Case Report: Stevens-Johnson Syndrome and Hepatotoxicity Induced by Osimertinib Sequential to Pembrolizumab in a Patient With EGFR-Mutated Lung Adenocarcinoma

Background: Lung cancer is a complex disease with many subtypes. However, histochemical characteristics, and genetic mutation determinations are contributing to better define therapeutic targets and new drugs. Although this guarantees patients the possibility of obtaining tailored treatment, it makes it more difficult for clinicians patient management more difficult for clinicians who have to define the most suitable therapeutic strategy and to deal with new treatment-related adverse events (TRAEs). It has been seen that the administration of a tyrosine kinase inhibitor (TKI) sequential to an immune checkpoint inhibitor (ICI) can lead to a higher rate of severe and life-threatening TRAEs. We report the case of a patient with advanced non-small cell lung cancer (NSCLC) who experienced severe hepatotoxicity and Stevens-Johnson syndrome (SJS) induced by osimertinib sequential to pembrolizumab. Case presentation: A 54-year-old woman with advanced NSCLC received one cycle of chemotherapy plus pembrolizumab after diagnosis. Ten days later she began osimertinib 80 mg daily because epidermal growth factor receptor (EGFR) analysis had revealed an exon 19 deletion. On day 23 of osimertinib the patient experienced an episode of grade (G) 3 hepatotoxicity resolved by discontinuing osimertinib and corticosteroid therapy. The patient restarted osimertinib 80 mg daily after the remission of symptoms but was hospitalized 14 days later following a second episode of severe G3 hepatotoxicity and the onset of SJS, successfully treated with high-dose corticosteroids. Despite the short exposure to osimertinib, the patient obtained a good pathological response. Conclusion: It is important to alert clinicians to carefully evaluate the sequential therapeutic strategy in patients with NSCLC who are candidates for TKI- or ICI-based treatment. Our experience suggests that the use of tyrosine kinase inhibitors (TKIs) as front-line treatment is a more reasonable and safe option for EGFR-mutated lung adenocarcinoma, with ICIs considered as a possible further treatment in sequential approaches

Variation in female reproductive tract morphology across the reproductive cycle in the zebra finch

Background In seasonally breeding birds, the reproductive tract undergoes a dramatic circannual cycle of recrudescence and regression, with oviduct size increasing 5–220 fold from the non-breeding to the breeding state. Opportunistically breeding birds can produce multiple clutches sequentially across an extended period in response primarily to environmental rather than seasonal cues. In the zebra finch, it has been shown that there is a significant reduction in gonadal morphology in non-breeding females. However, the scale of recrudescence and regression of reproductive tissue within a single breeding cycle is unknown and yet important to understand the cost of breeding, and the physiological readiness to breed in such flexible breeders. Methods We examined the reproductive tissue of breeding female zebra finches at six stages in the nesting cycle from pre-breeding to fledging offspring. We quantified the wet mass of the oviduct, the volume of the largest pre-ovulatory follicle, and the total number of pre-ovulatory follicles present on the ovary. Results Measures of the female reproductive tract were highest during nesting and laying stages and declined significantly in the later stages of the breeding cycle. Importantly, we found that the mass of reproductive tissue changes as much across a single reproductive event as that previously characterized between birds categorized as breeding and non-breeding. However, the regression of the ovary is less dramatic than that seen in seasonal breeders. This could reflect low-level maintenance of reproductive tissues in opportunistic breeders, but needs to be confirmed in wild non-breeding birds

Methods for Drainage of Distal Malignant Biliary Obstruction after ERCP Failure: A Systematic Review and Network Meta‐Analysis

There is scarce evidence on the comparison between different methods for the drainage of distal malignant biliary obstruction (DMBO) after endoscopic retrograde cholangiopancreatography (ERCP) failure. Therefore, we performed a network meta‐analysis to compare the outcomes of these techniques. We searched main databases through September 2021 and identified five randomized controlled trials. The primary outcome was clinical success. The secondary outcomes were technical success, overall and serious adverse event rate. Percutaneous trans‐hepatic biliary drainage was found to be inferior to other interventions (PTBD: RR 1.01, 0.88– 1.17 with EUS‐choledochoduodenostomy (EUS‐CD); RR 1.03, 0.86–1.22 with EUS-hepaticogastrostomy (EUS‐HG); RR 1.42, 0.90–2.24 with surgical hepaticojejunostomy). The comparison between EUS‐HG and EUS‐CD was not significant (RR 1.01, 0.87–1.17). Surgery was not superior to other interventions (RR 1.40, 0.91–2.13 with EUS‐CD and RR 1.38, 0.88–2.16 with EUS‐HG). No difference in any of the comparisons concerning adverse event rate was detected, although PTBD showed a slightly poorer performance on ranking analysis (SUCRA score 0.13). In conclusion, all interventions seem to be effective for the drainage of DMBO, although PTBD showed a trend towards higher rates of adverse events

