Exploring treatment outcomes in Stage II-III rectal cancer patients undergoing neoadjuvant therapy at a tertiary care center in Pakistan: a comprehensive analysis of pathological outcomes.

BACKGROUND: Rectal cancer treatment has transformed in recent years, with neoadjuvant treatment (NT) and total neoadjuvant treatment (TNT) aiming to enhance pathological responses. This pioneering study in our country delves into rectal cancer management, offering crucial insights by examining pathological outcomes in patients treated with the NT and TNT approach, shaping the evolving landscape. METHODS: In this retrospective-cohort study spanning January 2017 to December 2022 at a tertiary care hospital in Pakistan, ethical approval was obtained to examine outcomes of two treatments. Patients were divided into TNT (chemoradiation and pre-surgery 5 FU-based chemotherapy) and NT (chemoradiation, surgery, and subsequent 5 FU-based chemotherapy). The primary end-point was response rates-no response, pathological complete response (pCR), near complete response (near CR), and partial response (PR). The Chi-Square Test for Independence assessed the association between treatment response and type (TNT or NT). Data analysis used STATA MP 64; significance was set at p < 0.05 for all two-tailed tests. RESULTS: We analyzed 77 patients, 60 underwent standard neoadjuvant chemoradiation, and 17 followed the total neoadjuvant approach. Predominantly male, most were > 65 with ECOG 0-1. The TNT group showed higher response rates (76% vs 62%, p = 0.039), with 40.38% achieving pCR. In the overall population, pCR and near-CR were similar (27.2% vs 26%), while PR were 14%. Treatment characteristics correlated significantly with chemotherapy type, concurrent chemoradiation, LVI, PNI, and T, N, M staging (p < 0.05). Median overall survival was not reached, and mean survival was 89.1 months (CI: 95.0 to 83.3). Side effects varied, with notable differences in neuropathy, diarrhea, oral mucositis, and thrombocytopenia between NT and TNT groups. CONCLUSION: Our study adds to evidence favoring neoadjuvant approaches in managing rectal cancer in pakistan. Demonstrating a favorable pcr rate, ongoing research with extended follow-up is essential, given the dynamic landscape of rectal cancer treatment for improved patient outcomes.

Review of current literature on gestational trophoblastic neoplasia.

BACKGROUND: Gestational Trophoblastic Neoplasia (GTN) is a disease of the reproductive age group with an incidence rate of <1% among all tumors involving the female reproductive tract. It occurs because of aberrant fertilization. Patients are diagnosed early because of aggravated symptoms during pregnancy. Moreover, patients also bleed from the tumor sites, which leads to early presentation. A cure rate of 100% can be achieved with adequate treatment. MAIN BODY: In this literature review, the authors have brought to attention the risk factors, classification, and various treatment options in GTN patients according to their stratification as per the WHO scoring system. Patients are categorized into low and high risk based on the FIGO scoring system. Patients with low risk are treated with single-agent methotrexate or actinomycin-D. Despite the superiority of actinomycin-D in terms of efficacy, methotrexate remains the first choice of therapy in low-risk patients due to its better toxicity profile. Multi-agent chemotherapy with etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine (EMA-CO) leads to complete remission in 93% of high-risk GTN patients. Around 40% of patients with incomplete responses are salvaged with platinum-based multi-agent chemotherapy. Isolated chemo-resistant clones can be salvaged with surgical interventions. CONCLUSION: The mortality in patients with GTN has significantly reduced over time. With adequate multi-disciplinary support, patients with GTN can ultimately be cured and can spend every day healthy reproductive life.

Thin on the ground: Primary mucosal melanoma of the nasal cavity.

INTRODUCTION AND IMPORTANCE: Primary malignant melanoma of the head and neck region is an exceptionally unique neoplasm that accounts for 1 % of all mucosal melanomas diagnosed worldwide. Most patients are either symptomless or have vague symptoms. CASE PRESENTATION: In this report, we describe the case of a young female, who presented at a tertiary care institute in Pakistan, with a history of recurrent ipsilateral mucosal neoplasm arising in the nasal cavity. The patient was treated with surgical resection twice and was subsequently found to have widespread metastatic lymph nodes on workup. CLINICAL DISCUSSION: Malignant mucosal melanoma seldom originates from the nasal cavity. Surgical resection is the best chance of cure for localized nasal melanomas whereas for metastatic disease, systemic therapy with either chemotherapy or biologic agents is the mainstay of management. CONCLUSION: Approximately 5 % of the cases of mucosal melanoma have metastatic disease at presentation. This report highlights the presentation, clinical characteristics, management, and prognosis of non-cutaneous melanoma, arising within the head and neck region.

