Common single nucleotide polymorphisms associated with idiopathic pulmonary fibrosis: a systematic review.

BACKGROUND: Several genetic variants are associated with the risk of idiopathic pulmonary fibrosis (IPF). These have not been systematically reviewed. METHODS: We searched the PubMed, Embase and GWAS Catalog databases for studies indexed between inception and 15 January 2024 describing genetic variants associated with IPF susceptibility. We included studies describing common associated single nucleotide polymorphisms (SNPs). We excluded studies describing rare variants, non-SNP variants and those without an allelic model analysis. We recorded study type, participant characteristics, genotyping methods, IPF diagnostic criteria, the SNPs and the respective genes, odds ratios, and other details. We also searched databases for functions of the identified genes. RESULTS: The primary search retrieved 2697 publications; we included 42 studies. There were nine genome-wide association/linkage studies, while 27 were candidate gene studies. The studies included 22-11 160 IPF subjects. 88 SNPs in 58 genes or loci were found associated with IPF susceptibility. MUC5B rs35705950 was the most studied SNP. Most (n=51) SNPs were in the intronic or intergenic regions; only 11 were coding sequence variants. The SNPs had odds ratios ranging from 0.27 to 7.82 for an association with IPF. Only 22 SNPs had moderate-large effects (OR >1.5 or <0.67). Only 49.1% of the associated genes have a known functional role in IPF; the role of G protein-related signalling and transcriptional regulation (zinc-finger proteins) remain unexplored. CONCLUSION: Several common SNPs in over 50 genes have been found associated with IPF susceptibility. These variants may inform gene panels for future studies (PROSPERO CRD42023408912).

Pathologic Validation of Deauville Score-Based Disease on F-18 FDG PET/CT after First-Line Treatment in Patients with Lymphoma.

Purpose: PET/CT-based Deauville scoring (DS) is routinely used for lymphoma response assessment. However, pathological correlation of DS is not yet precisely documented. In the present study we aimed to pathological confirm the PET/CT-based Deauville scoring (DS) in lymphoma after first-line chemotherapy. Materials and methods: Participants undergoing PET/CT for response assessment following first-line treatment were recruited prospectively. DS ≥ 4 lesions were interpreted as PET-positive, while DS ≤ 3 as PET-negative. Participants with a PET-positive lesion or suspicious of inadequate response (DS ≤ 3) were recruited for metabolic core-needle biopsy. True-negative and benign histopathology were kept on follow-up for three months. Histopathological, clinical and imaging findings were assessed for diagnostic performance. Procedure-related complications were also noted. Results: In all, 148/480 participants were PET-positive, and 332/480 were PET-negative. 138/148 PET-positive and 12/332 PET-negative lesions were recruited for biopsy. Biopsy was performed in 147/150 participants (PET-positive 135; PET-negative 12). Three patients with inaccessible lesions were excluded. The diagnostic yield of the procedure was 97.3% (143/147). Histology revealed lymphoma in 106 participants (including 70% of total DS-4, 100% of DS-5a and 73.9% of DS-5b lesions), with three false-negative lesions. DS ≤ 3 lesions were true-negative except one diagnosed with lymphoma (8.3%) on follow-up. Non-lymphomatous malignancies (n = 5), granulomas (n = 12), non-specific inflammation (n = 9) and no residual disease (n = 11) were diagnosed in the rest. No major procedure-related adverse event was noted. Conclusion: A DS-5a lesion suggests residual disease; hence, a biopsy can be prevented unless Richter's transformation is suspected. DS-4 and DS-5b lesions require a biopsy before changing the treatment plan, as a certain number of participants had non-lymphomatous F-18 FDG-avid lesions.

A Randomized Control Trial Comparing the Yield of Bronchoalveolar Lavage Using Three Different Techniques in Patients Undergoing Flexible Bronchoscopy (BAL-3T).

