Detection and prognostic role of heterogeneous populations of melanoma circulating tumour cells.

BACKGROUND: Circulating tumour cells (CTCs) can be assessed through a minimally invasive blood sample with potential utility as a predictive, prognostic and pharmacodynamic biomarker. The large heterogeneity of melanoma CTCs has hindered their detection and clinical application. METHODS: Here we compared two microfluidic devices for the recovery of circulating melanoma cells. The presence of CTCs in 43 blood samples from patients with metastatic melanoma was evaluated using a combination of immunocytochemistry and transcript analyses of five genes by RT-PCR and 19 genes by droplet digital PCR (ddPCR), whereby a CTC score was calculated. Circulating tumour DNA (ctDNA) from the same patient blood sample, was assessed by ddPCR targeting tumour-specific mutations. RESULTS: Our analysis revealed an extraordinary heterogeneity amongst melanoma CTCs, with multiple non-overlapping subpopulations. CTC detection using our multimarker approach was associated with shorter overall and progression-free survival. Finally, we found that CTC scores correlated with plasma ctDNA concentrations and had similar pharmacodynamic changes upon treatment initiation. CONCLUSIONS: Despite the high phenotypic and molecular heterogeneity of melanoma CTCs, multimarker derived CTC scores could serve as viable tools for prognostication and treatment response monitoring in patients with metastatic melanoma.

Metastatic Cellular Blue Nevus: A Rare Case With Metastasis Beyond Regional Nodes.

In this study, we present a rare case of a 35-year-old man with a long-standing blue-black lesion on his left hand with subsequent infraclavicular and axillary lymph node tumor deposits. The hand lesion and lymph nodes were excised revealing histological, immunohistochemical, and molecular findings consistent with cellular blue nevus. Despite nonregional lymph node involvement, there has been no progression at 12-months follow-up. This is an index case of a cellular blue nevus with metastasis to both regional and nonregional lymph nodes. The lack of atypical/malignant features in this lesion makes the metastatic behavior extraordinary, and hence the prognosis of lesions of this type is indeterminate.

Cancer services in Western Australia: A comparison of regional outcomes with metropolitan Perth.

OBJECTIVE: To investigate whether any survival differences existed between advanced cancer patients treated in metropolitan Perth and those treated in regional Western Australia (WA). DESIGN: Retrospective study. SETTING: Advanced cancer patients treated through medical oncology clinics at Royal Perth Hospital and regional cancer centres (Kalgoorlie, Albany, Geraldton and Northam). PARTICIPANTS: Patients diagnosed with advanced melanoma, breast, colorectal, gastro-oesophageal, prostate, lung and pancreatic cancers between 1 January 2007 and 31 December 2011. INTERVENTIONS: Nil. MAIN OUTCOME MEASURE: Median survival. RESULTS: Data were available for 1581 patients with 75% living in a metropolitan setting and 25% in rural WA. Median overall survival was 8.3 months for metropolitan patients and 7.6 months for regional patients (P = 0.06, HR 0.89; 95% CI, 0.78-1.01). There was no statistically significant difference in median survival for different tumour types except pancreatic cancer: breast 22.1 months versus 21.3 months, colorectal 13.1 months versus 16.4 months, lung 5.1 months versus 3.1 months, upper GI 5.6 months versus 7.2 months, pancreatic 4.5 months versus 3 months (P = 0.02, HR 0.57; 95% CI, 0.32-0.99), melanoma 10.4 months versus 10.5 months, prostate 28.6 months versus 15.3 months. Rural cancer patients with breast and pancreatic cancers received fewer lines of anti-cancer therapy compared to metropolitan patients. The three-year survival rates for metropolitan compared to rural breast cancer patients were 34 and 23%, respectively (not statistically significant). CONCLUSION: Our findings suggest a trend towards inferior survival for regional cancer patients in WA compared with metropolitan-based patients.

Frequency of Amblyopia in strabismus patients presenting to tertiary care hospital.

Objective: The rationale of study was to find the magnitude of amblyopia with reference to type of squint among the strabismus patients visiting Hayatabad Medical Complex Peshawar, Pakistan. Materials and Methods: After ethical approval, a cross sectional study was carried out in the Department of Ophthalmology, Hayatabad Medical Complex, Peshawar, Pakistan, from April 2022 to October 2022, the total number of patients included being 237. Results: Amblyopia was observed in 113 out of 160 (70.6%) cases of uniocular squint, while in alternating squint it was found to be 11 out of 77 (14.2%). Amblyopia in patients with esotropia was seen in 73.2% (107 out of 146), while 59.3% (54 out of 91) exotropia had associated amblyopia. Conclusion: Strabismus amblyopia leads to developmental arrest of vision in early critical years of life. Permanent visual loss can be avoided with comprehensive screening and detailed examination of strabismic patient.

First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401.

PURPOSE: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.

Comparison of prilocaine/lidocaine cream with piroxicam gel for reducing pain during cannulation of arteriovenous fistula for adults undergoing haemodialysis: A randomized crossover clinical trial.

