Metabolic, Hormonal, Immunologic, and Genetic Factors Associated With the Incidence of Thyroid Disorders in Polycystic Ovarian Syndrome Patients.

Many endocrinopathies have been increasingly affecting females of reproductive age. Polycystic ovary syndrome (PCOS) and hypothyroidism are some of the most common endocrinopathies seen in females. The aim of this study is to find a relationship between the incidence of thyroiditis in polycystic ovarian syndrome patients. Literature review search was conducted via a series of systematic searches using multiple databases which lead to cross-referencing of articles within assigned criteria. Our study resulted in a review of 42 articles pertaining to our study. In this literature review article, factors were identified associating PCOS with thyroiditis. A viable relationship was found between the incidence of PCOS and thyroiditis. The combination of factors seen in this study proposes that clinicians may need to focus on certain markers regarding the screening of the incidence of thyroiditis. We also recommend future cohort studies to be conducted to further confirm the associations identified in this article.

The Effects of Mental Stress on Non-insulin-dependent Diabetes: Determining the Relationship Between Catecholamine and Adrenergic Signals from Stress, Anxiety, and Depression on the Physiological Changes in the Pancreatic Hormone Secretion.

Non-insulin-dependent diabetes or type II diabetes is prevalent around the world. A high-fat diet and chronic inactivity are often responsible for this chronic ailment. However, it is suspected that a high level of stress can also exacerbate diabetes. High anxiety can result in the release of sympathetic hormones that can elevate both cortisol and glucose levels, decrease insulin release, or affect the sensitivity and resistant of the insulin hormone. We have analyzed three research articles to see how stress and anxiety can affect non-insulin-dependent diabetes. In the first article, we selected participants with type II diabetes and injected them with saline or norepinephrine. The results indicated that participants with norepinephrine had experienced a decrease in glucose disposal and reduction in insulin secretion rate. Our second article utilizes African-American adults with type II diabetes. We provide them with a survey to determine how stress, anxiety, and depression can affect adherence to lifestyle modifications such as exercise and eating a proper diet. We find that subjects with higher stress levels tend to have lower compliance with their lifestyle regimes. Our third article focuses on female participants and divides them into two categories which are high chronic stress (HCS) and low chronic stress (LCS). We use an MRI to observe their brain activity while they stare at a picture of high-caloric type food. Our results indicate that there are different responses in various brain structure activities between subjects with HCS and LCS group. With these analyses, it can improve on the way healthcare providers can consult with their patients who have exacerbated type II diabetes despite proper medication and lifestyle modification.

Changing pattern of recurrences in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy in the era of dual anti-HER2 therapy.

BACKGROUND: Over the last 10 years, there has been a major treatment revolution for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to explore the outcome of different neoadjuvant chemotherapy in a tertiary breast cancer centre with early HER2-positive breast cancer as well as factors associated with pathological complete response (pCR) and recurrence-free survival (RFS). The pattern of recurrence was also studied. METHODS: This retrospective study analysed the outcome of neoadjuvant chemotherapy during the period 2005 to 2016 in a tertiary referral centre in Hong Kong. Patients were divided into three groups according to the neoadjuvant chemotherapy they received: chemotherapy only (Chemo), chemotherapy plus trastuzumab (Chemo-H) and chemotherapy plus double anti-HER2 therapy (Chemo-DH). RESULTS: There were 226 cases analysed during the study period. The rate of pCR was 5%, 26% and 60% in Chemo, Chemo-H and Chemo-DH groups, respectively (Chemo vs pooled Chemo-H/DH: p<0.0001; Chemo-H vs Chemo-DH: p<0.0001). This was accompanied by a trend of increased rate of breast conservation therapy in Chemo-DH cohort (p=0.046). Use of double anti-HER2 therapy, older age (>50 years) and hormone receptor negativity were associated with more pCR. pCR was associated with better RFS. Among those with recurrence, the proportion of patients with brain as the only site of recurrence increased remarkably with more efficacious anti-HER2 treatment (0% in Chemo, 8% in Chemo-H, 67% in Chemo-DH). CONCLUSION: pCR remains an important predictive factor for improved RFS. In the era of dual anti-HER2 neoadjuvant therapy, brain-only recurrence poses a challenge to disease surveillance and treatment.

Living With "Man's Fate" Away From Home.

Edward Nilges is a former software consultant who came from Chicago to Hong Kong in 2005, and has since worked as a teacher. Having been residing in Hong Kong for all these years, Edward fell ill with cancer and its complications. He choose to receive medical treatment in Hong Kong, where both the dominant culture and medical system were foreign to him. Here, he gives an account of his physical, psychological, social and existential experience, in quest of meaning away from home, while his physician discusses the clinician's perspective.