BACKGROUND: Three techniques have been described for aspirating the bronchoalveolar lavage (BAL) fluid, namely the wall mount suction (WMS), manual suction (MS), and manual suction with tubing (MST). However, there is no direct comparison among the 3 methods. METHODS: We randomized patients undergoing flexible bronchoscopy and BAL in a 1:1:1 ratio to one of the 3 arms. The primary outcome was to compare the optimal yield, defined as at least 30% return of volume instilled and <5% bronchial cells. The key secondary outcomes were the percentage of volume and total amount (in millimeters) return of BAL, as well as complications (hypoxemia, airway bleeding, and others). RESULTS: We randomized 942 patients [MST (n = 314), MS (n = 314), WMS (n = 314)]. The mean age of the study population [58.7% (n = 553) males] was 46.9 years. The most common indication for BAL was suspected pulmonary infection. Right upper lobes and middle lobes were the commonest sampled lobes. The optimal yield was similar in all the groups [MST (35.6%) vs MS (42.2%) vs WMS (36.5%); P = 0.27]. A significantly higher proportion of patients had BALF return >30% (P = 0.005) in the WMS (54.2%) and MS (54%) than in the MST arm (42.9%). The absolute and the percentage volume of BALF was also higher in WMS and MS than in the MST arm. There was no difference in the complication rate or other secondary outcomes across the groups. CONCLUSION: We found no difference in the optimal yield of BAL or complications using any one of the 3 methods for BAL fluid retrieval.

Pulmonary Langerhans Cell Histiocytosis: Diagnosis in Bronchoalveolar Lavage Liquid-Based Cytology Samples.

INTRODUCTION: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease characterized by the accumulation of Langerhans cells within the lung tissue. The diagnosis of PLCH traditionally involves clinical, radiological, and lung biopsy histopathological evaluations. CASE PRESENTATION: We present 2 cases where the diagnosis of PLCH was confirmed through the analysis of bronchoalveolar lavage (BAL) fluid cytology using immunoperoxidase technique, highlighting the significance of this minimally invasive technique in the diagnostic process. Clinical and radiological examination suggested advanced interstitial lung disease characterized by a fibrocystic pattern in both cases. The cytologic analysis of the BAL fluid revealed typical histiocytes with longitudinal grooves and eosinophils, which was better seen on liquid-based cytology (LBC) smears. ICC with CD1a, Langerin, and S-100 confirmed the diagnosis of PLCH. CONCLUSION: Detecting PLCH through the examination of BAL cytology poses challenges, yet it is achievable, particularly with the assistance of LBC and ICC.

Comparative morphology of tumour microenvironment in claudin-low and claudin-high breast cancers.

BACKGROUND: Claudin-low breast cancers (BCs) exhibit more aggressive behaviour compared to claudin-high types. Claudin-low BCs are often characterized by features such as a higher grade, enrichment of stemness characteristics, and a propensity for metastasis. Tumour microenvironment (TME) defined as the intricate network of surrounding cells, blood vessels, and extracellular matrix components influences the behaviour of cancer cells within the breast tissue. Understanding the TME is crucial for comprehending the aggressive characteristics of claudin-low BCs. METHODS: In this study, we have studied the morphology of immune and non-immune TME using Haematoxylin and eosin (H&E)-stained slides of 15 claudin-low and 12 claudin-high tissue samples of BC. RESULTS: TME of claudin-low BCs was observed to have a significantly higher frequency of retraction clefts (66.6 %; n = 10/15), immature desmoplastic response (40 %; n = 6/15), higher stromal cellularity (60 %; n = 9/15); and fibroblastic proliferation (53.3 %; n = 8/15) with a low prevalence of elastosis (66.6 %; n = 10/15). The immune microenvironment revealed a higher frequency of total (80 %; n = 12/15) as well as stromal (86.67 %; n = 13/15) and intra-tumoural TILs (60 %; n = 9/15) in them. CONCLUSION: The above morphology-based study revealed that claudin-low tumours have unique immune and non-immune TME as compared to claudin-high tumours. Future studies exploring the molecular correlates of each of the above morphological features can help in identifying novel therapeutic targets for the treatment of claudin-low BCs.

Double trouble: insights from a rare case of extranodal composite lymphoma in an elderly man, with comprehensive literature review.