Endoscopic ultrasound fine-needle biopsy vs fine-needle aspiration for lymph nodes tissue acquisition: A systematic review and meta-Analysis

Background: Endoscopic ultrasound (EUS)-guided tissue acquisition represents the choice of methods for suspected lymph nodes (LNs) located next to the gastrointestinal tract. This study aimed to compare the pooled diagnostic performance of EUS-guided fine-needle biopsy (EUS-FNB) and fine-needle aspiration (EUS-FNA) for LNs sampling. Methods: We searched PubMed/MedLine and Embase databases through August 2021. Primary outcome was diagnostic accuracy; secondary outcomes were sensitivity, specificity, sample adequacy, optimal histological core procurement, number of passes, and adverse events. We performed a pairwise meta-Analysis using a random-effects model. The results are presented as odds ratio (OR) or mean difference along with 95% confidence interval (CI). Results: We identified nine studies (1,276 patients) in this meta-Analysis. Among these patients, 66.4% were male; the median age was 67 years. Diagnostic accuracy was not significantly different between the two approaches (OR, 1.31; 95% CI, 0.81-2.10; P = 0.270). The accuracy of EUS-FNB was significantly higher when being performed with newer end-cutting needles (OR, 1.87; 95% CI, 1.17-3.00; P = 0.009) and in abdominal LNs (OR, 2.48; 95% CI, 1.52-4.05; P < 0.001) than that of EUS-FNA. No difference in terms of sample adequacy was observed between the two approaches (OR, 1.40; 95% CI, 0.46-4.26; P = 0.550); however, histological core procurement and diagnostic sensitivity with EUS-FNB were significantly higher than those with EUS-FNA (OR, 6.15; 95% CI, 1.51-25.07; P = 0.010 and OR, 1.87; 95% CI, 1.27-2.74, P = 0.001). The number of needle passes needed was significantly lower in the EUS-FNB group than in the EUS-FNA group (mean difference,-0.54; 95% CI,-0.97 to-0.12; P = 0.010). Conclusions: EUS-FNA and EUS-FNB perform similarly in LN sampling; however, FNB performed with end-cutting needles outperformed FNA in terms of diagnostic accuracy

Treatment with class a CpG oligodeoxynucleotides in cats with naturally occurring feline parvovirus infection: A prospective study

Feline parvovirus (FPV) causes severe gastroenteritis and leukopenia in cats; the outcome is poor. Information regarding specific treatments is lacking. Class A CpG oligodeoxynucleotides (CpG-A) are short single-stranded DNAs, stimulating type I interferon production. In cats, CpG-A induced an antiviral response in vivo and inhibited FPV replication in vitro. The aim was to prospectively investigate the effects of CpG-A on survival, clinical score, hematological findings, antiviral response (cytokines), viremia, and fecal shedding (real-time qPCR) in cats naturally infected with FPV. Forty-two FPV-infected cats were randomized to receive 100 g/kg of CpG-A (n = 22) or placebo (n = 20) subcutaneously, on admission and after 48 h. Blood and fecal samples were collected on admission, after 1, 3, and 7 days. All 22 cats showed short duration pain during CpG-A injections. The survival rate, clinical score, leukocyte and erythrocyte counts, viremia, and fecal shedding at any time-point did not differ between cats treated with CpG-A (50%) and placebo (40%). Antiviral myxovirus resistance (Mx) gene transcription increased in both groups from day 1 to 3 (p = 0.005). Antibodies against FPV on admission were associated with survival in cats (p = 0.002). In conclusion, CpG-A treatment did not improve the outcome in cats with FPV infection. FPV infection produced an antiviral response

Impact of biliary stents on the diagnostic accuracy of EUS-guided fine-needle biopsy of solid pancreatic head lesions: A multicenter study