Lobular breast cancers lack the inverse relationship between ER/PR status and cell growth rate characteristic of ductal cancers in two independent patient cohorts: implications for tumor biology and adjuvant therapy.

BACKGROUND: Although invasive lobular carcinoma (ILC) of the breast differs from invasive ductal carcinoma (IDC) in numerous respects - including its genetics, clinical phenotype, metastatic pattern, and chemosensitivity - most experts continue to manage ILC and IDC identically in the adjuvant setting. Here we address this discrepancy by comparing early-stage ILC and IDC in two breast cancer patient cohorts of differing nationality and ethnicity. METHODS: The clinicopathologic features of 2029 consecutive breast cancer patients diagnosed in Hong Kong (HK) and Australia (AUS) were compared. Interrelationships between tumor histology and other clinicopathologic variables, including ER/PR and Ki67, were analysed. RESULTS: Two hundred thirty-nine patients were identified with ILC (11.8%) and 1790 patients with IDC. AUS patients were older (p <0.001) and more often postmenopausal (p <0.03) than HK patients. As expected, ILC tumors were lower in grade and proliferative rate, and more often ER-positive and HER2-negative, than IDC (p <0.002); yet despite this, ILC tumors were as likely as IDC to present with nodal metastases (p >0.7). Moreover, whereas IDC tumors exhibited a strongly negative relationship between ER/PR and Ki67 status (p <0.0005), ILC tumors failed to demonstrate any such inverse relationship (p >0.6). CONCLUSION: These data imply that the primary adhesion defect in ILC underlies a secondary stromal-epithelial disconnect between hormonal signaling and tumor growth, suggesting in turn that this peritumoral feedback defect could reduce both the antimetastatic (adjuvant) and tumorilytic (palliative) efficacy of cytotoxic therapies for such tumors. Hence, we caution against assuming similar adjuvant chemotherapeutic survival benefits for ILC and IDC tumors with similar ER and Ki67, whether based on immunohistochemical or gene expression assays.

Advanced pancreatic cancer: flourishing novel approaches in the era of biological therapy.

The progress in the development of systemic treatment for advanced pancreatic cancer (APC) has been slow. The mainstream treatment remains using chemotherapy including gemcitabine, FOLFIRINOX, and nab-paclitaxel. Erlotinib is the only approved biological therapy with marginal benefit. Studies of agents targeting epidermal growth factor receptor, angiogenesis, and RAS signaling have not been satisfying, and the usefulness of targeted therapy in APC is uncertain. Understanding in molecular processes and tumor biology has opened the door for new treatment strategies such as targeting insulin-like growth factor 1 receptor, transforming growth factor ß, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Notch pathway. New directions also include the upcoming immunotherapy and many novel agents that act on the microenvironment. The practice of personalized medicine using predictive biomarkers and pharmacogenomics signatures may also enhance the effectiveness of existing treatment. Future treatment approaches may involve comprehensive genomic assessment of tumor and integrated combinations of multiple agents to overcome treatment resistance.

Effect of erythropoiesis-stimulating agents on hemoglobin level, fatigue and hospitalization rate in renal palliative care patients.

OBJECTIVES: To investigate the effect of erythropoiesis-stimulating agents (ESAs) on hemoglobin (Hb) level, fatigue and hospitalization rate in renal palliative care (PC) patients. METHOD: A retrospective cohort study was done between April 2011 and January 2013 in renal palliative care clinic of clustered hospitals in Hong Kong. The study participants included end-stage renal patients (CrCl < 15 ml/h) decided not for dialysis (ESA 39 patients; control 31 patients). From healthcare databases, we retrieved the patient demographics, laboratory results, reasons and time of hospitalizations during the study period. Fatigue was measured by Edmonton Symptom Assessment Scale. RESULTS: Most were elderly patients and about half of patients had underlying diabetes mellitus. Baseline mean Hb levels were similar (7.57 ± 0.97 g/dL for ESA vs 7.77 ± 0.72 g/dL for control). Mean Hb was raised significantly after 3 and 6 months of ESA injections (9.42 and 9.40 g/dL respectively, P < 0.05). Fatigue was reduced significantly at 3 and 6 months after treatment (P = 0.006 and P = 0.017 respectively). All-cause hospitalization was reduced significantly and there was a trend toward reduction in red blood cell transfusion requirement in the ESA group (P = 0.084). CONCLUSION: This study demonstrated that use of ESAs in renal PC was effective and might help in reducing fatigue and hospitalizations rate.

