Validation and comparison of prognostic scoring systems in patients with head and neck squamous cell carcinoma treated with nivolumab.

OBJECTIVE: Several scoring systems have been developed to predict prognosis in patients with refractory cancer. We aimed to validate eight scoring systems and determine the best method for predicting the prognosis of head and neck squamous cell carcinoma treated with nivolumab. METHODS: This multicentre retrospective study involved 154 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with nivolumab between 2017 and 2020. Oncological outcomes were assessed according to the scoring systems, including MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio and Hammersmith scores. Objective response, overall survival and progression-free survival were evaluated using logistic regression and Cox proportional hazards analyses. Receiver operating curve analysis was used to calculate the area under the curve and estimate the efficacy of each score. RESULTS: No significant associations were found between the responses and any score. Seven of the eight scoring systems were associated with disease control (odds ratio, 0.26-0.70). Amongst the eight scoring systems, MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio showed the highest area under the curve for predicting response and disease control. Seven scoring systems were prognostic factors for progression-free survival (hazard ratio, 1.22-1.95). All eight scoring systems were prognostic factors for overall survival (hazard ratio, 1.62-3.83). According to the time-dependent receiver operating characteristics analysis for overall survival, the Hammersmith scoring system had the best predictive ability at 3 months, and the MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio scoring system had the highest area under the curve between 6 and 24 months. CONCLUSIONS: MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio and Hammersmith scoring systems were better predictors of prognosis in patients with head and neck squamous cell carcinoma treated with nivolumab.

Faster surgery initiation in oral cancer patients during the COVID-19 pandemic in Osaka, Japan.

BACKGROUND: We investigated the impact of the COVID-19 pandemic on oral cancer (OC), comparing diagnosis and number of pre-operative days in the diagnosis of OC in 2019 (pre-COVID-19) and that in 2020 (during the COVID-19 pandemic). METHODS: Using data from a cancer registry-based study on the impact of COVID-19 on cancer care in Osaka (CanReCO), we collected details of sex, age, residential area, cancer site, date of diagnosis, clinical stage at first treatment and number of pre-operative days in OC patients. RESULTS: A total of 1470 OC cases were registered. Incidence of OC before and during COVID-19 was 814 and 656 cases, respectively. During the first wave of the pandemic (March to May 2020), incidence was about half that in the same period in 2019 (2019; n = 271, 2020; n = 145). Number of pre-operative days (median number of days between the first hospital visit and surgery date) was significantly shorter during the COVID-19 year (24.5 days) than in the pre-COVID-19 year (28 days, p = 0.0015). CONCLUSIONS: Incidence of OC during the COVID-19 pandemic was lower than in pre-COVID-19. Despite disruption in the healthcare system, the number of pre-operative days for OC cases was shorter during the pandemic.

Early detection of brain metastases and appropriate local therapy followed by systemic chemotherapy may improve the prognosis of gastric cancer.

Brain metastases develop in 0.5-0.7% of patients with gastric/gastroesophageal junction (G/GEJ) cancer. Although rare, brain metastasis is often identified when the patient is already symptomatic; hence prognosis is poor. Given the therapeutic developments for G/GEJ cancer, overall survival is prolonged, thereby the incidence of brain metastases is predicted to increase. We retrospectively surveyed the rate of brain metastasis among 1257 patients diagnosed with G/GEJ cancer who received chemotherapy between January 2011 and April 2021. We investigated the time of onset of brain metastasis, treatments administered, and impact of the metastasis on the overall treatment course and prognosis. Of the 741 patients included in the analysis, brain metastasis was confirmed in 16 (2.2%). The median survival time (MST) from G/GEJ cancer diagnosis was 14.9 months in patients with brain metastasis detected during the treatment period, and the MST from the diagnosis of brain metastasis was 2.8 months. Patients who received chemotherapy exhibited prolonged survival compared with those who did not (12.4 months vs 1.0 months, p < 0.001). Our findings suggest that the early detection of brain metastases and local therapy for poor responders to chemotherapy enable the continuation of chemotherapy and prolong survival.