Chaotic transformation of parotid acinic cell carcinoma to metastatic dedifferentiated high-grade pathology - A rare case with clinical and emotional challenge.

INTRODUCTION AND IMPORTANCE: Acinic cell carcinoma (AciCC) is a rare entity in which high-grade transformation (HGT), formerly dedifferentiation, is uncommon. This case report presents a rare case of AciCC, with rapid transformation to metastatic high-grade dedifferentiated pathology after initial curative treatment. CASE PRESENTATION: A 58-year-old woman presented in the medical oncology clinic with a progressive swelling on the right side of her face. Magnetic resonance imaging revealed a 5 × 5 cm lobulated parotid gland lesion, and fine needle aspiration biopsy was consistent with carcinoma. After informed consent, a Modified-Blair incision was given as a standard approach to the right preauricular area under general anaesthesia, and a right superficial parotidectomy with the removal of the tumor and selective lymph node dissection was performed. Histopathology of the resected mass was reported as parotid AciCC. She was given adjuvant radiation therapy. A repeat PET CT scan ten weeks after the completion of her adjuvant radiation treatment showed local disease recurrence as well as multiple pulmonary deposits. A repeat biopsy was reported as DOG-1 positive dedifferentiated (high-grade) acinic cell carcinoma, and she was offered platinum-based palliative systemic chemotherapy. CLINICAL DISCUSSION: Parotid acinic cell carcinomas with high-grade transformation are rare. This case highlights its critical diagnostic markers, curative and palliative management and long-term follow-up. CONCLUSION: The transformation of parotid AciCC to high-grade, dedifferentiated pathology is unusual and belligerent. Hence, these tumors need intense treatment with a multimodality approach. Close follow-ups with history and physical examination, along with periodic imaging, should be considered for these patients.

Multiple myeloma and its rare paraneoplastic manifestations simmering under the surface.

Paraneoplastic syndromes are complex clinical manifestations that occur because of the underlying malignancy in which the malignant cells produce hormones, cytokines, peptides or antibodies that causes symptoms and may affect multiple organ systems. These paraneoplastic conditions may be associated with different solid and hematological malignancies. Multiple Myeloma (MM) accounts for 10-15 % of hematological malignancies and 1-2 % of all malignancies. It is associated with some atypical clinical and laboratory paraneoplastic manifestations. Although there is a low incidence of these paraneoplastic, significant knowledge of these manifestations may assist in making a differential diagnosis in cases of doubt. The clinical presentation may vary and be evident even before or after the diagnosis of malignancy. These include vascular, neurological, dermatological, physiological, and other atypical conditions. Furthermore, these rare paraneoplastic manifestations need more valid, relevant scientific information, as most information about these conditions is derived from case reports. After the literature search, we have reported the paraneoplastic manifestations associated with multiple myeloma, published in the English literature, and the cognate management in this review article. To our knowledge, this is the first review article discussing various paraneoplastic manifestations of multiple myeloma.

Prognostic factors, oncological treatment and outcomes of uterine sarcoma: 10 years' clinical experience from a tertiary care center in Pakistan.