Composite lymphoma (CL) is a rare cancer characterized by the concurrent occurrence of more than one type of lymphoma within the same organ or tissue in an individual. Its occurrence at extranodal sites is exceptional, with only a few cases documented in the literature. A 62-year-old gentleman presented with dystonia, dysphagia, and irregular enlargement of the right tonsil for the last three months. Based on a clinical suspicion of tonsillar malignancy, tonsillectomy was done. The histopathologic examination revealed effacement of the architecture by large irregular lymphoid nodules with interfollicular expansion. The nodules showed sheets of small atypical lymphoid cells, while the interfollicular areas showed large atypical lymphoid cells with scattered typical binucleate Reed-Sternberg cells. Immunohistochemistry confirmed mantle cell lymphoma (MCL) in the nodules and classical HL (cHL) in the interfollicular areas. Based on these features, a diagnosis of composite MCL with cHL was rendered. He was treated with bendamustine and rituximab chemotherapy and remained in complete remission for five years when he presented with significant right-sided neck swelling. Percutaneous fine needle aspiration and subsequent flow cytometry confirmed a relapse of the MCL component of the CL. The index report documents an exceptional case of CL, comprising MCL and cHL, presenting at an uncommon extranodal site. In addition, it also emphasizes the importance of adequate sampling and the simultaneous use of immunochemistry and/or flow cytometry to confirm the presence of more than a single type of lymphoma, which may be easily overlooked on microscopy alone.

Chemotherapy related changes in cfDNA levels in squamous non-small cell lung cancer: correlation with symptom scores and radiological responses.

Aim: There is limited data on prognostic value of baseline plasma cell free DNA (cfDNA) in advanced squamous non-small cell lung cancer (sq-NSCLC). This prospective observational study aimed to assess change in plasma cfDNA levels in locally-advanced/metastatic sq-NSCLC with chemotherapy and its correlation with symptom-scores and radiological-responses. Methods: Chemotherapy-naive patients with stages-IIIB/IIIC/IV sq-NSCLC (n = 59), smokers with chronic obstructive pulmonary disease [COPD, COPD-controls (CC); n = 27] and healthy-controls (n = 25) were enrolled. Respiratory symptom burden (RSB) and total symptom burden (TSB) were calculated from mean visual-analog-scores (VAS) of dyspnoea, cough, chest pain, hemoptysis RSB, anorexia and fatigue (all six for TSB). cfDNA was isolated from peripheral blood. All patients received platinum-doublet chemotherapy. RSB/TSB/cfDNA assessment and contrast-enhanced computed tomography (CECT)-thorax scans were done at baseline and post-chemotherapy. Results: At baseline, 13/59 (22%) sq-NSCLC, 3/27 (11%) CC and none (0%) healthy-controls had detectable cfDNA. All three CC were heavy smokers with no evidence of malignancy and undetectable cfDNA levels on repeat testing. In sq-NSCLC group, majority were males (95%), current-smokers (88%), heavy-smokers (70%), had metastatic disease (59%) with median age of 65 years. Eastern Co-operative Oncology Group (ECOG) performance status (PS) was 0-1 (56%) and 2 (42%). Median RSB- and TSB-scores were 9 [interquartile range (IQR) = 5-14] and 16 (IQR = 9-23), respectively. Of the 59 patients, 54 received ≥ 1 cycle while 27 underwent post-C4 evaluation with detectable cfDNA levels in 18/27 (66.7%). No baseline characteristic correlated with cfDNA detectability. Median overall survival (OS) and progression-free survival (PFS) were 262 days and 167 days, respectively. ECOG PS ≥ 2, RSB-score > 9 and TSB-score > 16 were all associated with worse OS and PFS as was cfDNA detectability [median OS = 97 days vs. 298 days and median PFS = 97 days vs. 197 days; P = 0.025; hazard ratio (HR) = 2.17]. Conclusions: Baseline cfDNA detectability is independently associated with poor OS and PFS in patients with advanced sq-NSCLC on chemotherapy.

Bridging the gap: understanding contemporary autopsies in acute leukemia by comparing ante-mortem and post-mortem profiles.