Predictive factors for response to neoadjuvant chemotherapy: inflammatory and immune markers in triple-negative breast cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) predict response to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients. However, the TIL level can be determined at a few facilities. By contrast, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are easily and objectively determined from the results of full blood counts. We conducted a retrospective study to investigate whether TILs, NLR, and PLR predict NAC efficacy and whether NLR and PLR could be surrogate markers for TILs in TNBC. METHODS: Of the 266 patients diagnosed with TNBC between 2013 and 2019, 66 who underwent radical surgery after sequential administration of anthracycline and taxane as NAC were included in the study. TILs, NLR, and PLR were evaluated as predictors of pathologic complete response (pCR) using cutoff values determined from receiver operating characteristic curves. RESULTS: The cutoff values of TILs, NLR, and PLR were 20%, 2.6, and 180, respectively. High TIL level was associated with low NLR (P = 0.01) and low PLR (P = 0.01). High TIL level (odds ratio [OR] 4.28 [95% CI 1.40-13.1]; P = 0.01), low NLR (OR 5.51 [95% CI 1.60-18.9]; P = 0.01), and low PLR (OR 3.29 [95% CI 1.13-9.57]; P = 0.03) were associated with pCR. Low NLR predicted pCR independently (OR 6.59 [95% CI 1.45-30.0]; P = 0.01). CONCLUSIONS: TILs, NLR, and PLR predicted NAC efficacy against TNBC. TIL level was associated with NLR and PLR. NLR was an independent predictive factor and may be a useful surrogate marker for TILs when predicting pCR.

Checkpoint inhibitor-induced gastritis followed by delayed severe hepatitis in a patient with lung metastases of head and neck squamous cell carcinoma: a case report.

Pembrolizumab, an anti-programmed death-1 (PD-1) receptor monoclonal antibody, is an effective first-line therapy for metastatic head and neck squamous cell carcinoma. Immune-related adverse events (irAEs) are well-described complications of PD-1 inhibitors, and multiorgan irAEs are known to occur occasionally. We report a patient with pulmonary metastases of oropharyngeal squamous cell carcinoma (SCC), who developed gastritis followed by delayed severe hepatitis and recovered with triple immunosuppressant therapy. A 58-year-old Japanese male with pulmonary metastases of oropharyngeal SCC who was treated with pembrolizumab, subsequently developed new-onset appetite loss and upper abdominal pain. Upper gastrointestinal endoscopy revealed gastritis and immunohistochemistry revealed pembrolizumab-induced gastritis. The patient developed delayed severe hepatitis at 15 months after initiating pembrolizumab treatment, presenting "Grade 4 aspartate aminotransferase increase" and "Grade 4 alanine aminotransferase increase." Impaired liver function persisted despite pulse corticosteroid therapy with intravenous methylprednisolone 1,000 mg/day, followed by oral prednisolone 2 mg/kg/day and oral mycophenolate mofetil 2,000 mg/day. Tacrolimus, which reached target serum trough concentrations of 8-10 ng/mL, gradually improved irAE grades from Grade 4 to Grade 1. The patient responded well to triple immunosuppressant therapy comprising prednisolone, mycophenolate mofetil, and tacrolimus. Therefore, this immunotherapeutic approach could be effective for multiorgan irAEs in patients with cancer.

Risk of Abemaciclib-induced Liver Injury in Hormone Receptor-positive, HER2-negative Metastatic Breast Cancer: A Retrospective Analysis.

BACKGROUND/AIM: The efficacy of endocrine therapy combined with abemaciclib for hormone receptor-positive, HER2-negative metastatic breast cancer has been established through pivotal clinical trials. However, abemaciclib-induced liver injury (AILI) can be a cause for dose reduction or discontinuation. Therefore, it is critical to understand the risk factors for AILI. PATIENTS AND METHODS: This retrospective study analyzed data from patients who had received abemaciclib combined with endocrine therapy for metastatic breast cancer as first- or second-line therapy at our hospital between December 2018 and October 2021. Relevant data were extracted from their medical records. Logistic regression analysis was performed to identify characteristics associated with AILI. RESULTS: Of the 52 eligible patients, 12 (23%) received an aromatase inhibitor (AI), and 40 (77%) received fulvestrant, concomitantly with abemaciclib. Fifteen (29%) of the patients developed liver injury after starting abemaciclib. Univariate analysis revealed the following risk factors for AILI: age ≥65 years (p=0.047), fatty liver disease (p=0.047), and concomitant use of an AI (p=0.002). Concomitant use of an AI was identified by multivariate analysis as an independent risk factor for AILI [odds ratio (OR)=10.23, 95% confidence interval (CI)=2.02-51.91, p=0.005]. CONCLUSION: Concomitant use of an AI could be the most significant factor associated with increased risk of AILI. Future research on the mechanism by which the use of an AI plus abemaciclib can cause liver injury, and prospective studies to validate our findings regarding AILI risk factors, are warranted.

