Hypercalcemia with methotrexate pneumonitis: A rare, important and intriguing adverse event.

Methotrexate leading to hypercalcaemia is a rarely reported adverse event. We present three elderly patients with inflammatory arthritis who developed hypercalcemia probably due to methotrexate-induced granulomatous pneumonitis. All patients presented with worsening non-productive cough with dyspnea, nausea, loss of appetite, and confusion. Their clinical and radiologic features were consistent with methotrexate-induced pneumonitis. On evaluation, all patients concurrently had hypercalcemia with normal 25OH D3, and low PTH with markedly elevated levels of 1,25OH D3 seen in two patients. In all three patients, hypercalcemia and pneumonia responded to hydration, corticosteroids, and methotrexate withdrawal. There was no relapse of symptoms on long term follow-up. In these three patients with inflammatory arthritis, methotrexate-induced pneumonitis led to symptomatic hypercalcemia. Unless hypercalcemia is looked for and treated in this setting, the morbidity can be high.

Assessment of Patient Satisfaction Among Cancer Patients Undergoing Radiotherapy.

The patient-provider relationship is a key driver of patient satisfaction as it relates to overall healthcare experience. We surveyed patients undergoing radiation therapy to determine what they consider to be the most valued qualities in their interactions with the healthcare team. An ethics-approved 35-item patient satisfaction survey was developed in-house to gain insights on patients' perception of their relationship with the healthcare team throughout their cancer journey. There were 199 completed survey, median age 68 years, 54% women and 45% men. Almost all (95%) "agreed" or "strongly agreed" that their physicians had been sensitive and compassionate. Over 90% felt that they received adequate explanations about their treatment, and had their questions answered. The vast majority (93%) felt included in the decision-making process. Patients reported the 5 most highly rated qualities among their healthcare providers (HCPs) as knowledge, kindness, honesty, good communication, and a cheerful attitude. Overall satisfaction was high but areas for improvement were identified including being offered future appointments for further discussion, more information about clinical trials, other treatments, and community resources. Patients noted their HCPs tended to focus on the physical and emotional needs of patients, but spiritual and cultural needs were rarely addressed. Patients receiving radiotherapy reported high rates of satisfaction across many aspects of their care. These findings also reinforce the different aspects of holistic care that can be improved, and serve as a reminder to clinicians that patients perceive their role as more than just that of a medical expert.

The importance of humour in oncology: a survey of patients undergoing radiotherapy.

Background: Humour has long been considered an important coping tool for patients with cancer, but published quantitative data about its significance are limited. The purpose of our study was to survey patients with cancer undergoing radiotherapy regarding their opinions about the use of humour in their care. Methods: An anonymous 35-item questionnaire evaluating the patient experience, including the value of humour, was developed by an interdisciplinary team of health care providers (hcps) working within the Radiation Medicine program. This anonymous, voluntary, paper-based survey for self-completion required approximately 10 minutes to finish and was administered during the fall of 2018 and the spring of 2019. Results: For the 199 patients who completed the survey [108 women, 89 men (2 respondents did not specify)], median age was 68 years. That group represents approximately 30%-35% of the patients on treatment during the study period. Almost all respondents (86%) indicated that, during their visits to the cancer centre, it was "somewhat important" or "very important" for health care providers (hcps) to use appropriate humour, and 61% of respondents indicated using humour "frequently" or "always" when dealing with their individual cancers. Most respondents (79%) said that humour decreased anxiety, and 86% indicated that laughing was considered "somewhat important" or "very important." Approximately 4% of respondents even listed "sense of humour" as being the most important quality that they looked for in their interactions with their hcps. Conclusions: Cancer patients undergoing radiotherapy clearly view humour as being important for coping and dealing with their disease, and oncology hcps should routinely consider incorporating the use of appropriate humour into the care that they provide.

Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma.

