Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Clinical and molecular characterization of patients with cancer of unknown primary in the modern era.

BACKGROUND: On the basis of historical data, patients with cancer of unknown primary (CUP) are generally assumed to have a dismal prognosis with overall survival of less than 1 year. Treatment is typically cytotoxic chemotherapy guided by histologic features and the pattern of metastatic spread. The purpose of this study was to provide a clinical and pathologic description of patients with CUP in the modern era, to define the frequency of clinically actionable molecular alterations in this population, to determine how molecular testing can alter therapeutic decisions, and to investigate novel uses of next-generation sequencing in the evaluation and treatment of patients with CUP. PATIENTS AND METHODS: Under Institutional Review Board approval, we identified all CUP patients evaluated at our institution over a recent 2-year period. We documented demographic information, clinical outcomes, pathologic evaluations, next-generation sequencing of available tumor tissue, use of targeted therapies, and clinical trial enrollment. RESULTS: We identified 333 patients with a diagnosis of CUP evaluated at our institution from 1 January 2014 through 30 June 2016. Of these patients, 150 had targeted next-generation sequencing carried out on available tissue. Median overall survival in this cohort was 13 months. Forty-five of 150 (30%) patients had potentially targetable genomic alterations identified by tumor molecular profiling, and 15 of 150 (10%) received targeted therapies. Dominant mutation signatures were identified in 21 of 150 (14%), largely implicating exogenous mutagen exposures such as ultraviolet radiation and tobacco. CONCLUSIONS: Patients with CUP represent a heterogeneous population, harboring a variety of potentially targetable alterations. Next-generation sequencing may provide an opportunity for CUP patients to benefit from novel personalized therapies.

Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) is highly responsive to crizotinib. To determine whether ALK-positive NSCLC is also sensitive to pemetrexed, we retrospectively evaluated progression-free survival (PFS) of ALK-positive versus ALK-negative patients who had been treated with pemetrexed-based chemotherapy for advanced NSCLC. PATIENTS AND METHODS: We identified 121 patients with advanced, ALK-positive NSCLC in the USA, Australia, and Italy. For comparison, we evaluated 266 patients with advanced, ALK-negative, epidermal growth factor receptor (EGFR)-wild-type NSCLC, including 79 with KRAS mutations and 187 with wild-type KRAS (WT/WT/WT). We determined PFS on different pemetrexed regimens. RESULTS: Among 70 ALK-positive patients treated with a platinum/pemetrexed regimen, the median PFS (mPFS) was 7.3 months (95% confidence interval (CI) 5.5-9.5). The mPFS of 51 ALK-positive patients treated with single-agent pemetrexed or nonplatinum/pemetrexed combinations was 5.5 months (2.8-9.0). For ALK-negative patients, PFS on all pemetrexed-based regimens was similar to that of ALK-positive patients, except in the specific setting of first-line platinum/pemetrexed where the mPFS was only 4.2 and 5.4 months in KRAS and WT/WT/WT patients, respectively. However, among patients with a never/light-smoking history (0-10 pack-year smoking history) treated with first-line platinum/pemetrexed, there was no difference in PFS between ALK-positive and ALK-negative patients. CONCLUSIONS: PFS on pemetrexed or nonplatinum/pemetrexed combinations was similar in ALK-positive and ALK-negative patients. PFS on first-line platinum/pemetrexed may be prolonged in never/light-smoking patients regardless of ALK status.

Revised workflow practices in the management of acute invasive fungal sinusitis during the coronavirus disease 2019 pandemic.

OBJECTIVE: To document changes in evaluation protocols for acute invasive fungal sinusitis during the coronavirus disease 2019 pandemic, and to analyse concordance between clinical and histopathological diagnoses based on new practice guidelines. METHODS: Protocols for the evaluation of patients with suspected acute invasive fungal sinusitis both prior and during the coronavirus disease 2019 period are described. A retrospective analysis of patients presenting with suspected acute invasive fungal sinusitis from 1 May to 30 June 2021 was conducted, with assessment of the concordance between clinical and final diagnoses. RESULTS: Among 171 patients with high clinical suspicion, 160 (93.6 per cent) had a final histopathological diagnosis of invasive fungal sinusitis, concordant with the clinical diagnosis, with sensitivity of 100 per cent, positive predictive value of 93.6 per cent and negative predictive value of 100 per cent. CONCLUSION: The study highlights a valuable screening tool with good accuracy, involving emphasis on 'red flag' signs in high-risk populations. This could be valuable in situations demanding the avoidance of aerosol-generating procedures and in resource-limited settings facilitating early referral to higher level care centres.

Nasopharyngeal colonization of otopathogens in South Indian children with acute otitis media - A case control pilot study.