Pegfilgrastim-induced vasculitis of the subclavian and basilar artery complicated by subarachnoid hemorrhage in a breast cancer patient: a case report and review of the literature.

BACKGROUND: Pegfilgrastim (PEG) is a sustained-duration pegylated form of filgrastim, a granulocyte-colony stimulating factor agent that is widely used as prophylaxis against febrile neutropenia during chemotherapy. We report the case of a breast cancer patient who developed PEG-induced vasculitis complicated by subarachnoid hemorrhage (SAH) and review the relevant literature. CASE PRESENTATION: A 48-year-old woman had undergone surgery for breast cancer and was receiving docetaxel and cyclophosphamide as adjuvant chemotherapy (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2); on day 4 of treatment, PEG had been administered. On day 14, she was admitted to hospital with fever, general malaise, and neck pain, and her C-reactive protein level was found to be high (12.65 mg/dL). Although infection was initially suspected, antimicrobial treatment was ineffective and other laboratory test results were negative for this. Contrast-enhanced computed tomography on day 22 showed thickened vessel walls in the left subclavian artery, the origin of the common carotid artery, and the thoracoabdominal aorta. On day 26, magnetic resonance imaging of the head to investigate possible causes of headache showed signs consistent with SAH, and magnetic resonance angiography images showed irregularity in the basilar artery wall; the findings of both studies were considered to be due to PEG-induced vasculitis. Once treatment with prednisolone 40 mg/day had started, the wall thickening and irregularity improved. CONCLUSION: Although an uncommon adverse effect, vasculitis affecting vessels of various sizes may be caused by PEG. To the best of our knowledge, this report is the first to describe a case of G-CSF-induced vasculitis complicated by SAH. In cases of persistent high fever and elevated inflammatory response after PEG administration and in the absence of infection, clinicians should consider the possibility of drug-induced vasculitis.

Predictive significance of body composition indices in patients with head and neck squamous cell carcinoma treated with nivolumab: A multicenter retrospective study.

BACKGROUND: The identification of predictive factors is imperative for identifying patients with optimal responses to nivolumab. We aimed to determine whether body composition parameters can predict treatment outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with nivolumab. METHOD: We performed a multicenter retrospective chart review of patients with recurrent and/or metastatic HNSCC treated with nivolumab between 2017 and 2020. Computed tomography images and anthropometric measures were used to determine the skeletal muscle index (SMI), subcutaneous adipose index, visceral adipose index (VAI), and body mass index. Objective response, overall survival (OS), progression-free survival (PFS), and severe immune-related adverse events (irAEs) were the main outcomes. Odds ratios (ORs) and hazard ratios (HRs) for low-index groups compared with high-index groups were calculated for these outcomes. RESULTS: Our study comprised 114 patients with a median follow-up period of 23.1 months. Low SMI and low VAI were significantly associated with poor disease control [OR: 0.39, 95% confidence interval (CI): 0.15-0.97] and poor response (OR: 0.38, 95% CI: 0.15-0.94), respectively. Low SMI independently predicted poor OS (HR: 2.06, 95% CI: 1.16-3.67), poor PFS (HR: 1.74, 95% CI: 1.04-2.92), and increased incidence of irAEs (OR: 6.00, 95% CI: 1.04-34.61). Low VAI independently predicted poor PFS (HR 2.07, 95% CI: 1.15-3.73). CONCLUSION: The SMI and VAI are predictive factors of nivolumab therapy in patients with HNSCC. Body composition indices should be assessed before nivolumab treatment for achieving optimal responses to nivolumab.

