Sjogren's syndrome due to immune checkpoint inhibitors (ICIs): Insights from a single-institution series and systematic review of the literature.

INTRODUCTION: Careful adverse event assessment and management are important when prescribing immune checkpoint inhibitors (ICIs) to cancer patients. Iatrogenic Sjogren's syndrome is a relatively rare immune-related adverse event (irAEs) that affects the moisture-producing glands. METHODS: We describe a series of four patients who developed Sjogren's syndrome while being treated with ICIs at a community cancer center in Southern California, USA (1/1/2017-12/31/2023). Patient, drug and disease-related data were collected by retrospective chart review. A systematic search of the PubMed database was performed to identify similar cases in the literature (1/1/2016-12/31//2023). RESULTS: Of 224 cancer patients at our center treated with ICIs, four (1.8%) developed iatrogenic Sjogren's syndrome. All of our patients were male; three received PD-1 inhibitors (nivolumab, pembrolizumab) and one received the PD-L1 inhibitor atezolizumab. The median time to development of Sjogren's syndrome was 24 weeks (range, 8-36 weeks); dry mouth symptoms were more prominent than dry eye symptoms. None of the patients had elevated SS-A, SS-B or antinuclear antibodies. One patient developed multiple tooth cavities and had several extractions, due to severe xerostomia. Management of all patients was primarily symptomatic. Two cases were irreversible; one was reversible and the 4th case is undermined as he is still on ICI therapy. Our systematic review of the literature identified 80 cases in five articles. Incidence of xerostomia was twice of that of xerophthalmia. The male/female ratio was 1.5:1. SS-A, SS-B, or antinuclear antibodies were found in only 9% of patients. Steroids were reported to have had only a limited role in management. CONCLUSIONS: The incidence of Sjogren's syndrome due to ICIs in our center was 1.8%. Details of clinical course and management in these patients are presented. Caring for patients with ICI-related Sjogren's syndrome is facilitated by a multidisciplinary effort including oncologists, otolaryngologists, dentists, ophthalmologists and rheumatologists. Expanding the knowledge base pertaining to iatrogenic Sjogren's syndrome in patients on ICIs will be helpful in promoting early detection and treatment, and improving outcomes.

Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic mucosal melanoma.

INTRODUCTION: Nivolumab is an immune checkpoint inhibitor used in the treatment of several malignancies. A number of immune-related endocrinopathies have been linked to its use. CASE REPORT: We report a unique case of a 74-year-old man with well-controlled diabetes mellitus type 2 and metastatic mucosal anorectal melanoma who presented with diabetic ketoacidosis after receiving his third cycle of nivolumab 240 mg intravenous (IV) every 2 weeks. He was found to have autoantibodies against glutamic acid decarboxylase 65. Genotyping for human leukocyte antigens showed the presence of DQB1*02:01 and DRB1*03:01. MANAGEMENT AND OUTCOME: His presentation was complicated by acute renal failure. He required aggressive fluid resuscitation and insulin supplementation to reverse severe acid-base disturbance and multiple electrolyte abnormalities. After an 8-week interruption, the patient restarted nivolumab without any further evidence of adverse events over the next 12 weeks. He continues to require insulin replacement therapy. DISCUSSION AND CONCLUSION: Development of type 1 diabetes with the use of immune checkpoint inhibitors has been increasingly reported in the literature. The exact mechanism for autoimmune diabetes precipitated by nivolumab is yet to be elucidated. Patient education about the symptoms of diabetes and regular glucose monitoring cannot be overemphasized. Testing for antibodies against glutamic acid decarboxylase 65, insulin receptors, and islet cells may also prove useful. Human leukocyte antigen DQ and DR haplotyping prior to immune checkpoint inhibitor treatment might help determine susceptibility toward developing type 1 diabetes, and provide opportunities for earlier recognition, intervention, and possibly prevention.

Acquired angioedema late in the course of nivolumab treatment.