BACKGROUND: Acute otitis media (AOM) is an inflammatory disease of the middle ear causing significant morbidity in early childhood. A pilot study was undertaken to identify the role of various risk factors South Indian children with AOM, especially the role of nasopharyngeal otopathogens. METHODOLOGY: A prospective case control pilot study was conducted in children aged below six years, presenting to a single tertiary care from 2018 to 2019. Fifty cases with AOM and 45 age and gender matched controls were recruited. Two nasopharyngeal swabs were collected, one was processed for bacterial culture. The other swab was processed according to the CDC recommended broth enrichment method to identify carriage of S. pneumoniae. Subsequent serotyping was done by Quellung method and conventional sequential multiplex PCR. RESULT: Otalgia was the major presentation seen in 92% of the children with AOM. None of the clinical and demographic characteristics were found to be statistically significant between the cases and controls. The most common otopathogen was S. pneumoniae (55%) followed by H. influenza (29%). The common S. pneumoniae serotypes encountered were 11A and 19F.Nasopharyngeal colonization with S. pneumoniae [OR 6.57, p < 0.003] and H. influenzae [OR14.18, p < 0.003] were significant risk factors for AOM in children. The risk increased with co-colonization (OR 13.89,p < 0.003). CONCLUSION: This study strengthens the significant association between nasopharyngeal colonization of otopathogens and AOM as a risk factor that is enhanced by co-colonization.S. pneumoniae was the main otopathogen in this population, serotypes 11A and 19F being the most common.

Pediatric nasal dermoid- a decade's experience from a South Indian tertiary care centre.

INTRODUCTION: Nasal dermoid sinus cyst (NDSC) are uncommon congenital lesions in children. OBJECTIVE: To review the clinical and radiological presentation and study the surgical outcomes of this uncommon lesion. METHOD: Retrospective chart review of all children diagnosed with nasal dermoid from 2010 to 2020 at a tertiary referral hospital in South India was executed. The medical records were reviewed for demographics, lesion characteristics, imaging, operative details, and outcomes and literature review was performed. RESULT: A total of 25 children [Mean age 3.7 yrs (Range 2-9 yrs)] with nasal dermoid sinus cysts were treated in the last decade. While 13 presented with a sinus, 11 presented with cyst and 1 had both. The lesions mainly involved the upper third of the nose in 10 children, middle one third in 6 and upper one third in 9 children. All underwent Magnetic Resonance Imaging, in 11 Computed Tomography also was done. A flow chart of the lesion characteristics and its management has been presented. Intraoperatively intracranial extension was present in four children. The approach to intracranial extension and corresponding literature review has been presented. Follow up ranged from one to six years. (Median 3.5 yrs) and no recurrence or complication was noted. CONCLUSION: Nasal dermoid is an uncommon congenital anomaly. Preoperative evaluation must include imaging to assess extent and rule out intracranial extension. Surgical strategy depends on whether presentation is as sinus or cyst and location and extent of lesion. All surgical approaches have a good surgical and cosmetic outcome.

Five-year results of viscocanalostomy.

PURPOSE: To prospectively study the success rates and complications of viscocanalostomy. METHODS: Prospective nonrandomized case series of 46 eyes (46 patients) with medically uncontrolled primary and secondary open angle glaucoma. All patients in the study underwent viscocanalostomy. Control of intraocular pressure was used to measure success. Pre and postoperative glaucoma medications, visual acuity, complications, and adjunctive procedures were recorded. RESULTS: At 60 months, qualified success (intraocular pressure below 21 mmHg with glaucoma medication) was achieved in 37 (82%) patients and complete success (intraocular pressure below 21 mmHg without medication) in 25 (54%) patients. Nd:YAG laser goniopuncture was performed in 33 (72%) patients with significant post laser reduction of intraocular pressure. No sight threatening complications were observed in this series. Visual acuity remained unchanged in 33 patients (72%). CONCLUSIONS: Viscocanalostomy appears to be a safe and effective intraocular pressure lowering procedure in eyes with primary open angle glaucoma and certain types of secondary open angle glaucoma.

Nasopharyngeal angiofibroma (a report of 19 cases).

Nasopharyngeal Angiofibroma is a relatively rare benign, but locally aggresive tumor of the nasopharynx afflicting the adolescent males. The management of these tumors has been a subject of much interest and controversy in the past Here we present a series of 19 patients of nasopharyngeal angiofibroma (with CT Scan as the main stay of diagnosis) managed over the last 5 years at ENT and Head & Neck Surgery Department of S.S.G. Hospital, Vadodara, with infraoperative internal maxillary artery ligation via the trans maxillary approach permitting accurate removal of tumor with no major post operative complications, minimal blood loss, good cosmetic result and no recurrence till date. If further experience with this approach to management in a larger series of patients has the same results, surgery should be the gold standard in treatment of Nasopharyngeal angiofibroma.