BACKGROUND: Uterine sarcoma is an uncommon aggressive malignancy. Optimal management and prognostic factors have yet to be well recognized due to their rarity and various histological subtypes. This study aims to investigate these patients' prognostic factors, treatment modalities, and oncological outcomes. METHODS: A single-center retrospective cohort study was conducted on all patients diagnosed with uterine sarcoma and treated from January 2010 to December 2019 in a tertiary-care hospital in Pakistan. The data were analyzed using STATA software and stratified on the histological subtype. Survival rates were estimated using the Kaplan-Meier method. Crude and adjusted hazard ratios with 95% CI were estimated using univariate and multivariate analysis. RESULTS: Of the 40 patients, 16(40%) had uterine leiomyosarcoma (u-LMS), 10(25%) had high-grade endometrial stromal sarcoma (HGESS), 8(20%) had low-grade endometrial stromal sarcoma (LGESS) and 6(15%) had other histological subtypes. The median age of all patients was 49 (40-55.5). Thirty-seven (92.5%) patients underwent primary surgical resection, and 24 (60%) patients received adjuvant systemic chemotherapy. The survival plots showed the overall population's DFS of 64 months and the OS of 88 months (p-value = 0.001). The median DFS in all patients was 12 months, and the median OS was 14 months (p-value = 0.001). A small but significant DFS benefit was found in patients who received adjuvant systemic chemotherapy, 13.5 versus 11 months (p-value = 0.001). Multivariate Cox-regression analysis revealed that large tumor size and advanced FIGO stage were substantial factors associated with decreased survival. CONCLUSION: Uterine sarcomas are rare malignancies with poor prognosis. Multiple factors, including tumor size, mitotic count, stage of the disease, and myometrial invasion, impact survival outcomes. Adjuvant treatment may decrease the recurrence rate and improve DFS but do not affect OS.

Mean level of pretreatment neutrophil to lymphocyte ratio in patients with squamous cell carcinoma of the head and neck-Cross-sectional study.

Background: Squamous cell carcinoma of the head and neck have been characterized using various prognostic parameters. These include advanced age, lifestyle habits such as smoking, higher tumor stage at presentation & presence of metastasis. Many patients are diagnosed with head and neck cancers annually in Pakistan, but limited data is available for the prognosis of these patients. This study aims to investigate a new biomarker by estimating the mean level of pretreatment neutrophil to lymphocyte ratio (NLR) in patients with Squamous cell carcinoma of the head & neck. Methods: We conducted a cross-sectional study using non-probability consecutive sampling techniques for 222 biopsy-proven cases of head & neck squamous cell carcinoma. Clinical & pathological variables were analyzed, including the patient's profile and tumor characteristics. The NLR of each patient before treatment was calculated using the absolute neutrophil count divided by the absolute lymphocyte count in preoperative blood samples. An independent sample t-test was used to assess the mean difference. A p-value less than or equal to 0.05 was taken as statistically significant. Results: Of 222 patients, a male predominance was seen in the entire cohort. A median pretreatment NLR of 3.19 (2.47-4.97) was identified, and patients were classified into high and low NLRs based on this value. Data analysis revealed a statistically significant increase in NLR among patients with nodal metastasis. In addition, patients with NLR above the median cutoff value of 3.19 demonstrated that there was a significant increase in NLR values with high tumor (T) and nodal (N) classifications with a p-value of 0.001 and 0.003, respectively. Conclusion: Pretreatment neutrophil to lymphocyte ratio may be associated with increased nodal involvement. It may serve as a useful prognostic predictor for patients with squamous cell carcinomas of the head and neck. Identifying high-risk patients in the pretreatment phase with the help of such biomarkers will also facilitate early inclusion in clinical trials.

Role of circulating-tumor DNA in the early-stage non-small cell lung carcinoma as a predictive biomarker.

Lung cancer is one of the most common solid malignancies. Tissue biopsy is the standard method for accurately diagnosing lung and many other malignancies over decades. However, molecular profiling of tumors leads to establishing a new horizon in the field of precision medicine, which has now entered the mainstream in clinical practice. In this context, a minimally invasive complementary method has been proposed as a liquid biopsy (LB) which is a blood-based test that is gaining popularity as it provides the opportunity to test genotypes in a unique, less invasive manner. Circulating tumor cells (CTC) captivating the Circulating-tumor DNA (Ct-DNA) are often present in the blood of lung cancer patients and are the fundamental concept behind LB. There are multiple clinical uses of Ct-DNA, including its role in prognostic and therapeutic purposes. The treatment of lung cancer has drastically evolved over time. Therefore, this review article mainly focuses on the current literature on circulating tumor DNA and its clinical implications and future goals in non-small cell lung cancer.

No difference in treatment outcome between patients with nodal versus extranodal diffuse large B-cell lymphoma.