The iliac crest is the sampling site for minimal residual disease (MRD) monitoring in multiple myeloma (MM). However, the disease distribution is often heterogeneous, and imaging can be used to complement MRD detection at a single site. We have investigated patients in complete remission (CR) during first-line or salvage therapy for whom MRD flow cytometry and the two imaging modalities positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) were performed at the onset of CR. Residual focal lesions (FLs), detectable in 24% of first-line patients, were associated with short progression-free survival (PFS), with DW-MRI detecting disease in more patients. In some patients, FLs were only PET positive, indicating that the two approaches are complementary. Combining MRD and imaging improved prediction of outcome, with double-negative and double-positive features defining groups with excellent and dismal PFS, respectively. FLs were a rare event (12%) in first-line MRD-negative CR patients. In contrast, patients achieving an MRD-negative CR during salvage therapy frequently had FLs (50%). Multi-region sequencing and imaging in an MRD-negative patient showed persistence of spatially separated clones. In conclusion, we show that DW-MRI is a promising tool for monitoring residual disease that complements PET and should be combined with MRD.

Current practice in total-body irradiation: results of a Canada-wide survey.

BACKGROUND: Total-body irradiation (tbi) is used to condition patients before bone marrow transplant. A variety of tbi treatment strategies have been described and implemented, but no consensus on best practice has been reached. We report on the results of a survey created to assess the current state of tbi delivery in Canada. RESULTS: A 19-question survey was distributed to 49 radiation oncology programs in Canada. Responses were received from 20 centres, including 12 centres that perform tbi. A variety of tbi dose prescriptions was reported, although 12 Gy in 6 fractions was used in 11 of the 12 centres performing tbi. Half of the centres also reported using a dose prescription unique to their facility. Most centres use an extended-distance parallel-opposed-pair technique, with the patient standing or lying on a stretcher against a wall. Others translate the patient under the beam, sweep the beam over the patient, or use a more complicated multi-field technique. All but 1 centre indicated that they attenuate the lung dose; only 3 centres indicated attenuating the dose for other organs at risk. The survey also highlighted the considerable resources used for tbi, including extra staff, prolonged planning and treatment times, and use of locally developed hardware or software. CONCLUSIONS: At transplant centres, tbi is commonly used, but there is no commonly accepted approach to planning and treatment delivery. The important discrepancies in practice between centres in Canada creates an opportunity to prompt more discussion and collaboration between centres, improving consistency and uniformity of practice.

Spinal bone marrow necrosis with vertebral compression fracture: differentiation of BMN from AVN.

Bone marrow necrosis (BMN) is a rare malignancy-associated hematologic disorder characterized by necrosis of myeloid and stromal marrow elements with preservation of cortical bone. Overlap between the imaging appearances of BMN and avascular necrosis (AVN) raises the potential for diagnostic confusion. We report a case of BMN presenting with a traumatic multi-level vertebral body collapse, and finding that may potentially confound distinction between the two entities. We discuss important pathophysiologic, clinical, and radiologic differences between BMN and AVN with emphasis on features important in the differential diagnosis.

Loss of N-Myc interactor promotes epithelial-mesenchymal transition by activation of TGF-ß/SMAD signaling.

Epithelial-mesenchymal transition is one of the critical cellular programs that facilitate the progression of breast cancer to an invasive disease. We have observed that the expression of N-myc interactor (NMI) decreases significantly during progression of breast cancer, specifically in invasive and metastatic stages. Recapitulation of this loss in breast cell lines with epithelial morphology (MCF10A (non-tumorigenic) and T47D (tumorigenic)) by silencing NMI expression causes mesenchymal-like morphological changes in 3D growth, accompanied by upregulation of SLUG and ZEB2 and increased invasive properties. Conversely, we found that restoring NMI expression attenuated the mesenchymal attributes of metastatic breast cancer cells, accompanied by distinctly circumscribed 3D growth with basement membrane deposition and decreased invasion. Further investigations into the downstream signaling modulated by NMI revealed that NMI expression negatively regulates SMAD signaling, which is a key regulator of cellular plasticity. We demonstrate that NMI blocks TGF-ß/SMAD signaling via upregulation of SMAD7, a negative feedback regulator of the pathway. We also provide evidence that NMI activates STAT signaling, which negatively modulates TGF-ß/SMAD signaling. Taken together, our findings suggest that loss of NMI during breast cancer progression could be one of the driving factors that enhance the invasive ability of breast cancer by aberrant activation of TGF-ß/SMAD signaling.

