Immune Checkpoint Inhibitor-Associated Myocarditis: A Literature Review.

Recently in the field of oncology, immune checkpoint inhibitors (ICI) are being increasingly utilized both in clinical trials and in clinical practice. It is a form of biological therapy that targets tumors by activating the immune system, which in turn eliminates proliferating cancer cells. These have numerous immune-related adverse events (irAEs), one of which is myocarditis, which has high rates of mortality. This article was a narrative review of myocarditis related to ICI use.  Studies from the PubMed, Cochrane, and American Society of Clinical Oncology (ASCO) databases were used in writing this review. The databases were searched for original publications for adverse effects related to ICI use and myocarditis specifically. There are numerous published instances of cancer immunotherapy causing myocarditis. ICI therapy has numerous benefits, as it upregulates the immune system to target cancer cells, utilizing the body's own defense mechanisms to target proliferating cells. Myocarditis is a serious side effect, however. Therefore, on balance, these monotherapies are worth using. While this literature review primarily identifies cross-reaction as the main mechanism of myocarditis, there are other possible mechanisms. One proposed mechanism involves a shared antigen between the myocardial tissue and the tumor. This mechanism is called molecular mimicry, where the monoclonal antibody attacks both the myocardial tissue and the tumor cell. Management of ICI-induced myocarditis has not been studied by randomized controlled trials or prospective studies, but based on previous case reports and case series it is mostly treated with steroids initially. An ICI rechallenge after temporary discontinuation appears conceivable in many cases, especially given its therapeutic effects, but only limited data are available on the safety of a rechallenge after an irAE. The lack of RCTs regarding rechallenge with an ICI after irAE, more so specifically about myocarditis, along with the overall results and the complexity involved in such cases once again emphasize the need to make decisions on an individual basis by a multidisciplinary expert working group. At the same time, the focus should also be on publishing more data as the need will grow along with the indications for ICI therapies.

Role of granulocyte colony stimulating factor (G-CSF) in dengue patients with severe thrombocytopenia.

OBJECTIVE: To determine the effects of granulocyte colony-stimulating factor in improving platelet count in patients with dengue fever. METHODS: The retrospective, cross-sectional study was conducted at Northwest General Hospital and Research Centre, Peshawar, Pakistan, between January 2021 and October 2022, and comprised dengue fever inpatients regardless of age and gender who received granulocyte colony-stimulating factor subcutaneously. The impact of colony-stimulating factor on platelet and white blood cell counts as well as any unfavourable consequences was assessed. Convenient sampling was used and a structured format was used for data collection. Data was analysed using SPSS 21. RESULTS: Of the 100 patients, 67(67%) were males and 33(33%) were females. The largest age group was that of >55 years 31(31%), fever was present in all the 100(100%) cases, bleeding in 18(18%) and platelet count <30,000 in 83(83%) cases. Dengue fever was confirmed by rapid dengue nonstructural protein 1 antigen in 76(76%) cases, dengue immunoglobulin G antibody test 28(28%), and immunoglobulin M antibody test in 31(31%) cases. Overall, 72(72%) patients received only one dose of granulocyte colony-stimulating factor. Post-administration, a substantial rise in the median platelet and white blood cell counts was seen compared to the baseline (p<0.05) on day 2. CONCLUSIONS: Granulocyte colony-stimulating factor helped increase platelet and white blood cell counts quickly in dengue fever patients.

Pembrolizumab-Induced Myasthenia Gravis: A Case Report and Review of the Literature.

Myasthenia gravis (MG) is one of the most common neuromuscular adverse effects of immune checkpoint inhibitors (ICIs) and can result in significant morbidity and mortality when it affects the bulbar and respiratory muscles. Diagnosing immune-related MG (irMG) is challenging due to its nonspecific presentation and high negativity rate for MG antibody markers. Patients, primary care providers, and emergency care providers should be educated about MG as a potential adverse effect of ICIs for timely diagnosis and intervention.

Vancomycin-Induced Hemolytic Anemia.

Drug-induced hemolytic anemia is rare and can occur either by an immune-mediated mechanism or a non-immune-mediated mechanism. The drugs most frequently associated with immune-mediated hemolysis are penicillins and cephalosporins. It is usually difficult to distinguish drug-induced hemolysis from other more common causes of hemolysis; therefore, a high index of clinical suspicion is required to make the diagnosis. In this case report, we present a case of vancomycin-induced immune hemolytic anemia in a 75-year-old patient who developed hemolytic anemia after starting vancomycin for joint infection. Hematological parameters improved after the discontinuation of vancomycin. Mechanism and management of drug-induced immune hemolytic anemia are also reviewed in this report.

