence supporting the improvement in colorectal cancer outcomes with 'colorectal specialists' performing colon and rectal surgery. METHODS: A literature review was carried out using search engines such as Pubmed, Ovid and Cochrane Databases. Only studies looking at colorectal cancer outcome related to surgery were included in our review. RESULTS: Specialist surgeons performing a high volume of colorectal cancer surgery demonstrated better 5-year survival rates in patients, with less local recurrence. This was most evident in surgery for rectal cancer, where an association with increased sphincter saving surgery was also seen. Total mesorectal excision is now the accepted treatment for rectal cancer and has markedly improved survival rates and decreased local recurrence. CONCLUSION: The outcomes in colorectal surgery continue to steadily improve. The training of specialized colorectal surgeons is a major contributing factor towards this improvement.

Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients.

Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. However, how they evade the antiviral immune response and their selective delivery to, and replication in, tumor over normal tissue has not been investigated in humans. Here, we treated patients with a single cycle of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver. Tracking the viral genome in the circulation showed that reovirus could be detected in plasma and blood mononuclear, granulocyte, and platelet cell compartments after infusion. Despite the presence of neutralizing antibodies before viral infusion in all patients, replication-competent reovirus that retained cytotoxicity was recovered from blood cells but not plasma, suggesting that transport by cells could protect virus for potential delivery to tumors. Analysis of surgical specimens demonstrated greater, preferential expression of reovirus protein in malignant cells compared to either tumor stroma or surrounding normal liver tissue. There was evidence of viral factories within tumor, and recovery of replicating virus from tumor (but not normal liver) was achieved in all four patients from whom fresh tissue was available. Hence, reovirus could be protected from neutralizing antibodies after systemic administration by immune cell carriage, which delivered reovirus to tumor. These findings suggest new preclinical and clinical scheduling and treatment combination strategies to enhance in vivo immune evasion and effective intravenous delivery of oncolytic viruses to patients in vivo.

Acceptable outcome after kidney transplantation using "expanded criteria donor" grafts.

INTRODUCTION: With the worldwide shortage of donors, extra lengths are ongoing to enlarge the donor pool. One means has been a greater use of "expanded criteria donor" (ECD) grafts. A major concern regarding ECD kidneys is poor long-term graft survival. The aims of this study were to determine whether ECD grafts, as defined by the United Network for Organ Sharing, had a negative impact on graft survival and to identify the principle donor and recipient factors that influenced graft survival in our patient cohort. METHODS: We analyzed all deceased donor renal transplants in our unit from January 1995 to October 2005, in total 1,053 transplants. RESULTS: ECD grafts (United Network for Organ Sharing criteria) demonstrated higher rates of delayed graft function and higher early mean creatinine levels. However, there was no significant difference in 5-year graft survival. Multivariate analysis of our patient group identified donor hypertension and ischemic heart disease (IHD) as independent predictors of poor graft survival. Recipient age was significant on univariate but not on multivariate analysis. However, although younger recipients maintained acceptable 5-year graft survival despite donor hypertension, IHD, or a combination of both, these factors significantly reduced graft survival in older recipients. CONCLUSION: Although ECD grafts had slightly worse function, 5-year survival was comparable with standard grafts in all recipients. Donor hypertension, IHD, or a combination of both significantly reduced graft survival in older recipients, not evident in younger patients. We discuss the possible factors for improved outcome with ECD grafts in our patients and the implications of our patient analysis.

Clinical grade OK432-activated dendritic cells: in vitro characterization and tracking during intralymphatic delivery.

Dendritic cells (DC) are under intense preclinical and early clinical evaluation for the immunotherapy of cancer. However, the optimal culture conditions and route of delivery for DC vaccination have not been established. Here we describe the first human application of DC matured with the bacterial agent OK432 (OK-DC), using a short-term serum-free culture protocol, which generates mature DC from CD14+ precursors after 5 days. These cells were prepared within the framework of a National Blood Service facility, demonstrating that DC represent a product which is potentially deliverable alongside current standardized cell therapies within the UK National Health Service. In vitro analysis confirmed that OK-DC were mature, secreted tumor necrosis factor-alpha, interleukin-6, and interleukin-12, and stimulated both T cell and natural killer cell function. To explore effective delivery of OK-DC to lymph nodes, we performed an initial clinical tracking study of radioactively labeled, unpulsed OK-DC after intralymphatic injection into the dorsum of the foot. We showed that injected DC rapidly localized to ipsilateral pelvic lymph nodes, but did not disseminate to more distant nodes over a 48-hour period. There was no significant toxicity associated with OK-DC delivery. These results show that OK-DC are suitable for clinical use, and that intralymphatic delivery is feasible for localizing cells to sites where optimal priming of innate and adaptive antitumor immunity is likely to occur.