Pain assessment during conscious sedation for cervical cancer high-dose-rate brachytherapy.

BACKGROUND: This observational study set out to evaluate the effectiveness of conscious sedation anesthesia for pain control during high-dose-rate (hdr) brachytherapy using a ring-and-tandem applicator system for patients with cervical cancer. METHODS: At the time of initiation of the hdr cervical cancer brachytherapy program at our institution, patients received a detailed symptom assessment during the procedures. Brachytherapy was carried out using a Smit sleeve, together with a ring-and-tandem applicator. Midazolam and an opioid-hydromorphone, morphine, or fentanyl-were the main agents used to achieve conscious sedation. RESULTS: From January 2009 to October 2010, 20 patients (median age: 45 years) underwent 57 procedures. All patients received chemoradiation with curative intent. The median duration of the procedures was 1.4 hours, and no significant cardiovascular events were noted. The total dose of intravenous midazolam used ranged from 0.5 mg to 8.5 mg (median: 2.5 mg). The total dose of intravenous morphine equivalent used ranged from 2.5 mg to 60 mg (median: 8 mg). The mean and median pain scores during the procedures were 1.4 and 1.1 respectively. Brief moments of moderate to severe incidental pain were noted at the time of certain events during the procedure-specifically during insertion of the ring-and-tandem applicator. The maximal pain score during the entire procedure ranged from 0 to 10 (median: 4.7). The period of recovery from conscious sedation was relatively brief (median discharge time: 1 hour). CONCLUSIONS: We were able to demonstrate that patients undergoing hdr brachytherapy for cervical cancer can achieve good pain control with conscious sedation.

Effects of radiation and total androgen blockade on serum hemoglobin, testosterone, and erythropoietin in patients with localized prostate cancer.

OBJECTIVE: The objective of the present study was to evaluate the incidence, time of onset, and extent of hemoglobin, testosterone, and erythropoietin changes in patients with localized prostate cancer receiving either radiation alone or radiation combined with total androgen blockade (tab). METHODS: The study enrolled 35 patients (median age: 69 years) with clinically localized prostate cancer who received 3-dimensional conformal radiation with or without tab. Patients were generally treated with radiation alone (group 1), radiation plus short-term (≤6 months) tab (group 2), or radiation plus long-term (≥2 years) tab (group 3). Serum hemoglobin, testosterone, and erythropoietin in these patients were prospectively evaluated. RESULTS: The mean baseline serum hemoglobin for group 1 (n = 20), group 2 (n = 6), and group 3 (n = 9) was 149 g/L, 153 g/L, and 143 g/L respectively. We observed no significant decline in serum hemoglobin, testosterone, or erythropoietin among patients treated with radiotherapy alone. A significant drop in serum testosterone was noted in the group 2 and 3 patients within 1 month (p < 0.001), reaching a plateau at approximately 6 months. That change was followed by a significant decline (p < 0.001) in serum hemoglobin at 3-6 months (137 g/L in group 2 and 129 g/L in group 3). We observed a small but statistically significant increase in serum erythropoietin (p < 0.001) of 8 U/L in group 2 and 4 U/L in group 3 after 6 months of tab. No immediate recovery in serum hemoglobin, testosterone, or erythropoietin was observed upon completion of tab. CONCLUSIONS: Although conformal radiotherapy alone for localized prostate cancer had no effect on serum hemoglobin, testosterone, or erythropoietin, tab led to a significant decline in testosterone, which was followed by decline in hemoglobin that was not a result of a deficiency of erythropoietin.