BACKGROUND: Pain is a traumatic experience for most patients on hemodialysis. In this trial, we compared prilocaine/lidocaine cream with piroxicam gel for pain reduction during arteriovenous fistula needling. METHODS: This randomized double-blind crossover clinical trial was done at dialysis unit of a tertiary care hospital from June to August 2022. Adult patients, aged 18-75 years, on maintenance hemodialysis through an arteriovenous fistula were selected randomly. Pain severity during needling of fistula was assessed during initial two hemodialysis sessions without application of any drug. Patients were then randomized into two groups receiving 5% prilocaine/lidocaine cream or 0.5% piroxicam gel 1 h before the next two hemodialysis sessions. After a 7-day washout period, patients crossed over to other groups for another two hemodialysis sessions. Pain was assessed on all these occasions. Primary outcome was reduction in pain with each intervention. RESULTS: There were 32 patients aged 46.44 ± 11.58 years. Pain intensity was 6.69 ± 0.58, 3.13 ± 1.28, and 4.55 ± 1.95 without any medication, prilocaine/lidocaine cream and piroxicam gel respectively. There was greater pain reduction with prilocaine/lidocaine cream than piroxicam gel (3.56 ± 1.35 vs 2.14 ± 1.78; p = 0.001). Local redness with prilocaine/lidocaine cream was reported by one (3.13%) patient, whereas no side effects were seen with piroxicam gel (p = 1.000). CONCLUSION: Prilocaine/lidocaine cream provides better pain relief than piroxicam gel during arteriovenous fistula needling.

Gut microbiota diversity and composition in predicting immunotherapy response and immunotherapy-related colitis in melanoma patients: A systematic review.

BACKGROUND: Gut microbiome (GM) composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy (ICB) and of ICB-related colitis. AIM: To conduct a systematic review on the role of GM composition and diversity in predicting response and colitis in patients with melanoma treated with ICB. METHODS: The review protocol was registered in PROSPERO: CRD42021228018. From a total of 300 studies, nine studies met inclusion criteria. Two studies were phase I clinical trials, while the remainder were prospective observational studies. All but one study has moderate risk of bias. In addition, we conducted a relevant search by Reference Citation Analysis (RCA) (https://www.referencecitationanalysis.com). RESULTS: Fecal samples enriched in Firmicutes phylum were associated with good response to ICB, whereas the Bacteroidales family was associated with poor response to ICB. Samples with greater GM diversity were associated with more favorable response to ICB [hazard ratio (HR) = 3.57, 95% confidence interval = 1.02-12.52, P < 0.05]. Fecal samples with a higher abundance in Firmicutes were more susceptible to ICB-related colitis (P < 0.01) whereas samples enriched in Bacteroidetes were more resistant to ICB-related colitis (P < 0.05). Overall, there was limited concordance in the organisms in the GM identified to be associated with response to ICB, and studies evaluating GM diversity showed conflicting results. CONCLUSION: This highlights the need for further prospective studies to confirm whether the GM could be used as a biomarker and potential intervention to modulate ICB response in melanoma patients.

Calcium and magnesium prophylaxis for oxaliplatin-related neurotoxicity: is it a trade-off between drug efficacy and toxicity?

Oxaliplatin-based chemotherapy regimens are the current standard treatment in the management of colorectal cancer. Neurotoxicity is the major cause of treatment delay, dose reduction, and cessation of oxaliplatin. Evidence regarding the role of calcium and magnesium prophylaxis to prevent oxaliplatin-related neurotoxicity is conflicting and further randomized data are needed to answer this question accurately. The purpose of this paper is to provide a critical overview of various studies that have been conducted so far to evaluate the preventative role of calcium and magnesium prophylaxis against oxaliplatin-related neurotoxicity.

Predicting chemotherapy-induced menopause using baseline and post-chemotherapy anti-Müllerian hormone levels: Results of a pilot study.

BACKGROUND: Chemotherapy can cause premature menopause which may result in adverse effects such as fertility loss, osteoporosis, cardiovascular disease and menopausal symptoms. It is thus very important that women are provided with accurate information regarding their risk of premature menopause as a consequence of proposed chemotherapy. Unfortunately, at present there are no reliable tools which can be applied in clinical practice to estimate the risk of premature menopause in women undergoing chemotherapy, beyond age of the patient and form of chemotherapy utilized. AIM: This was a pilot study to determine whether AMH levels pre and during chemotherapy are able to predict for chemotherapy induced menopause, and to assess quality of life and menopausal symptoms. METHODS AND RESULTS: Premenopausal women between 18 to 45 who were planned to undergo gonadotoxic chemotherapy with curative intent for either breast cancer or haematologic malignancy were recruited from a single centre. AMH, FSH, LH and oestradiol levels were recorded prior to commencement of therapy, during and following completion of chemotherapy. Menstrual status, menopausal symptoms and quality of life data were collected at baseline and during follow-up. Twenty two women were recruited. The baseline AMH was higher in women who regained menses post-chemotherapy (median 23.1 vs 9.9 pM (P = .06). Menopausal symptoms were significantly higher at 1 year post diagnosis than at baseline however quality of life was similar. CONCLUSION: AMH may be useful for predicting chemotherapy induced menopause. Further research is still required to determine the place of such testing for patient counselling and management.