Background and Aim: Diffuse large B-cell lymphoma (DLBCL) has been classified using various parameters, including the site of origin. Studies have reported conflicting outcomes when DLBLC patients were stratified according to the site of origin. This study aimed to investigate the response rate and survival outcomes in nodal versus extranodal DLBCL and compare the results to a region-matched study covering the 1988 - 2005 period. Methods: A single-center retrospective cohort study was conducted on all patients diagnosed with DLBCL and treated in a tertiary care hospital in Pakistan during 2014 - 2019. We calculated the mean and median for continuous variables and frequency and percentages for all categorical variables. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier survival curves. A Cox proportional hazards model was used to determine the hazard ratio (HR) for OS. Results: Of the 118 patients, 49 patients (41.5%) had nodal disease and 69 patients (58.5%) were diagnosed with extranodal DLBCL. The majority of patients in the nodal and extranodal cohorts presented with Stages III and IV disease (73.4% and 62.3%, respectively). A complete response to (immuno) chemotherapy was achieved in 71.4% of nodal DLBCL patients and 65.2% of extranodal DLBCL patients. The 5-year PFS and median PFS in the entire cohort were 0.8% and 17 m, respectively. The PFS and median PFS in the nodal and extranodal DLBCL cohort were 0% and 1.4%, respectively, and 15 m and 19 m, respectively. The 5-year OS and median OS in the entire cohort were 16.1% and 19 m, respectively. The OS and median OS in the nodal and extranodal DLBCL cohort were 8.2% and 21.7%, respectively, and 19 m and 21 m, respectively. Multivariable linear regression revealed that the ABC phenotype (nodal, HR = 1.37, 95% CI = 1.37 - 3.20; extranodal, HR = 1.65, 95% CI = 1.46 - 3.17; GBC as reference) and double and triple hit DLBCL (nodal, HR = 1.29, 95% CI = 1.19 - 2.81; extranodal, HR = 1.87, 95% CI = 1.28 - 2.43; and non-expressors as reference) are independent negative predictors of OS. Conclusions: DLBCL incidence in the Karachi region has remained comparable but patient composition in the extranodal DLBCL cohort has shifted to predominantly advanced stage. Nodal and extranodal DLBCL were associated with similar PFS and OS profiles and first- and second-line treatment responses. Cell of origin and antigen expression status was independent negative predictors of OS, disfavoring the ABC phenotype and lesions with c-MYC and BCL2 and/or BCL6 overexpression. Relevance for Patients: DLBCL is an aggressive type of non-Hodgkin's lymphoma, however; patients respond well to standard systemic chemotherapy. Extranodal type of DLBCL patients tend to have more residual disease after first-line systemic chemotherapy, but physicians should keep in mind that the subsequent line treatment mitigates its negative impact on survival.

Cardiac sarcoma: A rare case of primary cardiac sarcoma.

INTRODUCTION AND IMPORTANCE: Primary cardiac sarcoma is a rare malignancy with a poor prognosis because of diagnostic delay, therapeutic difficulties, and high metastatic potential. The therapeutic approach includes surgery, chemotherapy, and radiation therapy, alone or in combination. However, there is a lack of evidence to guide the treatment. CASE PRESENTATION: We present a case of primary cardiac sarcoma. Our patient was presented in the department of emergency medicine (ED) in our institute with shortness of breath on exertion associated with orthopnea. Based on the history and cardiovascular examination, he underwent an echocardiogram, which revealed a sizeable echogenic density in the right ventricular outflow tract. He underwent surgical resection of the cardiac mass via median sternotomy and total cardiopulmonary bypass approach. The patient was eventually diagnosed with primary cardiac sarcoma, confirmed by tissue biopsy after surgical intervention. CLINICAL DISCUSSION: Through this report, we highlight the rarity of primary cardiac sarcomas, the importance of multidisciplinary tumor board (MDT) discussion and provide evidence of surgical excision being the treatment of choice, followed by systemic chemotherapy in selected cases. CONCLUSION: Cardiac sarcoma is a rare but highly malignant tumor with a poor prognosis. However, early diagnosis and surgical resection of a primary cardiac sarcoma can significantly increase the patient's survival and quality of life. Therefore, physicians should keep a high suspicion of a patient with clinical features suggestive of cardiac sarcoma, and echocardiography should be the diagnostic modality of choice in such patients.

Abdominal myoepithelial carcinoma: A rare abdominal wall entity of an uncommon tumor.