A systematic review on the available treatment modalities for Bacillus Calmette-Guérin-unresponsive carcinoma in situ and tumors in patients who are ineligible for or decline radical cystectomy.

Introduction: Globally, urothelial bladder carcinoma is a disease which carries a poor prognosis. There are various treatment modalities for urothelial bladder carcinoma with intravesical Bacillus Calmette-Guérin immunotherapy being the most efficacious intravesical therapy and the treatment of choice for patients with carcinoma in situ. A number of chemotherapeutic drugs are also available for the management of Ta/T1 tumors such as mitomycin C and epirubicin. However, relapse and progression is quite common. The optimal management of patients with Bacillus Calmette-Guérin-unresponsive disease remains to be a challenge. The purpose of this study was to conduct a systematic review on the treatment modalities available for the management of Bacillus Calmette-Guérin-unresponsive carcinoma in situ and urothelial bladder carcinoma in patients who are ineligible or decline radical cystectomy. Methods: Two authors independently searched three databases on the treatment modalities available for the management of Bacillus Calmette-Guérin-unresponsive carcinoma in situ and Bacillus Calmette-Guérin-unresponsive urothelial bladder carcinoma. Results: The systematic search resulted in 15 studies. We recommend the use of intravesical CG0070 adenovirus or hyperthermic intravesical chemotherapy mitomycin C in patients with carcinoma in situ only disease. In patients with carcinoma in situ ± Ta/T1 disease, we recommend the use of intravesical radiofrequency-induced chemohyperthermia or electromotive drug administration of mitomycin C. In patients who have Ta/T1 disease, we recommend the use of either hyperthermic intravesical chemotherapy epirubicin or electromotive drug administration mitomycin C followed by chemohyperthermia mitomycin C. If any of these second line therapies fail, an alternative regimen would be a combination of gemcitabine, cabazitaxel, and cisplatin. Conclusion: This recommendation is subject to the available resources and clinical expertise available in different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs with larger sample sizes and regular follow-up intervals should be performed to accurately assess the different medications and aid in designing guidelines to guide the management of Bacillus Calmette-Guérin-unresponsive non-muscle invasive intravesical bladder cancer.

Germ Cell Tumor With Somatic-Type Malignancy: A Case Report and Review of the Literature.

A malignant germ cell tumor (GCT) might contain or transform into malignant non-germ cell histology, commonly referred to as somatic-type malignancy (SM). It is a rare phenomenon with poorly understood pathogenesis. SMs are mostly associated with teratomas and are mainly observed in late relapsing cases. There are no consensus guidelines on the management of SMs; however, surgery is considered to be the mainstay of treatment. Prognosis is variable depending on the time of diagnosis, site of relapse, and type of histology. Here, we present a case of a 44-year-old male with a history of mixed GCT stage IIA, initially managed with right radical orchiectomy, who developed a relapse of GCT 10 years later with an SM of adenocarcinoma subtype.

Comparison of the performance of Tubex® TF, widal immunodiagnostic assay and blood culture in diagnosis of enteric fever in a private tertiary care hospital Peshawar, Pakistan.

OBJECTIVE: To determine and compare the performance of TUBEX®TF, Widal test and blood culture in the diagnosis of enteric fever. METHODS: The retrospective study was conducted at the Northwest General Hospital and Research Centre, Hayatabad, Peshawar, Pakistan, and comprised medical record from January to December 2018 related to patients who presented with fever. Typhidot, Widal test and blood culture had been performed as part of evaluation. Data was analysed using SPSS 16. RESULTS: Of the 241 patients, 68(28.21%) tested positive for salmonella in blood culture. Among them, TUBEX®TF was positive in 29(42.64%) and Widal was positive in 25(36.76%). TUBEX®TF had positive predictive value 33.33%, negative predictive value 71.77%, sensitivity 42.65% and specificity 62.34%. The corresponding values for Widal were 24.51%, 69.06%, 36.76% and 55.49%. CONCLUSIONS: Sensitivity, specificity, positive predictive value and negative predictive value of TUBEX®TF and Widal test were very low compared to blood culture.