This study investigates acute myeloid leukemia/lymphoblastic leukemia (AML/ALL) through a 14-year analysis (2009-2022) of 46 autopsied cases (age >12 years). B-ALL was the dominant subtype (34.8%). Liver and spleen were the common sites of active leukemia (63% cases). Symptoms like dyspnea and altered sensorium associated significantly with heart (p = .031) and brain leukostasis (p = .006). Measurable residual disease (MRD) negativity correlated with disease-free status outside the bone marrow, while MRD-positive cases displayed leukemic infiltrates. Infections were identified in 23 autopsied cases, notably linked to post-induction and post-transplant fatalities. Surprisingly, 18 of these 23 cases had unexpected infections mainly fungal (13 cases) with Aspergillus species as the most common. Diagnostic discrepancies were identified in 48% of cases. Malignant infiltration (46%) and infections (25%) were the leading causes of death. This research sheds light on leukemia in extra-medullary tissues, uncovers novel clinical-pathological associations, and highlights overlooked therapy side effects, offering insights for future case management.

Challenges in Administering Salvage Therapy and Outcomes of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients: A LMIC Real-World Study.

Standard therapy for patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR DLBCL) involves salvage chemotherapy followed by autologous hematopoietic stem cell transplant. However, information regarding the number of patients receiving salvage therapy and associated factors is not available from low/middle income countries (LMICs). All patients treated at our center with RR DLBCL from 2016 to 2021 were included in the study. Univariate and multivariate analyses was performed to find factors associated with the lack of receipt of salvage chemotherapy. Eighty-five patients were included in the study. Most patients had primary refractory disease (69.4%). Only 26 patients received standard salvage therapy, while the others (N = 59) received metronomic/palliative oral therapy. On univariate analysis, patients with an annual income below India's Gross National Income per capita (p = 0.014), an education level below Class XII (p = 0.025), Stage III/IV disease at relapse (p = 0.018) and CNS relapse (p = 0.027) were more likely to receive palliative therapy. Conversely, patients with a late relapse were more likely to receive salvage therapy (p = 0.001). On multivariate analysis, patients with Stage III/IV relapse (p = 0.030) and an education level less than Class XII (p = 0.012) were more likely to receive palliative therapy, while patients with a late relapse (p = 0.001) were more likely to receive salvage therapy. Patients who received salvage therapy had a longer Median OS than those who received palliative therapy (p < 0.001). Timing of relapse, stage at relapse and educational status of the patient are significant factors affecting access to effective therapy for patients with RR DLBCL in LMICs.

A novel indirect ELISA for serodiagnosis of mucormycosis using antigens from Rhizopus arrhizus.

BACKGROUND: Due to a delay in diagnosis by conventional techniques and high mortality, the development of a standardised and rapid non-culture-based technique is an unmet need in pulmonary, gastrointestinal, and disseminated forms of mucormycosis. Though limited studies have been conducted for molecular diagnosis, there are no established serologic tests for this highly fatal infection. OBJECTIVE: To develop and evaluate an indirect in-house enzyme-linked immunosorbent assay (ELISA) utilising antigens of Rhizopus arrhizus for detecting anti-Rhizopus antibodies (IgG and IgM) in sera of patients with mucormycosis. METHODS: We extracted both secretory and mycelial Rhizopus antigens using standardised protocols. Bradford assay was used for protein quantification. We then standardised an indirect ELISA using R. arrhizus mycelial and secretory antigens (10.0 µg/mL in bicarbonate buffer pH 9.2) for detecting anti-Rhizopus IgG and IgM antibodies in patient sera. We included patients with mucormycosis, other fungal infections, and healthy controls. Antibody index value (E-value) was calculated for each patient sample. RESULTS: Asparagine broth culture filtrate utilising 85% ammonium sulphate salt fractionation and mycelial homogenate grown in yeast extract peptone dextrose (YPD) broth precipitated with trichloroacetic acid (TCA) yielded a large amount of good-quality protein for the assay. We included 55 patients with mucormycosis (rhino-orbito-cerebral mucormycosis [ROCM, n = 39], pulmonary [n = 15], gastrointestinal [n = 1]), 24 with other fungal infections (probable aspergillosis [n = 14], candidiasis [n = 10]), and healthy controls (n = 16). The sensitivity of the antibody test for diagnosing mucormycosis ranged from 83.6-92.7% for IgG and 72.7-87.3% for IgM, with a specificity of 91.7-92.5% for IgG and 80-82.5% for IgM. The sera from patients with other fungal infections and healthy individuals did not show significant cross-reactivity. CONCLUSION: The detection of anti-Rhizopus IgG antibody performed significantly better in comparison to IgM-based ELISA for diagnosing both ROCM (sensitivity of 84.6% vs. 69.2%) and pulmonary cases (86.6% vs. 80.0%). More extensive studies are required to confirm our findings.