Efficacy and tolerability of adjuvant oral capecitabine plus intravenous oxaliplatin (XELOX) in Asian patients with colorectal cancer: 4-year analysis.

BACKGROUND: Although FOLFOX (infusional fluorouracil/leucovorin plus oxaliplatin) is established as a standard chemotherapeutic regimen, the long term efficacy of adjuvant XELOX (oral capecitabine plus intravenous oxaliplatin) in Asian colorectal cancer (CRC) patients remains anecdotal. Moreover, uncertainties persist as to whether pharmacogenetic differences in Asian populations preclude equally tolerable and effective administration of these drugs. METHOD: One hundred consecutive patients with resected colorectal cancer received adjuvant XELOX (oxaliplatin 130 mg/m2 on day 1 plus capecitabine 900 mg/m2 twice daily on day 1 to 14 every 3 weeks for 8 cycles) at Queen Mary Hospital, Hong Kong. Endpoints monitored during follow-up were disease-free survival (DFS) and disease recurrence, overall survival (OS) and adverse events (AEs). RESULTS: The median patient age was 56 years, 56% were diagnosed with rectal cancer and 44% with colonic cancer. After a median follow-up of 4.3 years (95% confidence interval, 3.2-4.7), 24 recurrences were confirmed including 13 patients who died due to progressive disease. Four-year DFS was 81% in colon cancer patients and 67% in rectal cancer patients (p=0.06 by log-rank test). For the cohort as a whole, OS was 90% at 3 years and 84% at 5 years. Treatment-related AEs led to early withdrawal in four patients. The commonest non-hematological AEs were neuropathy (91%), hand-foot syndrome (49%) and diarrhea (46%), while the commonest grade 3/4 AEs were neutropenia (11%) and diarrhea (10%). CONCLUSION: These results confirm the favourable long term survival benefit with good tolerability in using adjuvant XELOX in treating East Asian colorectal cancer patients.

Use of sertraline for antihistamine-refractory uremic pruritus in renal palliative care patients.

BACKGROUND: Uremic pruritus is a common and distressing symptom occurring in 42% to 75% of end-stage renal dialysis (ESRD) patients, even in patients who are adequately dialyzed. METHODS: We conducted a retrospective review of consecutive patients who presented to the renal palliative care clinic in a single institution with pruritus refractory to antihistamines between April 2011 and September 2012. A total of 99 patients were screened during this period; 20 were eligible for this study. Sertraline was initiated at 25 mg daily orally for the first month, with dosage increment of 25 mg monthly according to clinical response up to a maximum of 200 mg daily as necessary. Patients were followed up every 2 to 4 weeks in the renal palliative care clinic. RESULTS AND CONCLUSIONS: Study results showed that low-dose sertraline was effective for antihistamine-refractory uremic pruritus in renal palliative care patients. Further placebo-blinded randomized-controlled studies are warranted to clarify our findings.

Molecular targeted therapies in advanced gastric cancer: does tumor histology matter?

It is increasingly recognized that gastric cancer is a heterogeneous disease which may be divided into subgroups based on histological, anatomical, epidemiological and molecular classifications. Distinct molecular drivers and tumor biology, and thus different treatment targets and predictive biomarkers, may be implicated in each subtype. However, there is little evidence in the literature regarding the correlation among these different classifications, and particularly the molecular aberrations present in each subtype. In this review, we approach advanced gastric cancer (AGC) by presenting aberrant molecular pathways and their potential therapeutic targets in gastric cancer according to histological and anatomical classification, dividing gastric cancer into proximal nondiffuse, distal nondiffuse and diffuse disease. Several pathways are involved predominantly, although not exclusively, in different subtypes. This may help to explain the disappointing results of many published AGC trials in which study populations were heterogeneous regardless of clinicopathological characteristics of the primary tumor. Histological and anatomical classification may provide insights into tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic. However, some molecular pathways implicated in gastric cancer have not been studied in correlation with histological or anatomical subtypes. Further studies are necessary to confirm the suggestion that such classification may predict tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic.

The ophthalmological complications of targeted agents in cancer therapy: what do we need to know as ophthalmologists?

