Therapeutic strategies for BRAF mutation in non-small cell lung cancer: a review.

Lung cancer is the leading cause of cancer related deaths. Among the two broad types of lung cancer, non-small cell lung cancer accounts for 85% of the cases. The study of the genetic alteration has facilitated the development of targeted therapeutic interventions. Some of the molecular alterations which are important targets for drug therapy include Kirsten rat sarcoma (KRAS), Epidermal Growth Factor Receptor (EGFR), V-RAF murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase gene (ALK). In the setting of extensive on-going clinical trials, it is imperative to periodically review the advancements and the newer drug therapies being available. Among all mutations, BRAF mutation is common with incidence being 8% overall and 1.5 - 4% in NSCLC. Here, we have summarized the BRAF mutation types and reviewed the various drug therapy available - for both V600 and nonV600 group; the mechanism of resistance to BRAF inhibitors and strategies to overcome it; the significance of comprehensive profiling of concurrent mutations, and the role of immune checkpoint inhibitor in BRAF mutated NSCLC. We have also included the currently ongoing clinical trials and recent advancements including combination therapy that would play a role in improving the overall survival and outcome of NSCLC.

Erythema Multiforme: A Presentation of COVID-19 Pneumonia.

Since its emergence in December 2019, coronavirus disease 2019 (COVID-19) has been detrimental worldwide. Although COVID-19 infection is primarily known for its respiratory manifestations, extrapulmonary features are increasingly being reported. Among these, cutaneous manifestations are apparent but have a high likelihood of not being attributed to COVID-19. We present the case of a 63-year-old female unvaccinated against COVID-19. She presented with fever, cough, shortness of breath, and rash. The symptoms were present for four days and appeared after contact with a confirmed symptomatic COVID-19-positive family member. The rash started first on the chest and then spread to the face and whole body including the palms and soles. It was erythematous and maculopapular and is associated with ulceration and swelling of the lips. In places, it was confluent and had a target-like appearance. On admission, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) was negative. As she was septic with initial suspicion of tick-borne infections, she was started on doxycycline. Given her symptoms on presentation, the suspicion of COVID-19 was very high, and the SARS-CoV-2 nasal swab PCR was repeated, which was negative yet again. With the index of suspicion being very high, her presentation was speculated to be atypical, especially in the setting of a target-like rash involving the palms and soles. The antibody was checked. IgG antibodies for SARS-CoV-2 were positive. All other antibodies for mycoplasma, Lyme disease, Ehrlichia, and Rocky Mountain spotted fever (RMSF) were negative. Parvovirus DNA and chikungunya IgG, antinuclear antibody (ANA), and antineutrophil cytoplasmic antibody (ANCA) screens were negative. IgG for mycoplasma, dengue, and herpes simplex virus 1 (HSV1) were positive. During all this time, the patient did not show clinical improvement in spite of being on antibiotics. In fact, her oxygen saturation dropped, and she required oxygen through the nasal cannula. A lung tissue biopsy taken on bronchoscopy showed chronic inflammation and organizing pneumonia. To note, mycoplasma DNA PCR and HSV culture from bronchoalveolar lavage (BAL) were negative. The patient was started on intravenous steroids. A confirmatory skin biopsy was done, and it showed perivascular, interstitial, and spongiotic dermatitis related to a viral infection. While on steroids, the patient improved dramatically. Her skin rash also improved, and she was discharged. On outpatient follow-up, she was doing exceptionally well with ambulatory oxygen saturation of 100%. This patient who was COVID-19 PCR-negative twice could have been easily deemed as not having COVID-19. However, the fact that she was unvaccinated, had positive sick contact with imaging concern for COVID-19 pneumonia, and COVID-19 antibody being positive and no other test being positive clearly attributes her manifestations to the virus. The presence of a rash could easily be misleading. Awareness of the fact that a rash like erythema multiforme (EM) could be a sign of underlying COVID-19 is extremely prudent and is an addition to the ever-expanding knowledge of this virus.

Platypnea-Orthodeoxia Syndrome: A Rare and Treatable Cause of Positional Dyspnea.

Platypnea-orthodeoxia means low oxygen saturation and dyspnea in the upright posture which improves on lying down. The causes can be classified into the intrapulmonary shunt, intracardiac shunt, and ventilation-perfusion mismatch. A 62-year-old male presented with shortness of breath, which had worsened over a period of one year. Various investigations were done to rule bacterial, viral infection, pulmonary embolism, and other respiratory and cardiac causes. The initial echocardiogram showed an ejection fraction of 55%. The patient was observed to be having dyspnea only in the upright position. In the recumbent position, the dyspnea disappeared with a marked improvement in oxygen saturation. A repeat echocardiogram with a bubble study was done which showed an atrial septal defect. Surgical closure of the defect was performed which improved the patient's oxygen saturation to baseline normal. This case demonstrates that a vigilant approach is required in cases of dyspnea, keeping in mind the not-so-common phenomenon like platypnea-orthodeoxia syndrome.

DNA Ploidy Analysis and Cell Block Immunohistochemistry in the Diagnosis of Malignant Effusions.

BACKGROUND: Effusion cytology is a major diagnostic tool in medicine and has both therapeutic and prognostic implications. One of the dilemmas encountered is the differentiation between atypical cells and reactive mesothelial cells. The use of ancillary tools can reduce this grey zone and help to achieve a definitive diagnosis. OBJECTIVES: The main objective of this study was to evaluate the role of flow cytometry (FCM) and cell block with immunohistochemistry (IHC), along with the clinicoradiological investigations, to achieve a final diagnosis in effusion cytology to the maximum extent possible. METHOD: A prospective study was conducted. Effusion fluids, showing adequate amount and cellularity, were processed for conventional cytology, ploidy analysis by FCM, and cell block analysis, followed by IHC wherever required. Conventional cytological analysis was done by 2 independent pathologists, to look for interobserver variation, if any. The final result was achieved on the basis of integration of the results of the aforementioned studies, cytological details, clinicoradiological information, tissue biopsy findings, and follow-up. RESULT: A total of 90 samples were analyzed. On cytological examination, observer I categorized 60% samples as benign and 18.8% (n = 17) as malignant versus 58% categorized as benign and 23.3% (n = 21) as malignant by observer II. Observer I reported 19 (21.1%) equivocal cases and observer II reported 16 (17.7%). When both pathologists were considered together, the number of equivocal cases increased to 20. Sensitivity and specificity of FCM were 96.67 and 100%, respectively, and 100% for the cell block. On combining all techniques, the equivocal cases were resolved and a total of 33 cases were reported as malignant. However, 3 cases could still not be categorized and were labeled inconclusive. CONCLUSION: Conventional cytology combined with cell block IHC and FCM has the potential to minimize the requirement of tissue biopsy for confirmation. If the first sample is used judiciously for all the techniques, this may reduce the requirement for a second sample and possibly also the time required for a definite diagnosis and the initiation of therapy.