Acute liver failure caused by lymphocyte-depleted Hodgkin lymphoma in tuberculosis and HIV-infected patient.

The lymphocyte-depleted classic Hodgkin lymphoma (LDCHL), the rarest subtype of classic Hodgkin lymphoma (CHL), is usually diagnosed at an advanced stage (stage IV) and one that unusually involves the liver, causing a rapidly progressive clinical course. We describe a 40-year-old immunocompromised man presenting with a progressive non-cholestatic jaundice and intermittent fever. The abdominal ultrasonography revealed a nodular liver with coarse echotexture and periportal hypodensities. The thoracic and abdominal contrast-enhanced computed tomography revealed right cervical and paraaortic lymphadenopathy, hepatosplenomegaly, diffuse mural thickening of duodenal and jejunal loops, and bilateral lobulated kidneys. Subsequently, he succumbed to his illness secondary to refractory septic shock. On postmortem examination, he was diagnosed with classic Hodgkin lymphoma (lymphocyte-depleted type) involving paraaortic and mediastinal lymph nodes based on morphology and immunochemistry findings. The lymphomatous process involved the liver (causing multiacinar confluent hepatic necrosis) and spleen, both showing tuberculous foci. This autopsy case depicts an uncommon case of acute liver failure due to infiltration of the liver by LDCHL in an HIV-infected patient. The findings of angiotropism and angioinvasion establish the pathological mechanism of liver failure (hepatocellular necrosis) in such cases.

FDG PET/CT in the Diagnosis and After Sunitinib Follow-up of Synchronous Base of Tongue and Thyroid Metastases From Renal Cell Carcinoma.

ABSTRACT: Renal cell carcinoma (RCC) is a leading cause of mortality among genitourinary malignancies with limited therapeutic options. The hematogenous route, lymphatic spread, and direct invasion have been documented in RCC. Usually, metastases are regional lymph nodes, lungs, bone, liver, adrenal glands, contralateral kidney, and brain. Metastases to the rare sites such as skin, breast, head and neck were documented in the literature. In the present case, we describe the synchronous metastases to the base of the tongue and thyroid gland in RCC and the response to sunitinib therapy on 18F-FDG PET/CT.

Cancer associated fibroblasts modulate the cytotoxicity of anti-cancer drugs in breast cancer: An in vitro study.

BACKGROUND: Tumour microenvironment (TME) contributes to resistance to anti-cancer drugs through multiple mechanisms including secretion of pro-survival factors by cancer associated fibroblasts (CAFs). In this study, we determined the chemotherapy resistance producing potential of CAFs in molecular subtypes of breast cancer. METHODS: The CAFs were isolated from fresh lumpectomy/mastectomy specimens of different molecular subtypes of breast cancer. The CAFs were cultured and secretome was collected from each breast cancer subtype. Breast cancer cell lines MCF-7, SK-BR3, MDA-MB-231, and MDA-MB-468 were treated with different doses of tamoxifen, trastuzumab, cisplatin, and doxorubicin alone respectively and in combination with secretome of CAFs from respective subtypes. MTT assay was done to check cell death after drug treatment. Liquid chromatography-mass spectrometry (LCMS) analysis of CAF secretome was also done. RESULTS: MTT assay showed that anti-cancer drugs alone had growth inhibitory effect on the cancer cells however, presence of CAF secretome reduced the anti-cancer effect of the drugs. Resistant to drugs in the presence of secretome, was determined by increased cell viability i.e., MCF-7, 51.02% to 63.02%; SK-BR-3, 34.22% to 44.88%; MDA-MB-231, 52.59% to 78.63%; and MDA-MB-468, 48.92% to 55.08%. LCMS analysis of the secretome showed the differential abundance of CAFs secreted proteins across breast cancer subtypes. CONCLUSIONS: The treatment of breast cancer cell lines with anti-cancer drugs in combination with secretome isolated from molecular subtype specific CAFs, reduced the cytotoxic effect of the drugs. In addition, LCMS data also highlighted different composition of secreted proteins from different breast cancer associated fibroblasts. Thus, TME has heterogenous population of CAFs across the breast cancer subtypes and in vitro experiments highlight their contribution to chemotherapy resistance which needs further validation.