Immunotherapy in gastroesophageal cancers: Current state and future directions.

While gastroesophageal (GE) cancers are one of the most common cancers worldwide, unfortunately, the mortality remains high. Commonly used treatment options include surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy, which improve survival only minimally; thus, affirming the dire need for exploring alternative strategies to improve patient outcomes. Immunotherapy, which has revolutionized the world of oncology, has somewhat lagged behind in GE malignancies. Tumor-associated microenvironment and regulatory T cells, alongside cell cycle checkpoints, have been proposed by various studies as the mediators of carcinogenesis in GE cancers. Thus, inhibition of each of these could serve as a possible target of treatment. While the approval of pembrolizumab has provided some hope, it is not enough to override the dismal prognosis that this disease confers. Herein, we discuss the prospects of immunotherapy in this variety of cancer.

Senile Systemic Amyloidosis Presenting as Hematuria: A Rare Presentation and Review of Literature.

INTRODUCTION: Senile systemic amyloidosis is a multisystem disease where wild-type insoluble transthyretin (ATTRwt) protein gets deposited in the tissues leading to organ dysfunction. METHODOLOGY: We present the case of a patient who presented with hematuria and bladder involvement by ATTRwt amyloidosis who ultimately died of multiorgan failure. RESULTS: The patient was an 82-year-old white male with a history of ischemic cardiomyopathy (ejection fraction (EF): 20-25%), chronic atrial fibrillation, chronic kidney disease (CKD), and carpal tunnel syndrome who presented with acute hematuria, urinary retention, and progressive fatigue. He underwent cystoscopy and bladder biopsy which was positive on congo-red stain diagnostic for amyloidosis. Echocardiogram demonstrated worsening of EF to 10-15% and concentric left ventricle hypertrophy. MRI was not performed due to underlying CKD. His condition deteriorated during the hospital stay, and he developed cardiogenic shock and progressive liver dysfunction. Infectious workup was negative. Meanwhile, the biochemical investigations (serum protein electrophoresis, immunofixation, and urine kappa/lambda chains) ruled out plasma cell dyscrasias. Mass spectrometry analysis of the bladder biopsy specimen confirmed wild-type transthyretin (ATTRwt) amyloidosis consistent with senile systemic amyloidosis. Due to patients' extremely poor prognosis, his family wished to focus on patient's comfort-oriented measures only, and patient passed away shortly thereafter. CONCLUSION: Senile systemic amyloidosis can rarely present in an atypical fashion such as hematuria. The treatment options are limited in this disease process. Novel therapies are in the early phases of development. Concern also exists that in patients with multiple comorbidities, this entity is under recognized until the more advanced stages.

Nonbacterial thrombotic endocarditis as the initial presentation of prostate cancer- a case report.

Nonbacterial thrombotic endocarditis (NBTE) refers to noninfectious vegetations of the heart valves. It is commonly associated with malignancy and autoimmune diseases like systemic lupus erythematosus, Rheumatoid arthritis. Herein, we present Non-bacterial thrombotic endocarditis and Disseminated intravascular coagulation as the initial manifestations of prostate cancer. A 50-yearold gentleman, known case of hypertension and diabetes, presented with a history of recurrent ischaemic strokes, STEMI and a recent diagnosis of infective endocarditis. He had been taking antibiotics for the past 20 days without any improvement. Negative blood cultures in the presence of vegetations on repeat echocardiography led to a suspicion of NBTE. Laboratory investigations were suggestive of Disseminated intravascular coagulation. CT abdomen and pelvis demonstrated enlarged prostate with enlarged pelvic lymph nodes. Prostate specific antigen was raised at more than 100ng/ml. A bone scan showed extensive metastasis. The patient was started on GnRH analogue and bicalutamide. His Disseminated intravascular coagulation resolved and he was subsequently started on anticoagulants. The valvular lesions diminished without any residual dysfunction.

A typical presentation of dengue fever in a G6PD deficient patient: A case report.

Dengue is a mosquito-borne viral disease that has rapidly spread in the recent years, particularly in South Asia. While haematologic complications, such as cytopenia and bleeding, may occur in severe dengue infection, reports of haemolytic anaemia in dengue fever are scant. We report a patient who developed haemolytic anaemia following dengue fever. A 45 years old gentleman presented with five-day history of fever and was recently diagnosed with dengue fever. He developed jaundice and started vomiting on the third day of his clinical course. His laboratory investigations revealed deranged liver profile, Coombs negative haemolytic anaemia and G6PD deficiency. He was treated conservatively with fluids and blood transfusions. His liver functions and haemolytic anaemia gradually resolved. This case highlights the importance of recognising dengue fever-induced haemolytic anaemia in a G6PD deficient patient by physicians and pathologists, enabling better diagnosis and improved management of this life-threatening condition.

