Assessment of anti-PD-(L)1 for patients with coexisting malignant tumor and tuberculosis classified by active, latent, and obsolete stage

Background It is not a rare clinical scenario to have patients presenting with coexisting malignant tumor and tuberculosis. Whether it is feasible to conduct programmed death-(ligand) 1 [PD-(L)1] inhibitors to these patients, especially those with active tuberculosis treated with concurrent anti-tuberculosis, is still unknown. Methods This study enrolled patients with coexisting malignancy and tuberculosis and treated with anti-PD-(L)1 from Jan 2018 to July 2021 in 2 institutions. The progression-free survival (PFS), objective response rate (ORR), and safety of anti-PD-(L)1 therapy, as well as response to anti-tuberculosis treatment, were evaluated. Results A total of 98 patients were screened from this cohort study, with 45 (45.9%), 21 (21.4%), and 32 (32.7%) patients diagnosed with active, latent, and obsolete tuberculosis, respectively. The overall ORR was 36.0% for anti-PD-(L)1 therapy, with 34.2%, 35.5%, and 41.2% for each subgroup. Median PFS was 8.0 vs 6.0 vs 6.0 months (P=0.685) for each subgroup at the time of this analysis. For patients with active tuberculosis treated with concurrent anti-tuberculosis, median duration of anti-tuberculosis therapy was 10.0 (95% CI, 8.01–11.99) months. There were 83.3% (20/24) and 93.3% (42/45) patients showing sputum conversion and radiographic response, respectively, after anti-tuberculosis therapy, and two patients experienced tuberculosis relapse. Notably, none of the patients in latent and only one patient in obsolete subgroups showed tuberculosis induction or relapse after anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 33 patients (73.3%) when treated with concurrent anti-PD-(L)1 and anti-tuberculosis. Grade 3 or higher TRAEs were hematotoxicity (n = 5, 11.1%), and one patient suffered grade 3 pneumonitis leading to the discontinuation of immunotherapy. Conclusions This study demonstrated that patients with coexisting malignant tumor and tuberculosis benefited equally from anti-PD-(L)1 therapy, and anti-tuberculosis response was unimpaired for those with active tuberculosis. Notably, the combination of anti-PD-(L)1 and anti-tuberculosis therapy was well-tolerated without significant unexpected toxic effects.

The Potential of Snail Seromucous and Chitosan as Bioimunomodulator for Tuberculosis Therapy

Tuberculosis (TB) as a global emergency is a chronic disease caused by Mycobacterium tuberculosis (Mtb). Mtb plays an important role in inducing or suppressing the production of Interferon Gamma (IFNG) and IL-4 in the regulation of TB homeostasis and pathogenesis. The bioactive compounds of the snail seromucous (Achatina fulica Ferussac) and chitosan function as biological response modifiers. The study aimed to determine the potential effectiveness of snail seromucous and chitosan as bio-immunomodulator for TB therapy. The research method was based on the results of laboratory experiments with the physic-chemical, biochemical, microbiological examination, snail seromucous protein profile, lymphocyte proliferation, measurement of IFNG, and IL-4 levels. The results of the physic-chemical examination of the snail seromucous showed a specific gravity of 1.010; pH 8, glucose 16 mg/dL; cholesterol 9 mg/dL; protein 2.8 mg/dL and heavy metals (Pb, Cu, Hg, Al) negative. The results of microbiological tests showed that a 100% concentration of snail seromucous was antimicrobial against Staphylococcus aureus, Candida albicans, and Pseudomonas aeruginosa. The protein profile of snail seromucous shows that there are 3 protein subunits, namely the range 55 - 72 kDa and 1 specific protein sub-unit 43 kDa as a bioactive compound achasin sulfate. Addition of chitosan dose of 65 µg/mL; snail seromucous dose of 65 µg/mL and a mixture of chitosan (65 µg/mL): snail seromucous (65 µg/mL) ratio 1: 1, can increase lymphocyte proliferation; optimum levels of IFN-γ and IL-4. Snail seromucous and chitosan are effective immunomodulators and potential candidates for TB therapy.