Axillary management based on American college of surgeons oncology group Z0011 criteria makes it possible to omit intraoperative diagnosis of sentinel lymph nodes in early breast cancer patients.

The ACOSOG Z0011 trial has resulted in the omission of axillary lymph node dissection (ALND) in early breast cancer patients with one or two metastatic sentinel lymph nodes (SLNs). There has been increasing interest in the necessity of intraoperative assessment of SLNs in patients treated based on the Z0011 criteria. We evaluated the utility of intraoperative assessment in these eligible patients. A total of 1396 patients were treated following the Z0011 criteria from April 2012 to December 2019. We examined the proportion and clinicopathological features of patients who underwent ALND due to three or more metastatic SLNs and the sensitivity of intraoperative assessment. Only 16 (1.1%) patients had three or more metastatic SLNs diagnosed by intraoperative assessment, and they immediately underwent ALND. Of the clinicopathological factors, high clinical tumor stage (p = 0.002) and high Ki-67 labeling index value (p = 0.056) were more likely to be associated with the presence of three or more metastatic SLNs. The major independent risk factor for three or more metastatic SLNs was high clinical tumor stage (OR 3.94 [95% CI 1.42-11.0]; p = 0.009). Intraoperative assessment had low sensitivity (70.5%) and a high false-negative rate (29.5%) in detecting SLN metastases. The main finding of our study was the small proportion of patients who required ALND due to three or more metastatic SLNs according to the Z0011 criteria. The Z0011 strategy enables intraoperative assessment of SLNs to be omitted in early breast cancer patients.

Prevalence of BRCA1 and BRCA2 mutations in Japanese patients with triple-negative breast cancer: A single institute retrospective study.

Numerous databases for risk assessment of BRCA1/2 gene mutations contain insufficient data about Asians. Furthermore, few studies have reported the prevalence of germline BRCA1/2 mutations in Japanese patients, particularly those with triple-negative breast cancer (TNBC). The present study was a retrospective analysis of data from patients with TNBC who underwent BRCA1/2 mutation testing at Osaka International Cancer Institute (Osaka, Japan) between October 2014 and March 2020. A total of 65 patients with TNBC underwent a test for BRCA1/2 mutations, and 13 (20.0%) had deleterious mutations in the BRCA1 or BRCA2 genes. Furthermore, 12 out of 29 patients with a family history of breast or ovarian cancer had deleterious BRCA1/2 mutations, and only 1 of 34 without a family history had a mutation (41.4 vs. 2.9%; P=0.014). No patients aged >60 years had BRCA1/2 mutations; however, the age of diagnosis was not a significant risk factor for BRCA1/2 mutations (P=0.60). The prevalence of BRCA1/2 mutations in the present cohort of Japanese patients with TNBC was slightly higher than those reported in other larger studies from Europe and North America. Further data from large prospective studies are required to more precisely define the prevalence of BRCA1/2 mutations.

STK11 loss drives rapid progression in a breast cancer patient resulting in pulmonary tumor thrombotic microangiopathy.

We experienced a case of breast cancer in which liver metastases spread rapidly and the patient died of pulmonary tumor thrombotic microangiopathy (PTTM). PTTM is a fatal cancer-associated respiratory complication disease. To reveal genetic alterations of the clinical course, we performed next generation sequencing of the serial specimens using the Ion AmpliSeqTM Comprehensive Cancer Panel and RNA sequencing for transcriptomic data, followed by gene set analysis. The analysis revealed an oncogenic TP53 R213* mutation in all specimens and STK11 loss in tissues sampled after disease progression. Immunohistochemistry with an anti-STK11 antibody confirmed no STK11 expression in the samples after progression. Transcriptome analysis showed a significant downregulation of proteins associated with apoptosis in the specimens with STK11 loss. STK11 loss may have triggered the rapid progression of PTTM from a comprehensive genomic analysis.

[Primary Rhabdomyosarcoma of the Breast in a 16-Year-Old Girl].