Primary Hyperparathyroidism Masquerading as Rickets.

Primary hyperparathyroidism (PHPT) is common among adults. However, its incidence is rare among children associated invariably with delay in diagnosis. In children, it is caused by hyperplasia, adenoma or related hereditary disorders. Herein, a 17-year male with PHPT presented with rare skeletal manifestations of genu valgum and bilateral epiphyseal displacement of femur. Investigations done three years ago reported hypocalcemia and vitamin-D deficiency. He was diagnosed with rickets and received plenty of calcium and vitamin D supplements. Due to lack of clinical improvement following the supplementation, re-evaluation revealed hypercalcemia, elevated vitamin D levels and elevated parathyroid hormone (PTH). A 99mTc-sestamibi scan reported increased uptake in the left inferior lobe of the thyroid gland. Surgical removal of the parathyroid gland was done and histopathology revealed parathyroid adenoma. Rickets in the setting of PHPT can masquerade as PHPT. In a patient with rickets, hypercalcemia at presentation or following the calcium and vitamin supplementations, should warn the physicians to rule out PHPT.

Aplastic anemia secondary to propylthiouracil: A rare and life-threatening adverse effect.

BACKGROUND: Propylthiouracil has been in use for more than half a century for the treatment of hyperthyroidism. While it is largely known to cause agranulocytosis, its association with aplastic anemia is rarely heard of. Our case will be the third in literature to suggest aplastic anemia as a manifestation of propylthiouracil, which unfortunately culminated in the death of the patient. CASE: A 67-year-old female, with recently diagnosed metastatic adenocarcinoma of the lung, developed hyperthyroidism after being started on Nivolumab and Iplimumab. After she developed atrial fibrillation, she was started on propylthiouracil to control the thyroid activity. Soon after that, she was admitted with severe neutropenia, which progressed to pancytopenia confirmed as aplastic anemia on a bone marrow biopsy. Despite discontinuation of propylthiouracil and aggressive treatment, she developed septic shock and multi-organ failure, leading to her death. CONCLUSION: Aplastic anemia has been sparingly reported as an extremely rare complication of propylthiouracil. Further adding to the ambiguity is the unknown etiology and lack of specific therapy for the complication when attributed to propylthiouracil. The disease can carry an extremely poor prognosis if untreated, as proven by our case. Due to the same reasons, we recommend that further investigations be done to elucidate the pathogenesis and assist with treatment of the disease when caused by propylthiouracil.

Cholestatic jaundice: a unique presentation leading to the diagnosis of HLH with Hodgkin lymphoma, HIV and EBV.

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of dysregulated immune activity with macrophage activation that can manifest as pancytopenia, coagulopathy and other laboratory abnormalities, usually progressing to multiorgan failure and death. This report documents the rarely reported association between HLH and Hodgkin's lymphoma (HL) with simultaneous HIV and Epstein-Barr virus (EBV) and complete resolution with chemotherapy. The patient initially presented with cholestatic jaundice. He was then found to have HL associated with HLH with coexistent HIV and EBV viraemia. A-Brentuximab-VD regimen for the lymphoma was initiated, resulting in rapid resolution of HLH and ultimately remission of HL. HLH is a syndrome known to have high mortality; thus, early diagnosis and prompt treatment are crucial. Usual presentation includes non-specific symptoms and can easily be overlooked. This case highlights the importance of diagnosing the condition in unusual settings and attempting treatment by targeting the cause of HLH, HL in our case.

Trends in hospitalization for congestive heart failure, 1996-2009.