Recently, there has been an increase in the use of targeted therapies for cancer treatments. Nevertheless, the ocular side-effects of the commonly used targeted agents are generally under-reported and not well studied in the literature. We conducted multiple searches in databases, including Medline, EMBASE, Cochrane Library and conference proceedings, using the following strings: 'name of targeted therapeutic agent (both generic and commercial names)' AND 'eye OR ocular OR vision OR ophthalmological'. Various targeted agents have been found to be associated with ocular side-effects due to their specific targeting of activities in the eye. Imatinib commonly causes periorbital oedema, epiphora and occasionally conjunctival haemorrhage. Cetuximab causes corneal lesions, meibomian gland dysfunction, periorbital and lid dermatitis, blepharitis and conjunctivitis. Erlotinib is related to various ocular toxicities, mainly on the ocular surface, and perifosine has been reported to be associated with severe keratitis. Bevacizumab could potentially disrupt intrinsic ocular circulation and lead to the development of thromboembolic events; there are rare reported cases of optic neuritis or optic neuropathy. Other targeted agents, such as trastuzumab, sunitinib and crizotinib, also have specific ocular toxicities. In conclusion, ocular effects of targeted agents are not uncommon in cancer patients receiving targeted therapy. Ophthalmologists should have high indexes of suspicion to diagnose and treat these complications promptly.

Advances in the systemic treatment of neuroendocrine tumors in the era of molecular therapy.

Neuroendocrine tumors (NETs) are heterogeneous in underlying tumor biology and clinical presentations. They are generally classified according to their degree of differentiation and sites of origin. Moreover, NETs are further characterized by their secreted bioactive neuroamine. The treatment paradigm used to be surgical intervention in early disease and mostly palliative nature in the metastatic setting. With an increase in the understanding of the molecular signaling pathways involved in tumor growth, there are various emerging treatment options for patients with advanced NETs. Somatostatin analogs have both anti-tumor effects as well as symptom palliation associated with the secreted neuropeptides. Peptide-radio-receptor treatment (PRRT) using radio-labeled peptides which binds to somatostatin receptor is a useful anti-tumor treatment but limited by general availability. Sunitinib, a multi-targeted tyrosine kinase inhibitor, has recently been shown to improve the survival of pancreatic NETs patients. Similarly, the use of an mTOR inhibitor--everolimus, either alone or in combination with somatostatin analogs have demonstrated encouraging efficacy in treating advanced NETs. The success of these two agents in pancreatic NETS supports the notion that targeting angiogenesis and/or PI3K/AKT/mTOR pathway is an important strategy for making therapeutic advances in this disease. There are now many ongoing trials in exploring the role of other novel agents in treating patients with pancreatic NETs or carcinoid. The major plaguing problem in this era is the differential response to biological agents amongst NETs of different anatomical origins. Pancreatic NETs are generally more responsive to both chemotherapy and targeted agents than NETs of other sites. Thus, the development of potential predictive and prognostic biomarkers to tailor various molecular therapies to different NETs populations is a major unmet need.

Is there a role for unstimulated thyroglobulin velocity in predicting recurrence in papillary thyroid carcinoma patients with detectable thyroglobulin after radioiodine ablation?

BACKGROUND: In the follow-up of papillary thyroid cancer (PTC) patients treated with curative thyroidectomy and radioiodine ablation, raised thyroglobulin (Tg) predicts recurrence with reasonable sensitivity and specificity. However, a proportion of patients present with raised Tg level but no other clinical evidence of disease. Only limited data on Tg kinetics have been reported to date. Here we aim to evaluate the prognostic and predictive significance of nonstimulated serum Tg velocity (TgV). METHODS: Consecutive PTC patients treated with curative thyroidectomy and radioiodine ablation between 2003 and 2010 were analyzed. Patients with at least one detectable Tg measurement (>0.2 ng/mL) were included. TgV was defined as the annualized rate of Tg change. Logistic regression analyses were performed to evaluate the role of TgV in the prediction of disease recurrence. The optimal TgV cutoff was assigned by receiver-operating characteristic curve analysis. Overall survival of patients above versus below the TgV cutoff were determined by the Kaplan-Meier method and compared. RESULTS: Of a total of 501 patients, 87 had at least one Tg value >0.2 ng/mL; in these latter patients, 29 (33.3%) developed recurrence. TgV was an independent predictor of the recurrence. TgV ≥0.3 ng/mL per year predicted recurrence with a sensitivity of 83.3% and specificity of 94.4%. Patients with TgV below the cutoff had a significantly better overall survival (p = 0.038). CONCLUSIONS: TgV predicts recurrence with high sensitivity and specificity, and is a prognosticator of survival in postthyroidectomy and postablation PTC patients with raised Tg.

The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits.

BACKGROUND: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis. METHODS: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups. RESULTS: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups (P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P = .01), gastrointestinal bleeding (P = .02), and hepatic encephalopathy (P = .02). CONCLUSIONS: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed.

Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease.