Sulindac inhibits tumor cell invasion by suppressing NF-κB-mediated transcription of microRNAs.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely reported to display strong efficacy for cancer chemoprevention, although their mechanism of action is poorly understood. The most well-documented effects of NSAIDs include inhibition of tumor cell proliferation and induction of apoptosis, but their effect on tumor cell invasion has not been well studied. Here, we show that the NSAID, sulindac sulfide (SS) can potently inhibit the invasion of human MDA-MB-231 breast and HCT116 colon tumor cells in vitro at concentrations less than those required to inhibit tumor cell growth. To study the molecular basis for this activity, we investigated the involvement of microRNA (miRNA). A total of 132 miRNAs were found to be altered in response to SS treatment, including miR-10b, miR-17, miR-21 and miR-9, which have been previously implicated in tumor invasion and metastasis. We confirmed that these miRNA can stimulate tumor cell invasion and show that SS can attenuate their invasive effects by downregulating their expression. Employing luciferase and chromatin immunoprecipitation assays, NF-κB was found to bind the promoters of all four miRNAs to suppress their expression at the transcriptional level. We show that SS can inhibit the translocation of NF-κB to the nucleus by decreasing the phosphorylation of IKKß and IκB. Analysis of the promoter sequences of the miRNAs suppressed by SS revealed that 81 of 115 sequences contained NF-κB-binding sites. These results show that SS can inhibit tumor cell invasion by suppressing NF-κB-mediated transcription of miRNAs.

DNAJB6 chaperones PP2A mediated dephosphorylation of GSK3ß to downregulate ß-catenin transcription target, osteopontin.

Elevated levels of the oncoprotein, osteopontin (OPN), are associated with poor outcome of several types of cancers including melanoma. We have previously reported an important involvement of DNAJB6, a member of heat-shock protein 40 (HSP40) family, in negatively impacting tumor growth. The current study was prompted by our observations reported here which revealed a reciprocal relationship between DNAJB6 and OPN in melanoma specimens. The 'J domain' is the most conserved domain of HSP40 family of proteins. Hence, we assessed the functional role of the J domain in activities of DNAJB6. We report that the J domain of DNAJB6 is involved in mediating OPN suppression. Deletion of the J domain renders DNAJB6 incapable of impeding malignancy and suppressing OPN. Our mechanistic investigations reveal that DNAJB6 binds HSPA8 (heat-shock cognate protein, HSC70) and causes dephosphorylation of glycogen synthase kinase 3ß (GSK3ß) at Ser 9 by recruiting protein phosphatase, PP2A. This dephosphorylation activates GSK3ß, leading to degradation of ß-catenin and subsequent loss of TCF/LEF (T cell factor1/lymphoid enhancer factor1) activity. Deletion of the J domain abrogates assembly of this multiprotein complex and renders GSK3ß inactive, thus, stabilizing ß-catenin, a transcription co-activator for OPN expression. Our in-vitro and in-vivo functional analyses show that silencing OPN expression in the background of deletion of the J domain renders the resultant tumor cells less malignant despite the presence of stabilized ß-catenin. Thus, we have uncovered a new mechanism for regulation of GSK3ß activity leading to inhibition of Wnt/ß-catenin signaling.

Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61.