INTRODUCTION AND IMPORTANCE: Myoepithelial carcinomas are a diverse group of tumors exhibiting myoepithelial differentiation. There have been increasing reports of extra-salivary sites of origin for myoepithelial carcinomas such as soft tissues, bone and visceral areas. Due to this entity's rarity, definite diagnostic and treatment parameters are somewhat limited. We present the case of a myoepithelial carcinoma arising from the abdominal wall, a rare site of origin of an uncommon tumor. CASE PRESENTATION: A 37-year-old gentleman presented to our institution in Oct 2018 with a recurrent abdominal mass for which he underwent wide local excision after completing the workup, which included systemic scans and relevant blood investigations. The histopathology report was consistent with malignant abdominal myoepithelial carcinoma. However, subsequent follow-up scans in May 2019 showed disease progression with the appearance of multiple lung metastases. After a detailed discussion, he was started on Pazopanib 800 mg orally once a day, on which he remained stable till May 2022. It was then when he experienced clinical disease progression confirmed on systemic scans, so he was offered palliative systemic chemotherapy. CLINICAL DISCUSSION: Abdominal malignant myoepithelial carcinomas are an infrequent entity. However, this case highlights its critical diagnostic markers and primary and recurrent abdominal myoepithelial carcinoma management. CONCLUSION: Abdominal myoepithelial carcinomas, although rare, are also under-recognized. Thus, keeping an index of high suspicion for these tumors and being armed with knowledge regarding the heterogeneity of its features would lead to better diagnostic awareness and documentation, paving the way for better evidence-based treatments.

Inactivated COVID-19 vaccine triggering hemophagocytic lymphohistiocytosis in an immunocompetent adult - A case report.

Background and Aim: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome that is induced by hyper-activated macrophages, cytotoxic T cells, and reduced natural killer cell activity. A 46-year-old gentleman presented to us with complaints of intermittent fever for the past 2 weeks associated with fatigue along with oral ulcers and skin rashes which resolved spontaneously. These symptoms started after he received the second dose of the BBIP-CorV COVID-19 vaccine. His complete blood picture showed pancytopenia. A detailed infectious disease workup was unrevealing; however, his bone marrow biopsy revealed increased histiocyte activity, with some showing hemophagocytosis and dysplasia. Immunohistochemistry profile demonstrated strong CD 68 positivity. Further investigations showed raised serum ferritin and fasting triglyceride levels. He was immediately started on dexamethasone acetate at a dose of 10 mg/m2, after which his clinical symptoms, as well as his blood parameters, improved remarkably. This is the first documented case in Pakistan. Conclusion: The data from clinical trials support the general safety profile of inactivated COVID-19 vaccines. We endorse its mass implementation. However, we believe that robust data need to be generated to evidence any adverse events, especially those with serious outcomes. Physicians should be aware of inactivated COVID-19 vaccine as a possible trigger for HLH and start prompt treatment, resulting in favorable outcomes. Relevance for Patients: The presentation of HLH may vary and can present in an immunocompetent patient with no underlying risk factor. HLH should be kept in differentials when a patient presents with pancytopenia with a recent history of receiving COVID-19 vaccination. Steroids play a major role in the treatment of HLH, and definitive diagnosis and early treatment improve clinical outcomes.

Inactivated COVID-19 vaccine triggering hemophagocytic lymphohistiocytosis in an immunocompetent adult - A case report.

Background and Aim: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome that is induced by hyper-activated macrophages, cytotoxic T cells, and reduced natural killer cell activity. A 46-year-old gentleman presented to us with complaints of intermittent fever for the past 2 weeks associated with fatigue along with oral ulcers and skin rashes which resolved spontaneously. These symptoms started after he received the second dose of the BBIP-CorV COVID-19 vaccine. His complete blood picture showed pancytopenia. A detailed infectious disease workup was unrevealing; however, his bone marrow biopsy revealed increased histiocyte activity, with some showing hemophagocytosis and dysplasia. Immunohistochemistry profile demonstrated strong CD 68 positivity. Further investigations showed raised serum ferritin and fasting triglyceride levels. He was immediately started on dexamethasone acetate at a dose of 10 mg/m2, after which his clinical symptoms, as well as his blood parameters, improved remarkably. This is the first documented case in Pakistan. Conclusion: The data from clinical trials support the general safety profile of inactivated COVID-19 vaccines. We endorse its mass implementation. However, we believe that robust data need to be generated to evidence any adverse events, especially those with serious outcomes. Physicians should be aware of inactivated COVID-19 vaccine as a possible trigger for HLH and start prompt treatment, resulting in favorable outcomes. Relevance for Patients: The presentation of HLH may vary and can present in an immunocompetent patient with no underlying risk factor. HLH should be kept in differentials when a patient presents with pancytopenia with a recent history of receiving COVID-19 vaccination. Steroids play a major role in the treatment of HLH, and definitive diagnosis and early treatment improve clinical outcomes.