We report a case of primary breast rhabdomyosarcoma. A 16-year-old girl noticed tumor of her right breast and consulted a local clinic. From the result of core needle biopsy, breast sarcoma was suspected, so she attended our hospital. Breast ultrasonography showed a mosaic pattern tumor occupying the whole right breast. CT images revealed an axillary node metastasis and no distant organ metastasis. Immunohistochemical staining of the tumor yielded positive results for desmin, MyoD1, and myogenin. Based on reverse transcription polymerase chain reaction(RT-PCR), she was diagnosed as an alveolar rhabdomyosarcoma with PAX3-FKHR(FOXO1)fusion transcripts[t(2;13)(q35;q14)]. She underwent total mastectomy and dissection of axillary lymph nodes. After surgery, the whole-body magnetic resonance imaging(MRI) demonstrated metastases of sacrum and left foot, so she was under systemic chemotherapy.

Aldehyde dehydrogenase 2 genotype in tolerability of alcohol contained in paclitaxel in Japanese breast cancer patients.

BACKGROUND: Paclitaxel (PTX) is an essential anticancer drug used to treat breast cancer. Because it contains alcohol as a solvent, it is contraindicated in many Japanese breast cancer patients when they are suspected of alcohol intolerance. Aldehyde dehydrogenase 2 (ALDH2) is one of several enzymes that catalyzes dehydrogenation of aldehydes, and plays an important role in ethanol metabolism. Deficiency of this isozyme is believed to be responsible for facial flushing and other unpleasant symptoms following ethanol intake. In this study, we examined the safety of PTX for patients with the ALDH2 GA genotype. METHODS: We performed ALDH2 genotyping on 25 patients with various cancers who were suspected to be intolerant to alcohol based on an interview using a simple question. Ten patients with the ALDH2 GA genotype, including 5 breast cancer patients, underwent chemotherapy containing PTX up to 100 mg/m2 (range 80-100 mg/m2), and were questioned about 16 alcohol-related symptoms at 11 timepoints to evaluate sensitivity to alcohol. RESULTS: All patients completed the first course of planned chemotherapy with either no or grade 1 alcohol-related symptoms. CONCLUSIONS: Our study suggests that PTX up to 100 mg/m2 can be used safely for patients with the ALDH2 GA genotype. To confirm the necessity of a genotyping test for ALDH2, further studies evaluating alcohol sensitivity in response to PTX among patients with the ALDH2 AA genotype are required.

Development of a prediction model for lymph node metastasis in luminal A subtype breast cancer: the possibility to omit sentinel lymph node biopsy.

The present study aimed to construct a prediction model for axillary lymph node metastasis (ALNM) using a DNA microarray assay for gene expression in breast tumor tissues. Luminal A breast cancers, diagnosed by PAM50 testing, were analyzed, and a prediction model (genomic nodal index (GNI)) consisting of 292 probe sets for ALNM was constructed in a training set of patients (n=388), and was validated in the first (n=59) and the second (n=103) validation sets. AUCs of ROC were 0.820, 0.717, and 0.749 in the training, first, and second validation sets, respectively. GNI was most significantly associated with ALNM, independently of the other conventional clinicopathological parameters in all cohorts. It is suggested that GNI can be used to identify the patients with a low risk for ALNM so that sentinel lymph node biopsy can be spared safely.

72-gene classifier for predicting prognosis of estrogen receptor-positive and node-negative breast cancer patients using formalin-fixed, paraffin-embedded tumor tissues.