Prognostic value of HLA-I homozygosity in patients with non-small cell lung cancer treated with single agent immunotherapy.

BACKGROUND: We aimed to assess the impact of genomic human leukocyte antigen (HLA)-I/II homozygosity on the survival benefit of patients with unresectable locally advanced, metastatic non-small lung cancer treated by single-agent programmed cell death protein-1/programmed death ligand 1 (PD1/PDL1) inhibitors. METHODS: We collected blood from 170 patients with advanced lung cancer treated with immunotherapy at two major oncology centers in Western Australia. Genomic DNA was extracted from white blood cells and used for HLA-I/II high-resolution typing. HLA-I/II homozygosity was tested for association with survival outcomes. Univariable and multivariable Cox regression models were constructed to determine whether HLA homozygosity was an independent prognostic factor affecting Overall Survival (OS) and Progression Free Survival (PFS). We also investigated the association between individual HLA-A and -B supertypes with OS. RESULTS: Homozygosity at HLA-I loci, but not HLA-II, was significantly associated with shorter OS (HR=2.17, 95% CI 1.13 to 4.17, p=0.02) in both univariable and multivariable analysis. The effect of HLA-I homozygosity in OS was particularly relevant for patients with tumors expressing PDL1 ≥50% (HR=3.93, 95% CI 1.30 to 11.85, p<0.001). The adverse effect of HLA-I homozygosity on PFS was only apparent after controlling for interactions between PDL1 status and HLA-I genotype (HR=2.21, 95% CI 1.04 to 4.70, p=0.038). The presence of HLA-A02 supertype was the only HLA-I supertype to be associated with improved OS (HR=0.56, 95% CI 0.34 to 0.93, p=0.023). CONCLUSION: Our results suggest that homozygosity at ≥1 HLA-I loci is associated with short OS and PFS in patients with advanced non-small cell lung cancer with PDL1 ≥50% treated with single-agent immunotherapy. Carriers of HLA-A02 supertype reported better survival outcomes in this cohort of patients.

Gastric Duplication Cyst: A Rare Congenital Anomaly Causing Gastric Outlet Obstruction.

Gastrointestinal duplication cyst is a rare congenital anomaly with a reported incidence of 1 in 4500 live births. Any part of gastrointestinal tract from mouth to anus can be affected with this anomaly. Among gastrointestinal tract duplications, gastric duplication cyst is extremely rare (2- 9%). We are presenting a case of the stomach duplication in a four (04) day old male child who presented in our Emergency Department with complaints of non-bilious, non-projectile vomiting and visible bulge in upper abdomen since birth. Workup showed enteric duplication cyst which was excised. Complete surgical resection is the treatment of choice in gastric duplication cyst.

Ipilimumab activity in advanced uveal melanoma.

Uveal melanoma (UM) is a rare disease with a distinct molecular profile. About half of the patients with UM eventually develop metastatic disease. The prognosis of these patients remains poor. Treatment options are limited and none of them have been able to show a survival benefit. Ipilimumab was the first agent to show a survival benefit in patients with cutaneous melanoma in a randomized trial; however, there is limited published evidence for its role in the management of advanced UM. Here, we report our experience of ipilimumab in five patients with advanced UM treated at an academic cancer centre in the UK. Two patients had durable stable disease and three developed progressive disease. Of the patients with stable disease, one maintained disease control at 11 months from the commencement of treatment with ∼10% reduction in tumour volume compared with the baseline, and the second patient progressed after 15 months. We also examined the tumour kinetics and response patterns that resembled that of ipilimumab in cutaneous melanoma. Given the lack of randomized trial data, our findings indicate that ipilimumab might be a reasonable treatment option for patients with advanced UM.

Metyrapone: a management option for ectopic ACTH syndrome in small cell lung cancer treated with intravenous etoposide.

Small cell lung cancer (SCLC) with ectopic adrenocorticotropic hormone (ACTH) syndrome and resultant hypercortisolism carries a poor prognosis with a short median survival and high incidence of infective complications. The combination of etoposide with either carboplatin or cisplatin is the current standard chemotherapy used for the management of SCLC. Etoposide is metabolised by cytochrome P450 3A4. Ketoconazole is an imidazole derivative possessing antifungal properties and also causes inhibition of adrenal corticosteroid and androgen production. There is an additional increased risk of toxicity due to a potential interaction between etoposide and ketoconazole, which is a strong inhibitor of cytochrome P450 3A4, and theoretically can lead to greater myelosuppression. Metyrapone can be a safe alternative in such settings.