Emily Marchiano

Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis

We report a new class of thiophene (TP) compounds that kill Mycobacterium tuberculosis (Mtb) by the novel mechanism of Pks13 inhibition. An F79S mutation near the catalytic Ser-55 site in Pks13 conferred TP-resistance in Mtb. Over-expression of wild-type pks13 resulted in TP-resistance and over-expression of the F79S pks13 mutant conferred high-level resistance. In vitro, TP inhibited fatty acyl-AMP loading onto Pks13. TP inhibited mycolic acid biosynthesis in wild-type Mtb, but to a much lesser extent in TP-resistant Mtb. TP treatment was bactericidal and equivalent to the first-line drug isoniazid, but it was less likely to permit emergent resistance. Combined isoniazid and TP treatment exhibited sterilizing activity. Computational-docking identified a possible TP-binding groove within the Pks13 ACP domain. This study confirms that Mtb Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway.

Whole genome sequencing of Mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans.

Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10−10 mutations/bp/generation for recently transmitted tuberculosis and 7.3X10−11 mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10−11 mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques.

Polymorphous low‐grade adenocarcinoma of the head and neck: A population‐based study of 460 cases

Polymorphous low‐grade adenocarcinoma (PLGA) is a rare malignant neoplasm of the minor salivary glands. This study analyzes the demographic, clinicopathologic, incidence, and survival characteristics of head and neck PLGA (HN‐PLGA).

Head and neck microvascular free flap reconstruction: An analysis of unplanned readmissions

Unplanned readmissions within 30 days of surgery represent a significant marker for healthcare quality. Small institutional studies have described rates of readmission for patients undergoing head and neck free flap reconstruction. However, large, multi‐institutional analyses have not previously been described.

Laryngeal spindle cell carcinoma: A population-based analysis of incidence and survival

Laryngeal spindle cell carcinoma (LSpCC) is a rare variant of squamous cell carcinoma. Surgery is the reported mainstay of treatment, but previous analyses failed to demonstrate survival outcomes by therapeutic modality. This study aims to carry out the largest population‐based analysis of this histology to determine tumor characteristics, incidence, survival, and prognostic indicators.

Extended Endoscopic and Open Sinus Surgery for Refractory Chronic Rhinosinusitis

This review discusses extended endoscopic and open sinus surgery for refractory chronic rhinosinusitis. Extended maxillary sinus surgery including endoscopic maxillary mega-antrostomy, endoscopic modified medial maxillectomy, and inferior meatal antrostomy are described. Total/complete ethmoidectomy with mucosal stripping (nasalization) is discussed. Extended endoscopic sphenoid sinus procedures as well as their indications and potential risks are reviewed. Extended endoscopic frontal sinus procedures, such the modified Lothrop procedure, are described. Extended open sinus surgical procedures, such as the Caldwell-Luc approach, frontal sinus trephine procedure, external frontoethmoidectomy, frontal sinus osteoplastic flap with or without obliteration, and cranialization, are discussed.

Impact of chronic obstructive pulmonary disease on patients undergoing laryngectomy for laryngeal cancer

Although chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients undergoing laryngeal cancer surgery, the impact of this comorbidity in this setting is not well established. In this analysis, we used the Nationwide Inpatient Sample (NIS) to elucidate the impact of COPD on outcomes after laryngectomy for laryngeal cancer.

Utility of Surgery/Radiotherapy in Distant Metastatic Head and Neck Squamous Cell Carcinoma: A Population-Based Approach