BACKGROUND: The 95-gene classifier (95-GC) can classify patients with estrogen receptor (ER)-positive and node-negative breast cancer into those with low and high risk of relapse with an accuracy similar to that of 21-GC (Oncotype DX). Because 95-GC uses RNA from fresh-frozen (FF) tumor tissues, we herein attempted to develop a gene classifier that is applicable to RNA from formalin-fixed paraffin-embedded (FFPE) tumor tissues. PATIENTS AND METHODS: 25 paired FF and FFPE tumor tissues were subjected to DNA microarray for gene-expression analysis. Of the 95 probes included in the 95-GC, 72 were selected for construction of the gene classifier for FFPE tumor tissues, because the gene expression detected by these 72 probes was well preserved in the FFPE tumor tissues. RESULTS: The 72-GC was constructed with these 72 probes for the training set comprising 549 FF tumor tissues and validated with 434 FF tumor tissues (relapse-free survival at 10 years was 91% for the low-risk and 74% for the high-risk group (P = 3.74 × 10(-7)). The predictive capability of 72-GC for prognosis was found to be comparable to that of 95-GC. The 25 paired FF and FFPE tumor tissues from each of 25 patients were classified into the same risk group by 72-GC for 23 patients (92% concordance). 72-GC using the FFPE tumor tissues showed that the prognosis for the low-risk group was significantly (P = .007) better than for the high-risk group. CONCLUSION: 72-GC is comparable to 95-GC in terms of accuracy of prognosis prediction, and may be effective for FFPE tumor tissues.

Development of Severe Hyponatremia due to Salt-Losing Nephropathy after Esophagectomy for Esophageal Cancer.

A 72-year-old woman was admitted to our hospital for esophagectomy for esophageal cancer. On the third postoperative day, she developed polyuria (3.8 L/day), massive natriuresis, hyponatremia (112 mEq/L), hyperkalemia (5.6 mEq/L), and decreased central venous pressure, which was refractory to isotonic saline infusion. Laboratory findings indicated proximal tubular injury (high urinary beta2-microglobulin, coexistence of hypouricemia) together with reduced aldosterone action at the cortical collecting duct. A diagnosis of salt-losing nephropathy was made and sodium correction was done with 3% saline and fludrocortisone. She responded well to therapy. The cause of hyponatremia was considered renal tubular dysfunction together with elevated antidiuretic hormone level. Postoperatively, it is important to look for the development of salt-losing nephropathy.

A unique case of collagenous colitis presenting as protein-losing enteropathy successfully treated with prednisolone.

A 76-year-old woman with a 5-mo history of recurrent diarrhea and generalized edema was admitted to our hospital. Colonoscopy revealed edematous mucosa, and histopathological examination was compatible with collagenous colitis. Protein leakage from the colon, particularly in the ascending portion, was identified on 99mTc-human serum albumin scintigraphy. Collagenous colitis associated with protein-losing enteropathy (PLE) without small bowel disease was diagnosed. Prednisolone treatment ameliorated diarrhea and hypoproteinemia. Collagenous colitis should be included in the differential diagnosis of chronic diarrhea with hypoproteinemia for appropriate management.

A case of IgG4-related multifocal fibrosclerosis complicated by central diabetes insipidus.

A 55-years-old man was admitted to our hospital with a 6-month history of general fatigue, purulent nasal discharge, polyuria, and polydipsia. Endocrinological findings revealed central diabetes insipidus (CDI) with mild anterior pituitary dysfunction. Imaging studies revealed thickening of the proximal end of the pituitary stalk just below the third ventricle, a mass in the paranasal sinus, and a mass encompassing the abdominal aorta. Histopathology of the mass in the paranasal sinus revealed abundant IgG4-positive plasma cells, and the IgG4 serum level was markedly elevated. Thus, he was diagnosed with IgG4-related multifocal fibrosclerosis. Therapy with prednisolone resulted in complete resolution of clinical symptoms and reduction in size of the masses in the affected organs. However, CDI remained unchanged. This is the first case in which the cause of CDI was IgG4-related multifocal fibrosclerosis. IgG4-related sclerosing disease should be included in the differential diagnosis of thickening of the pituitary stalk with CDI, and a search for extra-pituitary involvement is essential.

Reversible posterior leukoencephalopathy syndrome: a possible manifestation of Wegener's granulomatosis-mediated endothelial injury.

We present the case of a 15-year-old girl who had Wegener's granulomatosis with severe intestinal involvement. During the clinical course, she developed generalized seizures and was diagnosed with reversible posterior leukoencephalopathy syndrome (RPLS). Plasma exchange combined with steroid pulse therapy was initiated and showed marked improvement. This is one of the few cases of RPLS without severe hypertension or renal failure, suggesting that RPLS is likely to be a manifestation of Wegener's granulomatosis-mediated endothelial injury.