BACKGROUND: Although heart failure (HF) is a common cause of hospital admissions, few data describe temporal trends in HF hospitalization. We present data on number of HF admissions, length of stay (LOS), and inpatient mortality in the United States, 1996-2009. HYPOTHESIS: To assess HF hospitalizations in a national sample of United States population. METHODS: Data were obtained from the National Hospital Discharge Survey (NHDS), a national probability sample survey of discharges conducted annually by the National Center for Health Statistics. Sampling weights are applied to raw NHDS data to produce national estimates. Hospitalizations with a primary diagnosis of HF were identified using ICD-9-CM codes. We excluded hospitalizations where HF was a secondary diagnosis. Weighted least squares regression was used to test for linear trends in HF hospitalizations. RESULTS: Approximately 15.5 million weighted primary HF hospitalizations were included. The number of total primary HF hospitalizations increased from 1 000 766 in 1996 to about 1 173 832 in 2009 (ß = 7371 hospitalizations per year; 95% confidence interval (CI): 552 to 14 190, P = 0.036). Mean LOS per hospitalization decreased from 6.07 days in 1996 to about 5.26 days in 2009 (ß = -0.059 days per year; 95% CI: -0.079 to -0.039, P < 0.001). Inpatient mortality rates declined from 4.92% in 1996 to 3.41% in 2009 (ß = -0.17% per year; 95% CI: -0.23 to -0.10, P < 0.001). CONCLUSIONS: In a nationally representative sample of HF hospitalizations, mean LOS and inpatient mortality rates declined over the past 2 decades. HF management cost is most likely to be reduced by decreasing the number of HF admissions.

Pattern of sexually transmitted diseases in patients presenting at Ayub teaching hospital, Abbottabad.

BACKGROUND: Sexually transmitted diseases are present in all societies across the globe. Different cultures and societies show a different spectrum of these diseases. The last study conducted in Hazara division was back in 1995. We have conducted this study to see the recent trends and patterns of sexually transmitted diseases in the region. METHODS: This cross-sectional study was conducted in Ayub Teaching Hospital, Abbottabad and included patients over a five year period from January 2010 till December 2014. Case sheets of 512 presenting with sexually transmitted diseases whose diagnosis was confirmed by related lab investigation were analysed retrospectively. Patients of all ages and both sexes were included. RESULTS: Out of these 512 patients only 47 were females and 465 were males. The age varied from 15-66 years. Gonorrhoea was the commonest disease with 231 cases. Genital warts were diagnosed in 60 cases. Non- gonococcal urethritis was seen in 57 patients. Genital Molluscum contagiosum was seen in 45 patients. Syphillis was diagnosed in 41 patients. Thirty-one cases of herpes genitalis, 25 cases of Chancroid, 13 cases of Lymphogranuloma venereum, were also seen. Five patients were found positive for HIV. Overwhelming majority of the patients were between the age of 19-35 years. 61% of the patients were married. The source of infection in male patients was mainly prostitutes (70%) but also included homosexual boys (21 %), married women (7.5%) and eunuchs (1.5%). The main source of infection in females was from husbands. CONCLUSION: The number of STD patients presenting in the region has increased significantly. The main factor is obviously the rise in population but also signifies the change in cultural and moral values.

Constitutional and behavioral risk factors for chilblains: a case-control study from Pakistan.

OBJECTIVES: To study constitutional and behavioral risk factors for chilblains in patients at Abbottabad and Sialkot, Pakistan. METHODS: One hundred patients and matched controls completed a single-page, close-ended questionnaire which included demographic data and questions related to possible constitutional and behavioral risk factors for chilblains. Computer program SPSS-10 was used to manage and analyze the data. Risk factors were identified statistically by determining odds ratios and 95% confidence intervals using multivariate analysis. RESULTS: There were an equal number of male and female respondents in each group. Age of the patients and controls ranged from 2 to 80 years with a mean of 24.51 +/- 16.02. Twenty-six patients and 3 controls had a positive family history for chilblains (odds ratio = 9.33); 42 patients and 14 controls reported a history of constipation (odds ratio = 2.69); 32 patients and 8 controls had a history of either numbness or tingling of fingers or toes (odds ratio = 2.93); 55 patients and 45 controls led sedentary lifestyles (odds ratio = 1.27); 85 patients and 58 controls consumed a low number of cups of tea daily (odds ratio = 3.20); 65 patients and 29 controls frequently washed their hands and/or feet (odds ratio = 4.93); and 56 patients and 33 controls had occasional sun exposure during winter months (odds ratio = 2.08). CONCLUSION: Significant risk factors for the development of chilblains for people at Abbottabad and Sialkot included a history of chilblains in first-degree relatives, numbness and tingling sensations of fingers or toes, frequent hand or feet washing, and lower tea consumption during winter months.