INTRODUCTION: Although programmed cell death-1 inhibitors have become the mainstay of treatment for many cancers, their use can at times be accompanied by unusual side effects. CASE REPORT: We describe herein a 43-year-old patient with Lynch syndrome and colon cancer who developed facial swelling 18 months after starting nivolumab therapy. Our patient also experienced a grade 1 maculopapular rash due to this agent. Naranjo nomogram assessment showed a probable causality between nivolumab and angioedema (score of 8). MANAGEMENT & OUTCOME: Given the modest intensity of symptoms and the excellent response of metastatic colon cancer to nivolumab, this agent was continued without interruptions. She was prescribed prednisone 20 mg orally daily as needed to be taken if the swelling progressed, or if respiratory symptoms developed. The patient experienced another two similar episodes over the next months; however, they were self-limiting and did not require steroids. Subsequently, she had no further similar symptoms. DISCUSSION: Rare reports of angioedema associated with immune checkpoint inhibitor (ICI) treatment have previously been described. The exact mechanism of these phenomena is unknown, but bradykinin release leading to increased vascular permeability might be involved. Clinicians, pharmacists, and patients should be aware of this rare side effect of ICIs as it can be life-threatening when involving the respiratory tract and causing impending airway obstruction.

Advanced uterine papillary serous cancer: Could there be a role for newer targeted therapeutic approaches or immune checkpoint inhibitors?

BACKGROUND: Although now available in oncology clinics, comprehensive germline mutation testing is being performed only in a minority of patients with advanced uterine papillary serous cancer (UPSC). Some of these patients might harbor various targetable mutations, either heritable or acquired.Data sources: We conducted a retrospective cohort study involving all consecutive patients with UPSC treated at our institution from 2009-2019. Data on epidemiology, with an accent on personal and family history of cancer, clinical presentation, disease stage, employed treatment modalities and cancer-specific survival (CSS) was sought. FINDINGS: Thirteen patients were seventy years of age or younger (≤70) while 15 were older than seventy (>70), and the two arbitrary patient cohorts were well-balanced for the TNM stage. Four UPSC patients >70 had a personal history of metachronous breast cancer. We also identified five cases of breast cancer, two cases of colon cancer, and one of each ovarian and uterine cancer in the first-degree relatives of UPSC patients >70. More than 90% of patients had surgical excision/debulking, and nearly half of the patients in each group received systemic chemotherapy. The most common chemotherapy regimen was carboplatin-paclitaxel every three weeks. Compared to patients ≤70, the UPSC patients >70 were less likely to undergo postoperative radiation therapy (6% vs 61.5%; p = 0.001) and had a worse CSS (21.8 vs. 27.4 months; HR 0.61, p = 0.03). CONCLUSIONS: Personal and family history in a cohort of older UPSC patients identified an excess of second primary cancers, and these patients displayed a shorter CSS. Comprehensive germline and tumor mutation analysis might identify optimal candidates for various targeted agents and immune checkpoint inhibitors, and ultimately improve survival. This may represent an unmet need in the UPSC patients, and further studies are needed to confirm the significance of our findings.

Severe terminal ileitis induced by single-agent nivolumab administered every four weeks.

INTRODUCTION: Use of immune checkpoint inhibitors has expanded to a variety of malignancies including hepatocellular carcinoma, where nivolumab and pembrolizumab have shown durable responses in approximately a sixth of patients. CASE REPORT: We report herein a patient with metastatic hepatocellular carcinoma who achieved a durable response to the second-line agent nivolumab administered intravenous 240 mg every two weeks. After 18 months of therapy, nivolumab schedule was changed to intravenous 480 mg every four weeks, per patient's request and for convenience of administration. Four days after this change, the patient developed severe terminal ileitis.Management and outcome: This condition was managed in hospital with intravenous steroids. The patient improved clinically and was discharged on an oral steroid taper. A month later, nivolumab was reinstated at 200 mg intravenous infusions every two weeks, without any re-occurrence of terminal ileitis to date as of six months after the probable drug reaction. DISCUSSION: To our knowledge, this is the first report of terminal ileitis with nivolumab administered every four weeks. As postmarketing evaluation of nivolumab continues, similar side effects may be observed. Prompt diagnosis and steroid therapy in these cases are imperative to ensure a favorable outcome. Resuming immunotherapy once the adverse event has resolved appears to be a safe option.