There is no clear evidence of a negative impact of biliary stents on the diagnostic yield of EUS-guided fine-needle biopsy (EUS-FNB) for diagnosing pancreatic head lesions. We aimed to evaluate the association between the presence of biliary stents and the diagnostic accuracy of EUS-FNB. Materials and Methods: A multicenter retrospective study including all jaundiced patients secondary to pancreatic head masses was performed. Patients were divided into two groups according to the presence of a biliary stent placed before EUS-FNB. Pathological results were classified according to the Papanicolaou classification and compared against the final diagnosis. Diagnostic measures in the two groups were compared. Multivariate logistic regression analyses including potential factors affecting EUS-FNB accuracy were performed. Results: Overall, 842 patients were included, 495 (58.8%) without and 347 (41.2%) with biliary stent. A plastic or a metal stent was placed in 217 (62.5%) and 130 (37.5%) cases, respectively. Diagnostic sensitivity and accuracy were significantly higher in patients without biliary stent than in those with stent (91.9% and 92.1% vs. 85.9% and 86.4%, P = 0.010 At multivariate analyses, lesion size (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.02-1.09, P = 0.01) and presence of biliary stent (OR: 0.51, 95% CI: 0.32-0.89, P = 0.01) were independently associated with diagnostic accuracy. In the subgroup of patients with biliary stent, the type of stent (plastic vs. metal) did not impact EUS-FNB yield, whereas the use of larger bore needles enhanced diagnostic accuracy (OR: 2.29, 95% CI: 1.28-4.12, P = 0.005). Conclusions: In this large retrospective study, an indwelling biliary stent negatively impacted the diagnostic accuracy of EUS-FNB. Preferably, EUS-FNB should precede endoscopic retrograde cholangiopancreatography, especially in the case of small tumors

Gemcitabine and cisplatin in a multimodality treatment for locally advanced non-small cell lung cancer

The role of new cytotoxic agents like gemcitabine has not yet been proven in the neoadjuvant settings. We designed a phase II study to test the feasibility of using gemcitabine and cisplatin before local treatment for stage III non-small cell lung cancer patients. Patients received three cycles of induction chemotherapy of gemcitabine (1000 mg m−2, days 1, 8, 15) and cisplatin (90 mg m−2, day 15) every 4 weeks before evaluation for operability. Operable patients underwent radical resection. Inoperable patients and patients who had incomplete resection received concurrent chemoradiotherapy with daily low dose cisplatin. All patients who did not progress after local treatment received three more cycles of adjuvant chemotherapy of gemcitabine and cisplatin. Fifty-two patients received induction treatment. Two patients had complete response and 31 patients had partial response (response rate 63.5%) after induction chemotherapy. Thirty-six patients (69%) were operable. Eighteen patients (35%) had their tumours completely resected. Two patients had pathological complete response. Median overall survival was 19.1 months, projected 1-year survival was 66% and 2-year survival was 34%. Three cycles of gemcitabine and cisplatin is effective and can be used as induction treatment before surgery for locally advanced non-small cell lung cancer patients

Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis?

<p>Abstract</p> <p>Background</p> <p>Lymphangioleiomyomatosis (LAM) is a rare lung disease characterised by progressive airflow obstruction. No effective medical treatment is available but therapy with sirolimus has shown some promise. The aim of this observational study was to evaluate sirolimus in progressive LAM.</p> <p>Methods</p> <p>Sirolimus (trough level 5 - 10 ng/ml) was administered to ten female patients (42.4 ± 11.9 years) with documented progression. Serial pulmonary function tests and six-minute-walk-distance (6-MWD) assessments were performed.</p> <p>Results</p> <p>The mean loss of FEV₁was -2.30 ± 0.52 ml/day before therapy and a significant mean gain of FEV₁of 1.19 ± 0.26 ml/day was detected during treatment (p = 0.001). Mean FEV₁and FVC at baseline were 1.12 ± 0.15 l (36.1 ± 4.5%pred.) and 2.47 ± 0.25 l (69.2 ± 6.5%pred.), respectively. At three and six months during follow-up a significant increase of FEV₁and FVC was demonstrated (3 months ΔFEV₁: 220 ± 82 ml, p = 0.024; 6 months ΔFEV₁: 345 ± 58 ml, p = 0.001); (3 months ΔFVC: 360 ± 141 ml, p = 0.031; 6 months ΔFVC: 488 ± 138 ml, p = 0.006). Sirolimus was discontinued in 3 patients because of serious recurrent lower respiratory tract infection or sirolimus-induced pneumonitis. No deaths and no pneumothoraces occurred during therapy.</p> <p>Conclusions</p> <p>Our data suggest that sirolimus might be considered as a therapeutic option in rapidly declining LAM patients. However, sirolimus administration may be associated with severe respiratory adverse events requiring treatment cessation in some patients. Moreover, discontinuation of sirolimus is mandatory prior to lung transplantation.</p