BACKGROUND: The combination of bevacizumab (B) and erlotinib (E) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients. We aimed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment. METHODS: Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited. All patients received bevacizumab(B) at 10 mg/kg every 2 weeks with erlotinib(E) at 150 mg daily for a maximum of 6 cycles. Response assessments using both RECIST and modified RECIST criteria were performed after every 6 weeks. The primary endpoint was clinical benefit (CB) rate and a Simon two-stage design was employed. RESULTS: The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited. The median age was 47 years (range, 28-61) and all patients were in ECOG performance status 1. Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis. Among these 10 patients, none of the enrolled patients achieved response or stable disease. The median time-to-progression was 1.81 months (95 % confidence interval [C.I.], 1.08-1.74 months) and overall survival was 4.37 months (95 % C.I., 1.08-11.66 months). Rash (70 %), diarrhea (50 %) and malaise (40 %) were the most commonly encountered toxicities. CONCLUSION: The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population. Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population.

Targeted therapy in the management of advanced gastric cancer: are we making progress in the era of personalized medicine?

BACKGROUND: Gastric cancer is one of the leading causes of cancer death. With greater understanding of the molecular basis of carcinogenesis, targeted agents have led to a modest improvement in the outcome of advanced gastric cancer (AGC) patients. METHODS AND RESULTS: We conducted an overview of the published evidence regarding the use of targeted therapy in AGC patients. Thus far, the human epidermal growth factor receptor (HER) pathway, angiogenic pathway, and phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin pathway have emerged as potential avenues for targeted therapy in AGC patients. The promising efficacy results of the Trastuzumab for Gastric Cancer trial led to the approved use of trastuzumab-based therapy as first-line treatment for patients with HER-2+ AGC. On the other hand, the Avastin® in Gastric Cancer trial evaluating bevacizumab in combination with chemotherapy did not meet its primary endpoint of a longer overall survival duration despite a significantly higher response rate and longer progression-free survival time in patients in the bevacizumab arm. Phase III data are awaited for other targeted agents, including cetuximab, panitumumab, lapatinib, and everolimus. CONCLUSION: Recent progress in targeted therapy development for AGC has been modest. Further improvement in the outcome of AGC patients will depend on the identification of biomarkers in different patient populations to facilitate the understanding of gastric carcinogenesis, combining different targeted agents with chemotherapy, and unraveling new molecular targets for therapeutic intervention.

Colon cancer in a patient with underlying aplastic anemia: A clinical challenge.

The association of gastrointestinal malignancy with aplastic anemia has rarely been reported in the literature. Although it is not clear whether there is any direct relationship between aplastic anemia and gastrointestinal cancers, a retrospective analysis did suggest the notion that patients with aplastic anemia might have a higher incidence of colorectal cancer. Here, we report the diagnostic and therapeutic challenges in managing a patient with aplastic anemia and advanced colorectal cancer. Early diagnosis is challenging due to overlapping symptomatology and clinical features, increased risk of diagnostic procedures, and confounding complications arising from aplastic anemia and its treatment. A high index of suspicion and multidisciplinary input are essential.

The outcomes and safety of single-agent sorafenib in the treatment of elderly patients with advanced hepatocellular carcinoma (HCC).

BACKGROUND: With the aging population, hepatocellular carcinoma (HCC) in the elderly represents a significant health burden. We aimed to evaluate and compare the efficacy and tolerability of single-agent sorafenib in treating elderly patients with advanced HCC versus the younger population. METHODS: We retrospectively analyzed a consecutive cohort of advanced HCC patients with Child-Pugh A or B liver function and an Eastern Cooperative Oncology Group performance status score of 0-2 treated with sorafenib. The patients were categorized into older (age ≥70 years) and younger (age <70 years) groups. Treatment outcomes and related adverse events (AEs) were compared. RESULTS: In total, 172 patients, 35 in the older (median age, 73 years) and 137 in the younger (median age, 55 years) group, were analyzed. The median progression-free survival time was similar in the older and younger groups (2.99 months versus 3.09 months; p = .275), as was the overall survival time (5.32 months versus 5.16 months; p = .310). Grade 3 or 4 AEs were observed in 68.6% of older and 62.7% of younger patients (p = .560), with neutropenia (11.4% versus 0.7%; p = .007), malaise (11.4% versus 2.2%; p = .033), and mucositis (5.7% versus 0.0%; p = .041) being more frequently reported in the elderly cohort. CONCLUSIONS: The survival benefits and overall treatment-related AEs of sorafenib are comparable in elderly and younger advanced HCC patients. Nevertheless, more vigilant monitoring in the elderly is warranted because they are more susceptible to develop neutropenia, malaise, and mucositis.

Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer.

Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.