Management and clinical outcomes in uterine malignant mixed Müllerian tumor: Lessons from a single-institution series.

Malignant mixed Müllerian tumor remains an important contributor to morbidity and mortality in women with uterine cancer. Surgery is the primary treatment modality, followed by chemotherapy and/or radiation for advanced disease or high-risk patients. Clinico-epidemiologic characteristics and outcomes in older versus younger women with Malignant mixed Müllerian tumor may differ. We analyzed and now report on 15 consecutive patients with uterine Malignant mixed Müllerian tumor treated at our institution from 2000 to 2018. The mean age at diagnosis was 65 years; 60% (9/15) patients were overweight/obese. Forty-six percent (7/15) had hypercholesterolemia, an association not previously linked with Malignant mixed Müllerian tumor in the literature. All patients but one had surgical excision of the tumor. A third of patients received adjuvant radiation therapy. A majority of patients received chemotherapy; the preferred regimen was carboplatin-paclitaxel. The patients older than 70 had a tendency towards a more advanced disease stage at diagnosis and a significantly shorter cancer-specific survival than their younger counterparts (6 months vs. 102 months (hazard ratio 1.32, p = 0.02)). Our study's conclusions are restricted due to its relatively small size, retrospective design, and some variation in the chemotherapy doses administered in individual patients. Larger studies are needed to confirm the significance of our findings.

Inferior outcomes in immunocompromised Merkel cell carcinoma patients: Can they be overcome by the use of PD1/PDL1 inhibitors?

Cases of Merkel cell carcinoma have become increasingly more common in the last two decades, and its incidence has been predicted to climb further. Immunosenescence might explain in part the higher Merkel cell carcinoma prevalence in seniors aged 70 and older. This cancer might also be more aggressive in immunocompromised patients. In a subset of immunocompromised Merkel cell carcinoma patients, we identified significant lymphopenia and a more advanced disease stage compared with their immunocompetent counterparts. Time to death in this cohort was much shorter than in immunocompetent subjects, and their likelihood of death from Merkel cell carcinoma was five times higher. Avelumab approval in 2017 represents an important step forward in the therapy of Merkel cell carcinoma. Hopefully, PD1/PDL1 inhibitors will improve survival in immunocompromised Merkel cell carcinoma hosts, traditionally linked with inferior clinical outcomes.

Severe left atrial enlargement due to carfilzomib use in multiple myeloma.

Several cardiovascular effects have been attributed to carfilzomib in the recent literature. These side effects must be recognized promptly by treating physicians and pharmacists. Special attention is required in patients with pre-existing cardiac conditions, liver function abnormalities and/or advanced age. This is the first report of a severe left atrial enlargement due to carfilzomib use in the setting of multiple myeloma. This condition improved dramatically seven months after cessation of carfilzomib. The authors discuss further various cardiac and vascular abnormalities linked with carfilzomib in the medical literature. Prompt withdrawal of this agent is essential in these cases as it may prevent dismal outcomes.

Clinico-epidemiologic characteristics and patterns of care in Kaposi's sarcoma: Data from a single-institution series.

In the late 20th to early 21st century, most new Kaposi's sarcoma cases were associated with HIV coinfection and low CD4 T-cell counts. After introduction of effective antiretroviral therapy, the clinical and epidemiologic characteristics of Kaposi's sarcoma may have changed. We analyzed and now report on 27 consecutive Kaposi's sarcoma patients treated at our institution from 2007 to 2017. Most patients were HIV-positive Caucasian men on antiretroviral therapy; the average CD4 T-cell count was above the AIDS-defining level of 200 cells/mm3. Seven patients had Kaposi's sarcoma with mucosal involvement, and 20 had skin-only Kaposi's sarcoma. Mucosal Kaposi's sarcoma patients had a mean CD4 T-cell count of 83 cells/mm3 as opposed to 381 cells/mm3 for patients with skin-only involvement (p = 0.005). Survival was significantly compromised in both groups but even more so in Kaposi's sarcoma patients with mucosal involvement (306 vs. 609 days). Along with other reports, our findings suggest that Kaposi's sarcoma may develop in HIV patients in the modern era despite well-controlled HIV disease. This is significant since Kaposi's sarcoma remains an important contributor to morbidity and mortality in HIV-infected patients.