The Hedgehog (Hh) pathway is well known for its involvement in angiogenesis and vasculogenesis during ontogeny. The ligand, Sonic Hh (SHH), has an important role in vascular formation during development. However, SHH expression is upregulated on tumor cells and can impact the tumor microenvironment. We have investigated the effects of autocrine as well as paracrine Hh signaling on tumor cells as well as on endothelial cells, respectively. Upon constitutive expression of SHH, breast cancer cells showed aggressive behavior and rapid xenograft growth characterized by highly angiogenic tumors that were spontaneously metastatic. In these cells, SHH caused activation of the Hh transcription factor, GLI1, leading to upregulated expression of the potent pro-angiogenic secreted molecule, CYR61 (cysteine-rich angiogenic inducer 61). Silencing of CYR61 from these SHH-expressing Hh activated cells blunted the malignant behavior of the tumor cells and resulted in reduced tumor vasculature and limited hematogenous metastases. Thus, CYR61 is a critical downstream contributor to the Hh influenced pro-angiogenic tumor microenvironment. We also observed concomitant upregulation of SHH and CYR61 transcripts in tumors from patients with advanced breast cancer, further ratifying the clinical relevance of our findings. In summary, we have defined a novel, VEGF-independent, clinically relevant, pro-angiogenic factor, CYR61, that is a transcriptional target of Hh-GLI signaling.

Giant cell arteritis in Mumbai.

OBJECTIVE: To study the clinical profile of patients with giant cell arteritis in Mumbai. METHODS: From our database, patients with a diagnosis of giant cell arteritis (GCA) over a fifteen year period (January 1990 to December 2005) were included. Clinical manifestations, temporal artery biopsy, treatment, and follow-up data of these patients were analyzed. RESULTS: Twenty one patients with GCA were identified. However, data were available only for 16 patients. The median age was 66.5 years (58-78 yrs) with male to female ratio of 1:1. The mean time from symptom onset to diagnosis was 5.18 months (0.5-24 months). Clinical manifestations included new onset headache (15), fever (9), weight loss (9), jaw claudication (9), polymyalgia rheumatica (5), visual disturbances (3), scalp nodule (1), temporal artery tenderness (11), tortuosity (9), and scalp tenderness (6). ESR was elevated in 15 patients with a median of 106.5 mm at 1 hr (25-135 mm/hr). Temporal artery biopsy was done in 11 patients and confirmed the diagnosis in 10 patients. Color doppler study of the temporal arteries (9 patients) revealed halo sign (indicating arterial wall edema) in 6 patients. Biopsy as per site by color doppler study was performed in 6 of these patients and was positive in 5. All patients had a good initial response to steroids, however, on follow up, 3 patients required addition of methotrexate. At a median follow up (n = 14) of 6 months (range 6-156), steroids were successfully stopped in 7 patients at 1 to 3 years interval. The disease relapsed in 1 patient. Of the remaining 7 patients, 2 were steroid dependent and 5 patients were doing well on low dose prednisolone. CONCLUSION: GCA, though uncommon in India, should be suspected in all elderly patients with a new onset headache, fever, jaw claudication, or high ESR. Color doppler sonography is a useful noninvasive method for the diagnosis of GCA and also helps to identify the site to biopsy. Most respond to steroid therapy while some need addition of steroid sparing agents.

Exploring cancer treatment decision-making by patients: a descriptive study.

OBJECTIVE: Using an interview-guided survey, our descriptive study aimed to document the extent to which cancer patients perceive they are involved in making treatment decisions and the factors that influence patient involvement. PATIENTS AND METHODS: Our study enrolled patients from a Canadian ambulatory oncology program who were undergoing chemotherapy or radiation therapy, or both, for cancer. The adapted Control Preferences Scale was used to survey perceived and preferred roles in decision-making. The study survey also included items from the Decisional Conflict Scale and the Preparation for Decision-Making Scale. RESULTS: Of 192 participants, 98 (51%) perceived that they were offered treatment choices. Of those 98, 47 (48%) thought that the options were presented equally. Compared with the patients not offered choices, those who were given choices were less passive (4% vs. 29%, p < 0.001) and more satisfied (100% vs. 95%, p < 0.03) in decision-making. Participants whose preferred and perceived roles were different would have preferred more involvement in decision-making. To attain the preferred involvement, patients wanted to receive more information on treatment options, to be given a choice, to have more discussion with the health care team, and to have providers better listen to their needs. CONCLUSIONS: Only half of surveyed patients thought that they were offered choices for their cancer treatment. When offered choices, patients were more active in decision-making. Further initiatives are required to determine approaches for supporting patients with cancer so that they can be more involved in decision-making.