68 Ga-FAPI PET/CT in an Interesting Case of Metastatic Pulmonary Meningioma.

ABSTRACT: Meningiomas are one of the major primary CNS tumors. Most meningiomas are benign, but rarely, these metastasize to distant organs, the lungs being the commonest site of metastasis. 18 F-FDG PET/CT has been used to evaluate metastatic pulmonary meningioma. However, 68 Ga-FAPI PET/CT has not yet been evaluated. The present case highlights the 68 Ga-FAPI uptake in metastatic pulmonary meningioma in a postoperated case of left tentorial meningioma presenting with lung masses. Image-guided biopsy from the lung mass was consistent with metastatic meningioma.

Diagnostic Yield and Safety of the 19-Gauge versus 22-Gauge Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Needle in Subjects with Sarcoidosis (GUESS).

INTRODUCTION: Observational data suggest that the 19-gauge (G) needle for endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) offers a higher diagnostic yield than the 22-G needle in sarcoidosis. No randomized trial has compared the yield of the two needles. METHODS: We randomized consecutive subjects with suspected sarcoidosis and enlarged thoracic lymph nodes to undergo EBUS-TBNA with either the 19-G or the 22-G needle. We compared the study groups for diagnostic sensitivity (primary outcome) assessed by the yield of granulomas in subjects finally diagnosed with sarcoidosis. We also compared the sample adequacy, difficulty performing the needle puncture assessed on a visual analog scale (VAS), the subject's cough intensity on an operator-rated VAS, and procedure-related complications (secondary outcomes). RESULTS: We randomized 150 (mean age, 43.0 years; 55% women) subjects and diagnosed sarcoidosis in 116 subjects. The diagnostic sensitivity of the 19-G needle (45/60, 75.0%) was not higher (p = 0.52) than the 22-G needle (39/56, 69.6%). We obtained adequate aspirates in 90.0% and 85.7% of subjects in the respective groups (p = 0.48). The operators had greater difficulty puncturing lymph nodes with the 19-G needle (p = 0.03), while the operator-assessed cough intensity was similar in the groups (p = 0.41). Transient hypoxemia was the only complication encountered during EBUS-TBNA (two subjects in either group). CONCLUSION: We did not find the 19-G needle superior to the 22-G in diagnostic sensitivity, specimen adequacy, or safety of EBUS-TBNA in sarcoidosis. Puncturing the lymph nodes was more difficult with the 19-G needle.

The conundrum of breast cancer mimics.

The BIRADS lexicon ensures a standard reporting terminology in breast imaging and serves as a means of smooth communication between the radiologist and the referring physician. BIRADS assessment categories 4 and 5 warrant a biopsy to rule out underlying malignancy. However, a substantial number of cases in these categories sometimes turn out to be benign on biopsy. These benign mimics encompass inflammatory, sclerosing, neoplastic and a few other miscellaneous conditions. Awareness of these various mimics of breast cancer can equip the radiologist to handle these apparent cases of radiologic-pathological (rad-path) discordance better, guide overall patient management, avoiding inadvertent excisional biopsies and help alleviate patient anxiety and confusion.

Periprosthetic metastases in carcinoma of unknown primary: A rare association.

ABSTRACT: Septic or aseptic loosening may cause bone loss around artificial prosthesis leading to prosthesis failure. This occurrence due to metastatic infiltration of bone or surrounding soft tissues is rare but has been occasionally reported. We report a case of an elderly lady presenting with swelling and pain at the site of previous hemiarthroplasty performed for traumatic injury. On evaluation, she was found to have a lytic femur lesion with a large soft-tissue component around the prosthetic joint. Biopsy suggested a metastatic carcinoma of renal origin, but screening of kidneys did not reveal any primary lesion. She had additional skeletal metastatic lesions but no other primary site was detected either. She was given palliative radiotherapy and systemic therapy (sunitinib) based on the histologic diagnosis of renal cell origin but did not tolerate it. Thereafter, she is continuing on zoledronate every 4 weeks and best supportive management since 4 months from diagnosis.