Impact of therapeutic modalities on disease-specific survival in older adults with glioblastoma: A single-institution retrospective cohort study.

The standard first-line therapy for glioblastoma consists of maximal surgical resection, followed by concurrent chemoradiotherapy. Optimal management for older glioblastoma patients is unknown as they have not been extensively studied in clinical trials. We report data from a series of 156 consecutive glioblastoma patients treated at our institution from 2007 to 2017. Compared to glioblastoma patients aged 70 or less, the patients older than 70 were less likely to undergo surgical resection (34% vs. 64%; p = 0.0003), be treated with adjuvant chemotherapy (37% vs. 59%; p = 0.01) or radiation therapy (36% vs. 56%; p = 0.03). Disease-specific survival was significantly shorter in this age group (4.7 vs. 15.3 months; p = 0.002). Nonetheless, when older patients did undergo surgery or chemotherapy, the proportional improvement in cancer-specific survival was similar to the one recorded in younger patients, which is concordant with the findings of other published reports. A multidisciplinary input from neurosurgeons, medical and radiation oncologists, oncology pharmacists and geriatricians remain paramount for the optimal management of glioblastoma in patients older than 70.

Merkel cell carcinoma: long-term follow-up of a single institution series and clinical outcomes by immunological status.

Merkel cell carcinoma (MCC) usually arises in sun-exposed areas of older patients and might be more aggressive in the immunocompromised. We performed a retrospective chart review of 40 consecutive MCC patients treated at our institution between the years 2006-2017. Clinical and epidemiologic data were utilized and therapy and survival were analyzed. Compared to Surveillance, Epidemiology, and End Results (SEER) data, our population was entirely Caucasian (100% versus 95%; P=0.11) and male predominant (75% versus 63%; P=0.11). The median age was 76. The patients more often had Tumor-Node-Metastasis (TNM) stage I disease (50% versus 39%; P=0.00003) and a primary tumor size <2cm (57.5% versus 34%; P<0.01). They received more frequently lymph node dissection (70% versus 63%, P=0.002) compared with the SEER findings. We identified a subset of immunocompromised patients (n=10) who presented with more stage III disease (40% versus 33%; P=0.021). Time to death averaged 290.1 days in this subset versus 618.2 days (P<0.001) in immunocompetent patients and their likelihood of death was 5 times higher. As clinical outcomes in MCC patients vary by immunological status, a multidisciplinary tumor-board approach may better optimize individual patient management.

Longitudinal thumbnail fissures due to erlotinib therapy for lung cancer.

While therapy with epidermal growth factor receptor inhibitors leads to meaningful clinical responses in several tumor types, it has also been linked with perplexing toxic effects. Skin effects of these agents such as generalized papulo-pustular rash, trichomegaly, fingertip fissures, xerosis, pruritus and paronichias are now well characterized. Though uncommon, nail atrophic changes have also been described in subjects treated with these classes of agents. We describe herein unusual longitudinal thumbnail fissures caused by erlotinib therapy for metastatic lung cancer. Unique features are bilateral thumbnail involvement and central location in the nail bed. This side effect of erlotinib has not been previously reported in the medical literature.

Diagnosis and treatment of Clostridium difficile (C. diff) colitis: Review of the literature and a perspective in gynecologic oncology.

Clostridium difficile infection (CDI) is a major cause of nosocomial diarrhea with the potential for significant morbidity and mortality. Colonization in a susceptible individual, with risk factors such as prior antibiotic use, advanced age, or medical comorbidities, may result in symptomatic infection. Although patients with a gynecologic malignancy may be at a higher risk of developing CDI due to an increased likelihood of having one or more risk factors, data do not consistently support the idea that chemotherapy or cancer itself are independently associated with CDI. For diagnosis of CDI, we recommended using a multi-step approach, with a highly sensitive initial rapid test such as the enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) or nucleic acid amplification testing (NAAT), followed by confirmatory testing with of the above two tests or EIA toxin A/B, which has high specificity. Treatment varies based on the severity of disease. We recommend vancomycin as first-line therapy for an initial episode of mild/moderate or severe CDI, with consideration of fidaxomicin for patients at particularly high risk for recurrence. Rectal vancomycin may play an adjunctive role for some severe cases, while surgical intervention is indicated for fulminant CDI if no improvement six or more days after initiating medical therapy. For non-severe recurrent disease, the initial treatment regimen should be repeated, while subsequent episodes are more appropriately treated with a tapered and pulsed dose of vancomycin, fidaxomicin, or fecal microbiota transplantation.