Overcoming the Prokaryote/Eukaryote Barrier in Tuberculosis Treatment: A Prospect for the Repurposing and Use of Antiparasitic Drugs

Antimicrobial resistance, the so-called silent pandemic, is pushing industry and academia to find novel antimicrobial agents with new mechanisms of action in order to be active against susceptible and drug-resistant microorganisms. In the case of tuberculosis, the need of novel anti-tuberculosis drugs is specially challenging because of the intricate biology of its causative agent, Mycobacterium tuberculosis. The repurposing of medicines has arisen in recent years as a fast, low-cost, and efficient strategy to identify novel biomedical applications for already approved drugs. This review is focused on anti-parasitic drugs that have additionally demonstrated certain levels of anti-tuberculosis activity; along with this, natural products with a dual activity against parasites and against M. tuberculosis are discussed. A few clinical trials have tested antiparasitic drugs in tuberculosis patients, and have revealed effective dose and toxicity issues, which is consistent with the natural differences between tuberculosis and parasitic infections. However, through medicinal chemistry approaches, derivatives of drugs with anti-parasitic activity have become successful drugs for use in tuberculosis therapy. In summary, even when the repurposing of anti-parasitic drugs for tuberculosis treatment does not seem to be an easy job, it deserves attention as a potential contributor to fuel the anti-tuberculosis drug pipeline.

Angioplasty With Stent Implantation for Portal Venous Stenosis Caused by Abdominal Tuberculosis: A Case Report and Literature Review

Abdominal tuberculosis is one of common forms of extra-pulmonary tuberculosis. However, portal vein involvement leading to portal venous stenosis and portal hypertension is a rare complication in abdominal tuberculosis. Because of the non-specific presentations and insensitive response to anti-tuberculosis therapy of the lesions involving portal vein, it continues to be both a diagnostic and treatment challenge. We have reported a 22-year-old woman presented with massive ascites and pleural effusion, which was proved to be TB infection by pleural biopsy. After standard anti-tuberculosis therapy, her systemic symptoms completely resolved while ascites worsened with serum-ascites albumin gradient >11 g/L. Contrast-enhanced computed tomography and portal venography showed severe main portal vein stenosis from compression by multiple calcified hilar lymph nodes. Finally, the patient was diagnosed with portal venous stenosis due to lymphadenopathy after abdominal tuberculosis infection. Portal venous angioplasty by balloon dilation with stent implantation was performed and continued anti-tuberculosis therapy were administrated after discharge. The ascites resolved promptly with no recurrence occurred during the six-month follow-up. Refractory ascites due to portal venous stenosis is an uncommon vascular complication of abdominal tuberculosis. Portal venous angioplasty with stent placement could be a safe and effective treatment for irreversible vascular lesions after anti-tuberculosis therapy.

Drug-induced hypocalcemia

Hypocalcemia (HCa) is one of the main water-electrolyte disturbances in clinical practice. An acute decrease in serum calcium levels can lead to seizures, ventricular arrhythmias, bronchospasm and laryngospasm. Chronic HCa can result in disorientation and confusion. To prevent these complications, the risk factors for low calcium levels must be carefully evaluated. One of these factors is drugs, in which case we are talking about drug-induced (DI) HCa. The list of drugs-inducers of DI HCa is quite extensive, but the leading role in this disorder is played by drugs for the treatment of osteoporosis, antineoplastic and antiepileptic drugs, as well as drugs for anti-tuberculosis therapy. When taking zoledronic acid, DI HCa is observed with a frequency of up to 39%. When taking imatinib, a targeted anticancer drug, a decrease in calcium levels was observed in 40% of cases. The pathophysiological mechanisms of DI HCa can be a decrease in bone resorption, a decrease in the concentration of vitamin D, inhibition of the action of parathyroid hormone and impaired calcium absorption. Risk factors in most cases of DI HCa are vitamin D deficiency and hypomagnesemia. An acute decrease in calcium levels leads to symptoms of neuromuscular excitability, abnormalities on the electrocardiogram (ECG) and electroencephalogram (EEG). The basis for the treatment of DI HCa is the drug withdrawal and the appointment of calcium. It is also necessary to prescribe vitamin D. The main methods of prevention of DI HCa are to determine the level of calcium and vitamin D before starting therapy with culprit medication, and to correct its level. It is also important to prescribe additional amounts of calcium and vitamin D during therapy with such drugs. Awareness of the attending physicians about the problem of DI HCa, a thorough assessment of its risk factors and the prophylactic administration of calcium and vitamin D preparations will help to effectively prevent those serious complications resulting from a decrease in calcium levels in clinical practice.