Bilateral congenital cryptorchidism and unilateral Leydig cell tumor in an adult presenting with gynecomastia and primary infertility: A case report.

INTRODUCTION AND IMPORTANCE: The neoplasms of the testis are sporadic tumors among men. Furthermore, the rarest subset of these is neoplasms belonging to the stromal tumors of the sex cord. Leydig cell tumors are the most common form among the testicular stromal tumors. In our case, the underlying risk factor associated with the development of Leydig cell tumors was cryptorchidism. While mostly unilateral, cases of bilateral cryptorchidism may be present and have been rarely reported. CASE PRESENTATION: We report a 36-year-old gentleman who presented to us with the inability to carry off intercourse without difficulty attaining erection on stimulation for the past two years. He had a history of left undescended testis since birth, for which he underwent left orchidopexy 20 years ago. An ultrasound of the pelvis showed an oval hypoechoic-shaped heterogeneous mass in the right mid-inguinal canal. Relevant blood investigations showed a deranged hormonal profile. He then underwent an uneventful right radical orchiectomy, histopathology of which was consistent with Leydig cell tumor. CLINICAL DISCUSSION: LCT with a history of bilateral cryptorchidism has rarely been reported. This case highlights its clinical presentation, management, and further follow-up in such patients. CONCLUSION: Bilateral congenital cryptorchidism may be associated with Leydig cell tumor years later in life hence long-term follow-up is required for these patients. The clinical presentation of these tumors may vary among individuals. Any change in physical appearance, hormonal assay, and imaging studies should promptly be followed for possible surgical resection and close monitoring.

Effect of Facebook on the life of Medical University students.

BACKGROUND: Facebook is a social networking service launched in February 2004, owned and operated by Facebook, Inc. As of June 2012, Facebook reports more than 1 billion active users. Objective of study was to evaluate the effect of Facebook on the social life, health and behavior of medical students. METHODOLOGY: It was a cross sectional, observational and questionnaire based study conducted in Dow University OF Health Sciences during the period of January 2012 to November 2012. We attempted to interview all the participants who could be approached during the period of the study. Participants were MBBS students, while all students of other courses and programs were taken as exclusion criteria. Approximately 1050 questionnaires were distributed to participants. Fifty questionnaires were rejected due to incomplete answers, yielding 1000 usable responses for an approximate 95% response rate. Informed verbal consent was taken from each participant. Study was ethically approved by Institutional Review Board of Dow University of Health Sciences. All the data was entered and analyzed through SPSS 19. RESULT: Out of total 1000 participants, males were 400 (40%) and females were 600 (60%). Participants were in the age group of 18-25 years with a mean age of 20.08 years. Most of the participants were using Facebook daily (N = 640, 64%) for around 3-4 hours (N = 401, 40.1%). Majority of them (N = 359, 35.9%) believed that they were equally active on Facebook and in real life while few believed their social life became worse after start using Facebook (N = 372, 37.2%). Most of the participants admitted that they were considered as shy in real world (N = 390, 39.0%) while in the world of Facebook they were considered as fun loving by their friends (N = 603, 60.3%). A large number of participants (N = 715, 75%) complained of mood swings. CONCLUSION: Youngsters are willing to compromise their health, social life, studies for the sake of fun and entertainment or whatever satisfaction they get after using Facebook. What we observed in our study was that although majority of our subjects showed multiple signs of Facebook addiction, they don't realize it and if even they realize it they don't want to quit Facebook and even if they want to quit, they can't. Our observance concluded that majority of the users are highly addicted.