Survival of women with microinvasive adenocarcinoma of the cervix is not improved by radical surgery.

BACKGROUND: Treatment for early-invasive adenocarcinoma of the cervix remains controversial. Although data have shown similar survival rates to those seen with squamous cell carcinoma, conservative options for patients with microinvasive adenocarcinoma have not been as widely accepted. Despite comparable survival outcomes, patients with early-invasive adenocarcinoma are still routinely subjected to more radical surgical techniques than their equivalently staged squamous cell counterparts. OBJECTIVE: The objective of the study was to evaluate how less radical surgery has an impact on 5 year survival in patients with microinvasive adenocarcinoma of the cervix. STUDY DESIGN: The Surveillance, Epidemiology, and End Results database was queried from 1988 through 2010 to perform a retrospective analysis of women with International Federation of Gynecology and Obstetrics stage IA1 or IA2 cervical carcinoma. Five year survival by procedure type (local excision, simple hysterectomy, or radical hysterectomy) was determined for each cell type (squamous or adenocarcinoma), as was lymph node status. RESULTS: Among 1567 patients with cervical adenocarcinoma, 5 year survival was 97.3% (confidence interval, 95.8-98.2%) for stage IA1 disease and 98.3% (confidence interval, 96.5%, 99.2%) for stage IA2. For comparison, the 5-year survival rates for 5,749 patients with stage IAI or lA2 squamous cell carcinoma were 96.7% (confidence interval, 96.0-97.3%) and 95.6% (confidence interval, 94.4-96.5%), respectively. For stage IA1 ACA, survival was 96.6%, 98.4% and 96.5% following excision, hysterectomy and radical hysterectomy, respectively. For stage IA2 ACA, survival rates were 100%, 96.9% and 99.4%, respectively. There was no statistical difference in survival between patients having either cell type undergoing local excision (P = .26), simple hysterectomy (P = .08), or radical hysterectomy (P = .87). We also found no statistically significant difference in survival among patients with adenocarcinoma compared by treatment type (local excision compared with simple hysterectomy [P = .64]; local excision compared with radical hysterectomy [P = .82]; or simple hysterectomy compared with radical hysterectomy [P = .70]). Among patients with adenocarcinoma, 0.97% had positive pelvic lymph nodes, none had positive aortic lymph nodes, and 91.85% had confirmed negative lymph nodes. For squamous cell carcinoma, 0.72% of patients had positive pelvic lymph nodes and 0.10% had positive aortic lymph nodes. CONCLUSION: There was no significant difference in survival when patients were compared by cell type or procedure, suggesting that survival of patients with microinvasive adenocarcinoma is not improved by utilizing more invasive surgical methods. Regardless of histology, the frequency of nodal involvement was very low among both groups, supporting an overall excellent prognosis for all patients with microinvasive disease. We submit these data as evidence that preoperative planning of more conservative techniques is appropriate, not just for those with squamous histology or who desire future fertility, but for all patients with microinvasive cervical disease.

Persistently curly hair phenotype with the use of nivolumab for squamous cell lung cancer.

Increasing use of programmed cell death protein 1/programmed cell death protein 1 ligand inhibition for the treatment of patients with various malignancies such as advanced lung cancer, kidney cancer, and melanoma has resulted in valuable clinical responses, along with the occurrence of new and often puzzling side effects. Known cutaneous effects of CTLA4 and programmed cell death protein 1/programmed cell death protein 1 ligand inhibitors include generalized pruritus, vitiligo, maculopapular lesions, and lichenoid skin eruptions. Alopecia has been the only hair effect previously associated with this class of agents. We describe herein the first case of a persistent curly hair phenotype with the use of nivolumab in a patient with metastatic squamous cell lung cancer.