Osteopontin: an effector and an effect of tumor metastasis.

Osteopontin (OPN) is a matricellular protein that is produced by multiple tissues in our body and is most abundant in bone. It is also produced by cancer cells and plays a determinative role in the growth, progression and metastasis of cancer. Clinically, OPN has been reported to be upregulated in tumor cells per se; this is also reflected by increased levels of OPN in the circulation. Thus, increased OPN levels the plasma are an effect of tumor growth and progression. Functionally, high OPN levels are determinative of higher incidence of bone metastases in mouse models and are clinically correlated with metastatic bone disease and bone resorption in advanced breast cancer patients. Several research efforts have been made to therapeutically target and inhibit the activities of OPN. In this article we have reviewed OPN in its role as an effector of critical steps in tumor progression and metastasis, with a particular emphasis on its role in facilitating bone metastasis of breast cancer. We have also addressed the role of the host-derived OPN in influencing the malignant behavior of the tumor cells.

Knowledge and utilization of palliative radiotherapy by pediatric oncologists.

BACKGROUND AND PURPOSE: Palliative radiotherapy (PRT) is a routine part of oncology care in adult patients, but it is used much less frequently among children with incurable cancer. We surveyed Canadian pediatric oncologists to learn about their knowledge and use of PRT and to identify potential barriers to referral. METHODS: A 13-item questionnaire assessing PRT knowledge and utilization was sent to 80 Canadian pediatric oncologists. RESULTS: The survey completion rate was 80%, with most respondents being providers of palliative care for children and making referrals for PRT. Although 62% had received training in radiation oncology, only 28% had received formal palliative care training. Respondents with palliative care training were found to be significantly more knowledgeable about PRT and were more likely to refer children for PRT (p < 0.01). Only 59% of respondents thought that they had adequate knowledge about the indications for PRT. A positive correlation was found between knowledge about the indications for PRT and referral for treatment (p < 0.01). Among survey respondents, 51% believed that PRT was underutilized, and the perceived barriers to PRT referral included patient or family reluctance, distance to the cancer centre, belief that PRT has little impact on quality of life, and concerns about toxicity. CONCLUSIONS: Palliative radiotherapy is considered to be underutilized among children. This situation appears to be related, in part, to inadequate knowledge and training among pediatric oncologists, suggesting that more emphasis needs to be placed on pediatric palliative care education.

The emerging role of IG-IMRT for palliative radiotherapy: a single-institution experience.

Many modern radiotherapy centers now have image-guided intensity-modulated radiotherapy (IG-IMRT) tools available for clinical use, and the technique offers many options for patients requiring palliative radiotherapy. We describe a single-institution experience with IG-IMRT for short-course palliative radiotherapy, highlighting the unique situations in which the technique can be most effectively used.

Total scalp radiation using image-guided IMRT for progressive cutaneous T cell lymphoma.

Modern radiotherapy has advanced dramatically over the past decade and it is now possible to focus radiotherapy with extreme precision. This allows the radiation dose to be targeted to the area(s) of tumour while sparing adjacent normal tissues even in seemingly complicated and difficult parts of the body. The case report presented here will illustrate how it is possible to irradiate the entire scalp for extensive cutaneous T cell lymphoma while minimising radiotherapy to the underlying brain, orbits and other critical structures.

Contemporary management of stage I testicular seminoma: a survey of Canadian radiation oncologists.

Recently published studies clearly indicate that there are now several acceptable options for managing stage i testicular seminoma patients after orchiectomy. We therefore decided to survey Canadian radiation oncologists to determine how they currently manage such patients and to compare the results with previous surveys. Our results demonstrate that adjuvant single-agent chemotherapy is being considered as an option by an increasing proportion of radiation oncologists (although it is not considered the preferred option), the routine use of radiotherapy is declining, and surveillance is becoming increasingly popular and is recommended most often.