Objectives The aim of this study is to analyze the survival benefits of surgery and/or radiation therapy over no therapy in patients with metastatic (M1) squamous cell carcinoma of the head and neck region (HN-SCC). Study Design Retrospective administrative database analysis. Subjects and Methods The Surveillance, Epidemiology, and End Results (SEER) database was queried for M1 HN-SCC cases from 1988 to 2012 (6663 patients). Patient demographics, initial treatment, and survival outcomes were analyzed. Survival was analyzed with the Kaplan-Meier model. Results Of the 6663 patients identified with M1 HN-SCC in the SEER database, 1669 patients received no therapy; 2459 patients, radiotherapy; 570 patients, surgery; and 1100 patients, surgery with adjuvant radiotherapy. The mean survival was 8.44 months for patients who did not undergo any therapy. In comparison, patients who underwent radiotherapy alone, surgery alone, or surgery with radiotherapy had mean survivals of 18.03 (P < .0001), 31.07 (P < .0001), and 39.93 (P < .0001) months, respectively. The 5-year disease-specific survival rates were 6.35% for no therapy, 17.51% for radiotherapy alone, 30.50% for surgery alone, and 33.75% for surgery with radiotherapy (P < .0001). Site-specific analysis revealed that surgery and/or radiation provides disease-specific survival benefit as compared with no therapy at all subsites within the head and neck region. Conclusions Surgery and/or radiation—which has been shown to improve quality of life in patients with advanced cancer—is associated with an increased survival when utilized in patients with distant metastatic disease.

Subglottic Squamous Cell Carcinoma: A Population-Based Study of 889 Cases

Objective Subglottic squamous cell carcinoma (SCCa) is a rare malignancy representing <5% of all laryngeal cancers. Patients often present with late-stage disease, and survival outcomes are reportedly worse than those for SCCa in other regions of the larynx. Study Design Analysis of a population-based tumor registry. Setting Academic medical center. Subjects and Methods The US National Cancer Institute’s Surveillance, Epidemiology, and End Results database was queried for cases of subglottic SCCa from 1973 to 2011 (889 cases). Resulting data were analyzed, including patient demographics, therapeutic measures, and survival outcomes. Results Subglottic SCCa most frequently occurred in the fifth to seventh decade of life, with a mean age at diagnosis of 65.7 ± 11.3 years. There was a strong male predilection, with a male:female ratio of 3.83:1. Most patients were stage III and IV (64.4%) per the American Joint Committee on Cancer. The most common treatment modality was a combination of radiotherapy and surgery (38.8%), followed by radiotherapy alone (33.9%), and surgery alone (17.0%). Overall 5-year disease-specific survival rate was 53.7%. When stratified by treatment modality, 5-year disease-specific survival was 62.4% for surgery alone, 56.7% for radiotherapy alone, and 55.1% for surgery with adjuvant radiotherapy (P = .3892). Conclusion This study represents the largest cohort of subglottic SCCa. It shows a strong predilection for men in the US population. Surgery with adjuvant radiotherapy was the most commonly employed treatment modality. No statistically significant differences were observed in 5-year DSS by treatment modality.

Impact of Nodal Level Distribution on Survival in Oral Cavity Squamous Cell Carcinoma A Population-Based Study

Objective Regional lymph node metastasis is an important prognostic factor in squamous cell carcinoma of the head and neck, decreasing survival by up to 50%. Oral cavity squamous cell carcinoma (OC-SCCa) most commonly spreads to levels I, II, and III. Study Design Retrospective analysis of a population-based tumor registry. Setting Academic medical center. Subjects and Methods The Surveillance, Epidemiology, and End Results (SEER) database was queried for cases of OC-SCCa from 2004 to 2011 (22,973 cases). Resulting data including patient demographics, clinicopathological features, topographical distribution of nodal metastasis, and survival based on lymph node level involvement were analyzed. Results In total, 8281 patients were identified with OC-SCCa who underwent neck dissection. Level I, closely followed by levels II and III, represented the most commonly involved nodal basins. The 5-year disease-specific survival (DSS) for patients with only level I, II, or III was 42.0% compared with 30.6% for the level IV group (P < .0001) and 26.4% for the level V group (P < .0001). Surgery with adjuvant radiotherapy improved 5-year DSS for patients with level I to III, level IV, and level V neck disease compared with surgery alone (50.7% vs 48.6%, P = .0109; 39.9% vs 23.2%, P < .0001; and 33.3% vs 9.1%, P = .0005, for levels I-III, IV, and V, respectively). Conclusion Oral cavity squamous cell carcinoma most commonly involves nodal levels I, II, and III. Involvement of nodal level IV or V portends a worse prognosis than patients with only level I to III disease, and multimodality therapy should be considered for these patients.