Urinary diversions: A time to enrich surgical training?

OBJECTIVE: To assess the potential exposure to complex urologic procedures, specifically urinary diversion, during a gynecologic oncology fellowship. METHODS: We queried the University HealthSystem Consortium (UHC) database to determine the total number of urinary diversions performed from October 2008 to August 2012. This data was used to estimate the mean number of urinary diversions performed each year. Gender, primary diagnosis, type of diversion, gynecologic oncologist involvement, and medical center were explored. RESULTS: Of the nearly 21,000 urinary diversions performed in UHC participating hospitals during the study period, 6180 (29.5%) were performed in women. On average, 1648 urinary diversions are performed in women each year, with gynecologic malignancies accounting for 6.8% of cases. We estimate that a gynecologic oncologist was involved with 87 cases per year at nonprofit academic medical centers in the US. With approximately 112 clinically active fellows per year during the study period, this equates to less than one diversion per clinical fellow per year if cases are equally distributed among centers. However, the majority of urinary diversions with gynecologic oncologist involvement were performed at just a fraction of centers. Thus, only a small contingent of fellows may be getting the greatest exposure to urinary diversions. CONCLUSIONS: The majority of urinary diversions in women in the US are performed for bladder carcinoma by urologists. The estimated number of cases per clinical gynecologic oncology fellow per year is less than one. Strategies to improve fellow exposure to urinary diversion and consideration of alternative surgical training modalities should be explored.

Ovarian Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algorithms were added for LCOHs and current algorithms were revised for the 2016 update. The new LCOHs algorithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas. The LCOHs also include carcinosarcomas (malignant mixed Müllerian tumors of the ovary), borderline epithelial tumors (also known as low malignant potential tumors), malignant sex cord-stromal tumors, and malignant germ cell tumors.

Squamous Cell Carcinoma of the Vulva Presenting as an Isolated Inguinal Lymph Node Metastasis: A Case Report.

Background: Vulvar carcinoma is usually diagnosed after a patient notices bleeding, pruritis, or a lesion. We describe a case of vulvar carcinoma presenting as an isolated lymph node metastasis in the setting of negative pelvic examinations, with interval development of a vulvar lesion. Case: A 45-year-old woman presented with a left groin mass, and a biopsy revealed squamous cell carcinoma of unknown primary. She underwent an extensive work-up including several evaluations by gynecologic oncologists, all with negative results. Only after 11 months of clinical monitoring did a vulvar lesion appear and the primary tumor was diagnosed. Conclusion: Cancers of unknown primary site presenting in an inguinal lymph node are relatively rare. Vulvar carcinoma should remain in the differential diagnosis even in the setting of a previously negative pelvic examination.

Increased prevalence of comorbid conditions in women with uterine cancer.

OBJECTIVES: To compare comorbidities of women with uterine cancer (UC) to controls so as to aid in development of survivorship care plans and programs. METHODS: Retrospective cohort study using the University HealthSystem Consortium (UHC) database that compared women who had a hysterectomy for UC to women without UC undergoing hysterectomy. Frequencies and odds ratios (ORs) of 26 comorbidities were calculated. Mantel-Haenszel stratified ORs were determined to correct for different age distributions between the UC and control groups using UHC predetermined age groups. RESULTS: 23,227 patients in the dataset were included in the UC cohort, and 142,601 patients served as controls. Uncorrected ORs≥2 were found for hypertension, diabetes, obesity, congestive heart failure, pulmonary circulatory diseases, peripheral vascular disease, and renal failure. Higher ORs for UC remained significant after stratification by age for hypertension (OR=1.7), diabetes (OR=2.1), obesity (OR=3.3), congestive heart failure (OR=1.5), pulmonary circulatory disorders (OR=1.7), and renal failure (OR=1.2). CONCLUSIONS: Multiple comorbid conditions, specifically those related to the metabolic syndrome, were more prevalent in UC survivors than in the general population, and this difference persisted after adjustment for age. UC survivorship programs should plan to allocate resources to account for these differences in healthcare needs.